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Clinical Trial Results:
A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults with Refractory Aggressive Non-Hodgkin Lymphoma

Summary
EudraCT number	2015-005007-86
Trial protocol	NL DE FR
Global end of trial date	27 Jul 2023

Results information
Results version number	v1(current)
This version publication date	23 Jun 2024
First version publication date	23 Jun 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

KTE-C19-101

ISRCTN number

US NCT number

NCT02348216

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Jul 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Jul 2023

Global end of trial reached?

Yes

Global end of trial date

27 Jul 2023

Was the trial ended prematurely?

Main objective of the trial

This study was separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6). The primary objectives of this study were: - Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens - Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel - Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities Subjects who received an infusion of KTE-C19 completed the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 25

Country: Number of subjects enrolled

France: 32

Country: Number of subjects enrolled

Germany: 24

Country: Number of subjects enrolled

Israel: 6

Country: Number of subjects enrolled

Netherlands: 42

Country: Number of subjects enrolled

United States: 178

Worldwide total number of subjects

307

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

215

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled at study sites in Canada, France, Germany, Israel, Netherlands, and the United States.

Screening details

390 participants were screened. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot

Arm description

Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) received conditioning chemotherapy (fludarabine 30 mg/m^2 intravenously [IV] over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0.

Arm type

Experimental

Investigational medicinal product name

Axicabtagene Ciloleucel

Investigational medicinal product code

Other name

Yescarta®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Phase 2 (Pivotal Study): Cohort 1

Arm description

Participants with refractory DLBCL received conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.

Arm type

Experimental

Investigational medicinal product name

Axicabtagene Ciloleucel

Investigational medicinal product code

Other name

Yescarta®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Phase 2 (Pivotal Study): Cohort 2

Arm description

Participants with refractory PMBCL or TFL received conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.

Arm type

Experimental

Investigational medicinal product name

Axicabtagene Ciloleucel

Investigational medicinal product code

Other name

Yescarta®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Phase 2 (Safety Management Study): Cohort 3

Arm description

Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received conditioning chemotherapy (fludarabine 30 mg/m^2 IV over 30 minutes and cyclophosphamide 500 mg/m^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants also received a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).

Arm type

Experimental

Investigational medicinal product name

Axicabtagene Ciloleucel

Investigational medicinal product code

Other name

Yescarta®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Phase 2 (Safety Management Study): Cohort 4

Arm description

Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants received tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).

Arm type

Experimental

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Axicabtagene Ciloleucel

Investigational medicinal product code

Other name

Yescarta®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

High-dose methylprednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Phase 2 (Safety Management Study): Cohort 5

Arm description

Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy received debulking therapy (R-CHOP:rituximab 375mg/m^2 D1,doxorubicin 50mg/m^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m^2 D1,vincristine 1.4 mg/m^2 D1 or R-ICE:rituximab 375mg/ m^2 D1,ifosfamide 5g/m^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m^2 D1,gemcitabine 1000mg/m^2 D2,oxaliplatin 100mg/m^2 D2 or R-GDP:rituximab 375mg/m^2 D1 or D8,gemcitabine 1g/m^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants also received a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.

Arm type

Experimental

Investigational medicinal product name

Axicabtagene Ciloleucel

Investigational medicinal product code

Other name

Yescarta®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Phase 2 (Safety Management Study): Cohort 6

Arm description

Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m^2 HDMP for 3 days with rituximab at 375mg/m^2 weekly for 3 weeks or bendamustine 90 mg/m^2 on Days 1 and 2 and rituximab 375mg/m^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m^2 IV and cyclophosphamide 500mg/m^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants received tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).

Arm type

Experimental

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Axicabtagene Ciloleucel

Investigational medicinal product code

Other name

Yescarta®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.

Investigational medicinal product name

Fludarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Methylprednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

High-dose methylprednisolone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Bendamustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered according to package insert

Number of subjects in period 1	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Started	8	81	30	42	46	58	42
Completed	0	0	0	0	0	0	0
Not completed	8	81	30	42	46	58	42
Enrolled but did not take axicabtagene ciloleucel	1	4	6	4	5	8	2
Death	5	53	11	20	16	32	17
Full consent withdrawal	-	-	-	1	3	-	3
Reason not specified	2	19	11	17	21	17	19
Lost to follow-up	-	5	2	-	1	1	1

Baseline characteristics

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Reporting group title

Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot

Reporting group description

Reporting group title

Phase 2 (Pivotal Study): Cohort 1

Reporting group description

Reporting group title

Phase 2 (Pivotal Study): Cohort 2

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 3

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 4

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 5

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 6

Reporting group description

Reporting group values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6	Total
Number of subjects	8	81	30	42	46	58	42	307
Age categorical
Units: Subjects
18 – 64 Years	5	64	21	33	32	39	21	215
65 – 84 Years	3	17	9	9	14	19	20	91
85 Years and Over	0	0	0	0	0	0	1	1
Gender categorical
Units: Subjects
Female	2	27	7	18	13	15	18	100
Male	6	54	23	24	33	43	24	207
Race
Units: Subjects
White	6	71	23	34	37	39	36	246
Other or More Than One Race	1	6	3	3	9	12	5	39
Black or African American	1	3	1	4	0	2	1	12
Asian	0	1	3	1	0	5	0	10
Ethnicity
Units: Subjects
Hispanic or Latino	1	18	2	6	0	1	3	31
Not Hispanic or Latino	7	63	28	36	45	57	39	275
Unknown or Not Reported	0	0	0	0	1	0	0	1

End points

Top of page

Reporting group title

Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot

Reporting group description

Reporting group title

Phase 2 (Pivotal Study): Cohort 1

Reporting group description

Reporting group title

Phase 2 (Pivotal Study): Cohort 2

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 3

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 4

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 5

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 6

Reporting group description

Primary: Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma

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End point title

Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma ^[1] ^[2]

End point description

ORR was defined either a complete response (CR) or partial response (PR),assessed by the study investigators by revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007).CR: complete disappearance of all detectable clinical evidence of disease and symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size,not be palpable,and no nodules;bone marrow aspirate and biopsy must show no evidence of disease.PR: a ≥ 50% decrease in sum of product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses;no increase in size of nodes, liver or spleen and no new sites; multiple splenic and hepatic nodules regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% confidence interval (CI) was calculated by Clopper-Pearson method. The Modified Intent-to-Treat (mITT) analysis set included all participants treated with at least 1.0 x 10^6 anti-CD19 CAR T cells/kg.

End point type

Primary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7 years)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparison was planned or performed.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 2 (Cohorts 1 and 2) of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2
Number of subjects analysed	77	24
Units: percentage of participants
number (confidence interval 95%)	83 (73 to 91)	83 (63 to 95)

No statistical analyses for this end point

Primary: Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) defined as Dose Limiting Toxicities (DLTs)

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End point title

Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) defined as Dose Limiting Toxicities (DLTs) ^[3] ^[4]

End point description

DLT was defined as axicabtagene ciloleucel-related events with onset within first 30 days following infusion:Grade (GR) 4 neutropenia lasting > 21 days and GR 4 thrombocytopenia lasting > 35 days from day of cell transfer;Any axicabtagene ciloleucel-related AE requiring intubation; All other GR 3 toxicities lasting > 3 days and all GR 4 toxicities, exception conditions: aphasia/dysphasia or confusion/cognitive disturbance which resolved to GR ≤ 1 ; fever GR 3; myelosuppression, decreased hemoglobin, neutropenia and thrombocytopenia ; immediate hypersensitivity reactions occurring within 2 hours of cell infusion that were reversible to a ≤ GR 2 within 24 hours of cell administration; hypogammaglobulinemia GR 3 or 4. DLT-Evaluable Analysis Set included participants treated in Phase 1 dosing cohort who received the target dose and were followed for at least 30 days after the axicabtagene ciloleucel infusion.

End point type

Primary

End point timeframe

First infusion date of axicabtagene ciloleucel up to 30 days

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparison was planned or performed.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 1 of the study, all the arms in the baseline period were not included.

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot
Number of subjects analysed	6
Units: participants	1

No statistical analyses for this end point

Primary: Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades

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End point title

Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades ^[5] ^[6]

End point description

TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1:No life threatening symptoms and require symptomatic treatment only;Grade2:Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms, requirements for ventilator support or continuous venovenous hemodialysis (CVVHD),and Grade 5: Death. Neurologic toxicities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Grade 1:Mild, asymptomatic or mild symptoms; Grade 2:Moderate and minimal, local or noninvasive intervention;Grade 3: Severe or medically significant but not life-threatening,hospitalization;Grade 4: Life-threatening and urgent intervention indicated;Grade 5: Death related to AE. The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.

End point type

Primary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 6.8 years)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparison was planned or performed.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 2 (Cohort 3) of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Safety Management Study): Cohort 3
Number of subjects analysed	38
Units: percentage of participants
number (not applicable)
Worst Grade 1 CRS	34
Worst Grade 2 CRS	55
Worst Grade 3 CRS	0
Worst Grade 4 CRS	3
Worst Grade 5 CRS	0
Worst Grade ≥ 3 CRS	3
Worst Grade 1 Neurologic Toxicities	24
Worst Grade 2 Neurologic Toxicities	21
Worst Grade 3 Neurologic Toxicities	37
Worst Grade 4 Neurologic Toxicities	3
Worst Grade 5 Neurologic Toxicities	3
Worst Grade ≥ 3 Neurologic Toxicities	42

No statistical analyses for this end point

Primary: Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

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End point title

Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades ^[7] ^[8]

End point description

TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE. The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.

End point type

Primary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 5.4 years)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparison was planned or performed.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical comparison was planned or performed.

End point values	Phase 2 (Safety Management Study): Cohort 4
Number of subjects analysed	41
Units: percentage of participants
number (not applicable)
Worst Grade 1 CRS	32
Worst Grade 2 CRS	59
Worst Grade 3 CRS	2
Worst Grade 4 CRS	0
Worst Grade 5 CRS	0
Worst Grade ≥ 3 CRS	2
Worst Grade 1 Neurologic Toxicities	34
Worst Grade 2 Neurologic Toxicities	10
Worst Grade 3 Neurologic Toxicities	17
Worst Grade 4 Neurologic Toxicities	0
Worst Grade 5 Neurologic Toxicities	0
Worst Grade ≥ 3 Neurologic Toxicities	17

No statistical analyses for this end point

Primary: Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

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End point title

Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades ^[9] ^[10]

End point description

TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE. The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.

End point type

Primary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.4 years)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparison was planned or performed.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 2 (Safety Management Study): Cohort 5
Number of subjects analysed	50
Units: percentage of participants
number (not applicable)
Worst Grade 1 CRS	38
Worst Grade 2 CRS	46
Worst Grade 3 CRS	0
Worst Grade 4 CRS	2
Worst Grade 5 CRS	0
Worst Grade ≥ 3 CRS	2
Worst Grade 1 Neurologic Toxicities	26
Worst Grade 2 Neurologic Toxicities	18
Worst Grade 3 Neurologic Toxicities	10
Worst Grade 4 Neurologic Toxicities	2
Worst Grade 5 Neurologic Toxicities	0
Worst Grade ≥ 3 Neurologic Toxicities	12

No statistical analyses for this end point

Primary: Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

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End point title

Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades ^[11] ^[12]

End point description

TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE. The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.

End point type

Primary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.1 years)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparison was planned or performed.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	40
Units: percentage of participants
number (not applicable)
Worst Grade 1 CRS	35
Worst Grade 2 CRS	45
Worst Grade 3 CRS	0
Worst Grade 4 CRS	0
Worst Grade 5 CRS	0
Worst Grade ≥ 3 CRS	0
Worst Grade 1 Neurologic Toxicities	23
Worst Grade 2 Neurologic Toxicities	18
Worst Grade 3 Neurologic Toxicities	8
Worst Grade 4 Neurologic Toxicities	5
Worst Grade 5 Neurologic Toxicities	5
Worst Grade ≥ 3 Neurologic Toxicities	18

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DOR) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

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End point title

Phase 2: Duration of Response (DOR) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma ^[13]

End point description

Among participants who experience an objective response (OR), DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death regardless of cause. CR and PR as defined in outcome measure 1. Participants in the mITT Analysis Set with objective response were analyzed. 99.99=median was not estimable because almost 50% of participants were censored;99= lower limit of 95% CI was not estimable because almost 50% of participants were censored; 99999= upper limit of 95% CI was not estimable because almost 50% of participants were censored.

End point type

Secondary

End point timeframe

First OR to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 2 of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	64	20	24	31	36	38
Units: months
median (confidence interval 95%)	5.0 (2.1 to 34.7)	75.4 (11.1 to 9999)	99.99 (5.0 to 99999)	99.99 (99 to 99999)	27.5 (2.2 to 99999)	99.99 (7.8 to 99999)

No statistical analyses for this end point

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): ORR per Independent Radiological Review Committee (IRRC)

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End point title

Phase 2 Pivotal Study (Cohorts 1 and 2): ORR per Independent Radiological Review Committee (IRRC) ^[14]

End point description

ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma. CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method. Participants in the mITT Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on the arms under Phase 2 (Cohorts 1 and 2) of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2
Number of subjects analysed	77	24
Units: percentage of participants
number (confidence interval 95%)	70 (59 to 80)	88 (68 to 97)

No statistical analyses for this end point

Secondary: Phase 1 Study: ORR as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

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End point title

Phase 1 Study: ORR as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma ^[15]

End point description

ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 1 of the study, all the arms in the baseline period were not included.

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot
Number of subjects analysed	7
Units: percentage of participants
number (not applicable)	71

No statistical analyses for this end point

Secondary: Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

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End point title

Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma ^[16]

End point description

PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored. Disease progression was defined by at least one of ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter node > 1 cm in its short axis. KM estimates was used for analyses. Participants in the mITT Analysis Set were analyzed. 99.99=median was not estimable because almost 50% of participants were censored;99999= upper limit of 95% 99.99=median was not estimable because almost 50% of participants were censored.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel to disease progression or death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 2 of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	77	24	38	41	50	40
Units: months
median (confidence interval 95%)	5.1 (3.0 to 8.8)	49.1 (3.7 to 99999)	6.2 (2.4 to 99999)	99.99 (3.0 to 99999)	3.1 (2.9 to 29.1)	99.99 (8.7 to 99999)

No statistical analyses for this end point

Secondary: Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator per the Revised IWG Response Criteria for Malignant Lymphoma

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End point title

Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator per the Revised IWG Response Criteria for Malignant Lymphoma ^[17]

End point description

ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; > 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method. Participants in the mITT Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel to last follow-up visit (maximum duration: 6.8, 5.4, 4.4, 4.1 years for Cohorts 3, 4, 5, and 6 respectively)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under the Phase 2 safety Management Study (Cohorts 3, 4, 5, and 6) of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	38	41	50	40
Units: percentage of participants
number (confidence interval 95%)	63 (46 to 78)	76 (60 to 88)	72 (58 to 84)	95 (83 to 99)

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[18]

End point description

OS was defined as the time from axicabtagene ciloleucel infusion to the date of death. Participants who did not die by the analysis data cutoff date were censored at their last contact date. KM estimates was used for analyses. Participants in the mITT Analysis Set were analyzed. 99.99=median was not estimable because almost 50% of participants were censored;99999= upper limit of 95% 99.99=median was not estimable because almost 50% of participants were censored.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel to the date of death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 2 of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	77	24	38	41	50	40
Units: months
median (confidence interval 95%)	15.4 (10.4 to 45.7)	99.99 (15.0 to 99999)	34.8 (5.4 to 99999)	99.99 (14.6 to 99999)	20.6 (12.6 to 43.1)	99.99 (18.9 to 99999)

No statistical analyses for this end point

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC per Cheson 2007

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End point title

Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC per Cheson 2007 ^[19]

End point description

The best overall response for each participant was based on the assessments of response (CR, PR, stable disease [SD], PD, and not done [ND]) made by the the IRRC using IWG 2007 criteria (Cheson et al, 2007). CR and PR as defined in outcome measure 1. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentage of participants with best overall response of CR, PR, SD, PD, and ND was reported. Participants in the mITT Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on the arms under Phase 2 (Cohorts 1 and 2) of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2
Number of subjects analysed	77	24
Units: percentage of participants
number (not applicable)
CR	51	67
PR	19	21
SD	21	4
PD	8	4
ND	1	4

No statistical analyses for this end point

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC per Cheson 2007

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End point title

Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC per Cheson 2007 ^[20]

End point description

Among participants who experience an objective response, DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to PD, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death regardless of cause. CR and PR as defined in outcome measure 1. PD was defined by at least one:≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes,or at least a 50% increase in the product of the diameters of a single node;appearance of a new lesion > 1.5 cm in any axis; ≥ 50% increase in size of snodules;≥ 50% increase in the longest diameter of anode > 1 cm in its short axis. Kaplan-Meier (KM) estimates. Participants in the mITT Analysis Set with objective response were analyzed. 99.99=median was not estimable because almost 50% of participants were censored;99999= upper limit of CI was not estimable because almost 50% of participants were censored.

End point type

Secondary

End point timeframe

First objective response up to the data cutoff date of 11 August 2018 (maximum: 2.7 years)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on the arms under Phase 2 (Cohorts 1 and 2) of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2
Number of subjects analysed	54	21
Units: months
median (confidence interval 95%)	99.99 (5.4 to 99999)	99.99 (11.1 to 99999)

No statistical analyses for this end point

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC per Cheson 2007

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End point title

Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC per Cheson 2007 ^[21]

End point description

PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. PD defined by at least: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes,or at least a 50% increase in the product of the diameters of a single node; appearance of a new lesion > 1.5 cm; ≥ 50% increase in size of nodules; ≥ 50% increase in the longest diameter of any node > 1 cm in its short axis. KM estimates were used for analyses. Participants in the mITT Analysis Set were analyzed. 99.99=median was not estimable because almost 50% of participants were censored;99999= upper limit of 95% of CI was not estimable because almost 50% of participants were censored.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 2 (Cohorts 1 and 2) of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2
Number of subjects analysed	77	24
Units: months
median (confidence interval 95%)	6.9 (4.5 to 15.0)	99.99 (9.0 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)

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End point title

Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)

End point description

An adverse event was defined as any untoward medical occurrence in a clinical trial participants. The event did not necessarily have a relationship with study treatment. Adverse events included worsening of a pre-existing medical condition. Worsening indicated that the pre-existing medical condition had increased in severity, frequency, and/or duration or had an association with a worse outcome. A pre-existing condition that had not worsened during the study or involved an intervention such as elective cosmetic surgery or a medical procedure while on study, was not considered an adverse event. TEAE was defined as any AE with onset on or after the start of treatment. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years)

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	7	77	24	38	41	50	40
Units: percentage of participants
number (not applicable)	100	100	100	100	100	100	100

No statistical analyses for this end point

Secondary: Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs

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End point title

Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs

End point description

Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years)

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	7	77	24	38	41	50	40
Units: percentage of participants
number (not applicable)	100	96	96	97	98	100	100

No statistical analyses for this end point

Secondary: Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood

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End point title

Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood

End point description

Peak was defined as the maximum number of CAR T cells measured post-infusion. Participants in the Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline up to Month 60 (for Phase 1 and Phase 2 Cohorts 1, 2, and 3); Baseline up to Month 24 (for Phase 2 Cohorts 4, 5, and 6)

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	6	76	22	36	39	49	40
Units: cells/µL
median (inter-quartile range (Q1-Q3))	58.512 (18.028 to 147.732)	31.512 (12.445 to 74.746)	58.633 (27.884 to 103.190)	53.670 (22.813 to 146.075)	52.91 (27.25 to 92.78)	26.63 (12.52 to 117.53)	64.38 (6.27 to 131.24)

No statistical analyses for this end point

Secondary: Percentage of Participants with Anti-Axicabtagene Ciloleucel Antibodies

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End point title

Percentage of Participants with Anti-Axicabtagene Ciloleucel Antibodies

End point description

Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively)

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	7	77	24	38	41	50	40
Units: percentage of participants
number (not applicable)	29	5	8	11	0	8	8

No statistical analyses for this end point

Secondary: Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)

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End point title

Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) ^[22]

End point description

Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: interferon-gamma induced protein 10 (IP-10), ferritin, granzyme B, intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-gamma), interleukin-1 receptor antagonist (IL-1RA), IL-2, interleukin-2 receptor alpha (IL-2 R alpha), IL-6, IL-7, IL-8, IL-10, IL-15, perforin, tumor necrosis factor alpha (TNF alpha), and vascular cell adhesion molecule- 1 (VCAM-1). Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to Month 3

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3
Number of subjects analysed	7	77	24	38
Units: pg/mL
median (full range (min-max))
IP-10	2000.0 (147.0 to 2000.0)	2000.0 (628.1 to 2000.0)	2000.0 (434.2 to 2000.0)	2000.0 (541.0 to 2000.0)
Granzyme B	33.1 (0.6 to 463.8)	31.1 (1.0 to 3306.0)	17.3 (1.0 to 406.8)	44.1 (1.0 to 534.6)
ICAM-1	792754.3 (537796.8 to 2424877.7)	1322829.3 (557025.0 to 7495123.2)	989188.4 (544589.3 to 4588974.8)	1009966.4 (256768.6 to 4879749.7)
IFN-gamma	792.0 (81.1 to 1876.0)	493.8 (32.4 to 1876.0)	364.9 (7.5 to 1876.0)	1857.2 (65.0 to 1876.0)
IL-1 RA	2173.3 (544.3 to 4000.0)	2371.2 (510.8 to 4000.0)	1999.9 (649.9 to 4000.0)	2160.5 (653.7 to 4000.0)
IL-2	18.4 (3.1 to 91.0)	25.0 (0.9 to 123.1)	13.4 (0.9 to 63.7)	20.0 (0.9 to 189.4)
IL-2 R alpha	16872.7 (2189.0 to 34044.5)	14383.7 (78.0 to 100000.0)	7817.3 (78.0 to 66024.6)	12386.4 (3002.6 to 100000.0)
IL-6	305.3 (2.4 to 976.0)	89.4 (3.5 to 976.0)	44.6 (3.6 to 976.0)	921.8 (13.3 to 976.0)
IL-7	51.5 (31.2 to 71.5)	38.9 (13.8 to 153.5)	44.1 (27.9 to 98.8)	38.8 (19.1 to 83.8)
IL-8	86.4 (17.1 to 750.0)	118.4 (14.2 to 750.0)	77.2 (9.8 to 750.0)	120.9 (10.3 to 750.0)
IL-10	52.5 (3.8 to 614.0)	43.9 (0.7 to 466.0)	18.8 (0.7 to 263.6)	48.2 (1.8 to 466.0)
IL-15	57.1 (18.7 to 271.3)	56.5 (13.1 to 226.6)	47.6 (11.3 to 195.2)	50.3 (21.9 to 537.3)
Perforin	5389.0 (2582.7 to 20724.3)	11309.5 (2282.3 to 39818.9)	8278.7 (2332.6 to 31857.7)	15411.9 (4327.4 to 30575.9)
TNF alpha	10.5 (1.8 to 443.1)	8.6 (2.6 to 166.9)	6.8 (2.2 to 44.9)	10.9 (3.3 to 52.1)
VCAM-1	1387033.6 (609223.2 to 8424222.9)	1478356.8 (642372.6 to 3859375.8)	1058453.9 (634769.7 to 2864040.2)	1367940.7 (721050.0 to 5184238.4)

No statistical analyses for this end point

Secondary: Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6)

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End point title

Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) ^[23]

End point description

Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: IP-10, granzyme B, IFN-gamma, IL-1 RA, IL-2, IL-6, IL-7, IL-8, IL-10, IL-15, TNF alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Participants in the Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline up to Month 3

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	41	50	40
Units: pg/mL
median (full range (min-max))
IP-10	1549.70 (469.20 to 2000.00)	1746.15 (349.80 to 2000.00)	1560.03 (347.00 to 2000.000)
Granzyme B	23.10 (1.00 to 322.60)	27.90 (1.00 to 375.76)	18.40 (1.00 to 162.30)
IFN-gamma	334.50 (24.90 to 1876.00)	314.90 (7.50 to 1876.00)	207.95 (18.80 to 1876.00)
IL-1 RA (N=31, 50, 40)	1093.70 (193.30 to 4493.10)	908.00 (229.00 to 9000.00)	1279.50 (227.00 to 9000.00)
IL-2	11.20 (0.90 to 79.40)	11.85 (0.90 to 142.70)	8.40 (0.90 to 277.60)
IL-6	136.70 (1.60 to 976.00)	97.95 (1.60 to 976.00)	47.25 (1.60 to 976.00)
IL-7	33.10 (18.00 to 67.50)	29.80 (1.40 to 65.20)	28.25 (13.20 to 74.30)
IL-8	67.40 (8.50 to 750.00)	75.10 (5.80 to 750.00)	52.55 (10.00 to 750.00)
IL-10	19.60 (1.40 to 466.00)	14.45 (0.70 to 300.90)	13.30 (0.70 to 171.20)
IL-15	45.80 (22.30 to 272.70)	34.15 (1.40 to 140.00)	37.20 (9.50 to 86.30)
TNF alpha	5.70 (2.00 to 54.60)	5.25 (1.40 to 33.30)	4.80 (2.10 to 20.20)
GM-CSF	4.40 (1.90 to 47.00)	2.90 (1.90 to 35.60)	1.90 (1.90 to 47.40)

No statistical analyses for this end point

Secondary: Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)

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End point title

Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) ^[24]

End point description

Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to Month 3

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	41	50	40
Units: ng/mL
median (full range (min-max))
Ferritin	1086.36 (95.55 to 23900)	1516.11 (89.29 to 31600)	903.50 (171.61 to 6555.10)
ICAM-1	907.97 (359.51 to 5141.64)	636.74 (361.38 to 4835.93)	654.81 (355.15 to 4419.09)
IL-2 R	10.78 (2.81 to 94.59)	7.82 (1.36 to 83.60)	6.43 (1.70 to 33.31)
Perforin	17.22 (3.88 to 44.42)	10.85 (2.53 to 100.00)	10.12 (1.97 to 39.62)
VCAM-1	1255.32 (594.51 to 3932.61)	854.63 (476.60 to 6501.14)	836.04 (411.93 to 5079.25)

No statistical analyses for this end point

Secondary: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)

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End point title

Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2) ^[25]

End point description

Peak was defined as the maximum post-baseline level of the cytokine. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to Month 3

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2
Number of subjects analysed	7	77	24
Units: pg/mL
median (full range (min-max))	1973400.0 (1201900.0 to 32984400.0)	3681400.0 (780.0 to 25000000.0)	1979360.0 (780.0 to 25000000.0)

No statistical analyses for this end point

Secondary: Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum

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End point title

Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum

End point description

Peak was defined as the maximum post-baseline level of the cytokine. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to Month 3

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	7	77	24	38	41	50	40
Units: mg/mL
median (full range (min-max))	112.6 (14.6 to 655.0)	215.7 (31.0 to 496.0)	186.6 (18.5 to 496.0)	137.8 (2.1 to 496.0)	126.53 (18.19 to 496.00)	74.84 (1.81 to 496.00)	76.11 (7.31 to 496.00)

No statistical analyses for this end point

Secondary: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)

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End point title

Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3) ^[26]

End point description

Peak was defined as the maximum post-baseline level of the cytokine. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to Month 3

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 2 (Safety Management Study): Cohort 3
Number of subjects analysed	38
Units: ng/mL
median (full range (min-max))	2440.2 (0.8 to 25000.0)

No statistical analyses for this end point

Secondary: Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score

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End point title

Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score ^[27]

End point description

EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant scoring 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was divided into 5 levels of severity: “No problem”, “Slight problems”, “Moderate problems”, “Severe problems”, and “Extreme problems (unable to perform)”. EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by applying a formula that attaches values (also called QOL weights or QOL utilities) to each of the levels in each dimension. EQ-5D Summary Index values range from -0.11 (worst health state) to 1.00 (perfect health state). Participants in Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Week 4, Month 3, and Month 6

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data has been reported only for the specified arms for which participants were available and data was evaluable for the specified outcome measure.

End point values	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	38	39	47	34
Units: participants
Baseline: Mobility : No problem	30	25	33	26
Baseline: Mobility : Slight problem	7	9	5	4
Baseline: Mobility : Moderate problem	1	5	7	3
Baseline: Mobility : Severe problem	0	0	1	1
Baseline: Mobility : Unable to perform	0	0	1	0
Wk 4: Mobility : No problem N=32,37,38,29	16	21	23	20
Wk 4: Mobility : Slight problem N=32,37,38,29	11	7	9	5
Wk 4: Mobility : Moderate problem N=32,37,38,29	4	5	4	4
Wk 4: Mobility : Severe problem N=32,37,38,29	0	3	1	0
Wk 4: Mobility : Unable to perform N=32,37,38,29	1	1	1	0
Month 3: Mobility : No problem N=23,31,33,29	14	20	21	22
Month 3: Mobility : Slight problem N=23,31,33,29	6	8	6	3
Month 3: Mobility : Moderate problem N=23,31,33,29	2	2	6	3
Month 3: Mobility : Severe problem N=23,31,33,29	1	1	0	1
Mon 3: Mobility : Unable to perform N=23,31,33,29	0	0	0	0
Month 6: Mobility : No problem N=18,25,17,27	10	19	11	15
Month 6: Mobility : Slight problem N=18,25,17,27	6	4	2	8
Month 6: Mobility : Moderate problem N=18,25,17,27	2	2	4	3
Month 6: Mobility : Severe problem N=18,25,17,27	0	0	0	1
Mon 6: Mobility : Unable to perform N=18,25,17,27	0	0	0	0
Baseline: Self-care : No problem	37	38	44	32
Baseline: Self-care : Slight problem	1	1	3	1
Baseline: Self-care : Moderate problem	0	0	0	1
Baseline: Self-care : Severe problem	0	0	0	0
Baseline: Self-care : Unable to perform	0	0	0	0
Wk 4: Self-care : No problem N=32,37,38,29	25	33	31	24
Wk 4: Self-care : Slight problem N=32,37,38,29	5	3	6	3
Wk 4: Self-care : Moderate problem N=32,37,38,29	1	0	1	1
Wk 4: Self-care : Severe problem N=32,37,38,29	0	1	0	1
Wk 4: Self-care : Unable to perform N=32,37,38,29	1	0	0	0
Month 3: Self-care : No problem N=23,31,33,29	19	29	32	25
Month 3: Self-care : Slight problem N=23,31,33,29	4	2	1	4
Mon 3: Self-care : Moderate problem N=23,31,33,29	0	0	0	0
Month 3: Self-care : Severe problem N=23,31,33,29	0	0	0	0
Mon 3: Self-care : Unable to perform N=23,31,33,29	0	0	0	0
Month 6: Self-care : No problem N=18,25,17,27	17	25	16	20
Month 6: Self-care : Slight problem N=18,25,17,27	1	0	1	7
Mon 6: Self-care : Moderate problem N=18,25,17,27	0	0	0	0
Month 6: Self-care : Severe problem N=18,25,17,27	0	0	0	0
Mon 6: Self-care : Unable to perform N=18,25,17,27	0	0	0	0
Baseline: Usual activities : No problem	22	22	24	16
Baseline: Usual activities : Slight problem	10	6	13	14
Baseline: Usual activities : Moderate problem	4	8	8	2
Baseline: Usual activities : Severe problem	2	1	1	2
Baseline: Usual activities : Unable to perform	0	2	1	0
Wk 4: Usual activities : No problem N=32,37,37,29	6	12	12	12
Wk 4: Usu act : Slight problem N=32,37,37,29	13	11	13	11
Wk 4: Usu act : Moderate problem N=32,37,37,29	11	8	8	4
Wk 4: Usu act : Severe problem N=32,37,37,29	0	3	2	1
Wk 4: Usu act : Unable to perform N=32,37,37,29	2	3	2	1
Mon 3: Usual activities : No problem N=23,31,33,29	8	16	19	12
Mon 3: Usu act : Slight problem N=23,31,33,29	9	9	10	14
Mon 3: Usu act : Moderate problem N=23,31,33,29	5	5	2	2
Mon 3: Usu act : Severe problem N=23,31,33,29	1	1	1	1
Mon 3: Usu act : Unable to perform N=23,31,33,29	0	0	1	0
Mon 6: Usual activities : No problem N=18,25,17,27	9	15	10	11
Mon 6: Usu act : Slight problem N=18,25,17,27	5	7	4	12
Mon 6: Usu act : Moderate problem N=18,25,17,27	3	3	2	3
Mon 6: Usu act : Severe problem N=18,25,17,27	1	0	1	0
Mon 6: Usu act : Unable to perform N=18,25,17,27	0	0	0	1
Baseline: Pain/Discomfort : No problem	18	17	16	15
Baseline: Pain/Discomfort : Slight problem	9	17	18	14
Baseline: Pain/Discomfort : Moderate problem	8	5	7	4
Baseline: Pain/Discomfort : Severe problem	1	0	5	1
Baseline: Pain/Discomfort : Unable to perform	2	0	1	0
Wk 4: Pain/Discomfort : No problem N=32,37,37,29	12	19	20	17
Wk 4: Pai : Slight problem N=32,37,37,29	12	13	10	9
Wk 4: Pai : Moderate problem N=32,37,37,29	7	2	5	3
Wk 4: Pai : Severe problem N=32,37,37,29	1	3	2	0
Wk 4: Pai : Unable to perform N=32,37,37,29	0	0	0	0
Mon 3: Pain/Discomfort : No problem N=23,31,33,29	9	10	18	16
Mon 3: Pai : Slight problem N=23,31,33,29	5	14	9	5
Mon 3: Pai : Moderate problem N=23,31,33,29	9	6	6	5
Mon 3: Pai : Severe problem N=23,31,33,29	0	1	0	3
Mon 3: Pai : Unable to perform N=23,31,33,29	0	0	0	0
Mon 6: Pain/Discomfort : No problem N=17,25,17,27	8	9	6	12
Mon 6: Pai : Slight problem N=17,25,17,27	4	14	8	8
Mon 6: Pai : Moderate problem N=17,25,17,27	5	1	3	4
Mon 6: Pai : Severe problem N=17,25,17,27	0	1	0	3
Mon 6: Pai : Unable to perform N=17,25,17,27	0	0	0	0
Baseline: Anxiety/Depression : No problem	16	23	18	21
Baseline: Anxiety/Depression : Slight problem	16	13	17	9
Baseline: Anxiety/Depression : Moderate problem	3	3	10	3
Baseline: Anxiety/Depression : Severe problem	1	0	1	1
Baseline: Anxiety/Depression : Unable to perform	2	0	1	0
Wk 4: Anx : No problem N=32,37,38,29	9	25	21	23
Wk 4: Anx : Slight problem N=32,37,38,29	15	8	12	3
Wk 4: Anx : Moderate problem N=32,37,38,29	7	3	5	3
Wk 4: Anx : Severe problem N=32,37,38,29	1	1	0	0
Wk 4: Anx : Unable to perform N=32,37,38,29	0	0	0	0
Mon 3: Anx : No problem N=23,31,33,29	11	19	16	19
Mon 3: Anx : Slight problem N=23,31,33,29	5	8	12	7
Mon 3: Anx : Moderate problem N=23,31,33,29	6	4	4	2
Mon 3: Anx : Severe problem N=23,31,33,29	1	0	1	1
Mon 3: Anx : Unable to perform N=23,31,33,29	0	0	0	0
Mon 6: Anx : No problem N=18,25,17,26	9	14	7	18
Mon 6: Anx : Slight problem N=18,25,17,26	5	10	8	5
Mon 6: Anx : Moderate problem N=18,25,17,26	3	0	1	3
Mon 6: Anx : Severe problem N=18,25,17,26	0	1	1	0
Mon 6: Anx : Unable to perform N=18,25,17,26	1	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Positive Replication Competent Retrovirus (RCR)

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End point title

Percentage of Participants With Positive Replication Competent Retrovirus (RCR)

End point description

RCR was analyzed in blood samples by central laboratory. Because axicabtagene ciloleucel comprised retroviral vector transduced T cells, the presence of RCR in the blood of treated participants was reported. Participants in the Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Day 0 (pre-infusion) up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively)

End point values	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	7	77	24	38	41	50	40
Units: percentage of participants
number (not applicable)	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score

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End point title

Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score ^[28]

End point description

EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant. The EQ-5D-VAS records the participant's self-rated health on a vertical visual analogue scale and is asked to make a global assessment of their current state of health with 0 indicating the worst health they can imagine and 100 indicating the best health they can imagine. Participants in Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline, Week 4, Month 3, and Month 6

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the endpoint was focused on only the arms under Phase 2 of the study, all the arms in the baseline period were not included.

End point values	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Phase 2 (Safety Management Study): Cohort 6
Number of subjects analysed	38	38	47	34
Units: units on a scale
arithmetic mean (standard deviation)
Baseline	71.2 ( 21.3 )	69.5 ( 18.8 )	66.7 ( 20.7 )	70.9 ( 17.0 )
Wk 4 N=32,36,38,29	67.8 ( 15.6 )	67.2 ( 20.9 )	70.8 ( 14.8 )	76.1 ( 13.2 )
Month 3 N=23,31,33,29	74.9 ( 16.6 )	78.8 ( 14.7 )	73.3 ( 19.9 )	76.5 ( 15.0 )
Month 6 N=18,25,17,27	77.1 ( 21.4 )	85.1 ( 12.1 )	77.1 ( 14.7 )	79.8 ( 14.0 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse event:Up to 7.7years;All-cause Death:Enrollment upto last followup visit(maximum:7.7 years);Death for Participant Flow of Phase 2 Cohort 1(53) is more than deaths(49) reported here because deaths are separately given for main and retreatment arms.

Adverse event reporting additional description

Adverse events:The Safety Analysis Set included participants treated with any dose of axicabtageneciloleucel;Retreatment groups:The Safety-Retreatment Analysis Set included participants re-treated of axicabtageneciloleucel.All-cause mortality:All Enrolled Analysis Set included enrolled participants,Retreatment group:Safety-Retreatment Analysis Set.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot

Reporting group description

Reporting group title

Phase 2 (Pivotal Study): Cohort 1

Reporting group description

Reporting group title

Phase 2 (Pivotal Study): Cohort 2

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 3

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 4

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 5

Reporting group description

Reporting group title

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5

Reporting group description

Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose.

Reporting group title

Retreatment Axicabtagene Ciloleucel: Phase 1

Reporting group description

Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the axicabtagene ciloleucel regimen selected for Phase 2.

Reporting group title

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1

Reporting group description

Reporting group title

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2

Reporting group description

Reporting group title

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3

Reporting group description

Reporting group title

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4

Reporting group description

Reporting group title

Phase 2 (Safety Management Study): Cohort 6

Reporting group description

Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot

Phase 2 (Pivotal Study): Cohort 1

Phase 2 (Pivotal Study): Cohort 2

Phase 2 (Safety Management Study): Cohort 3

Phase 2 (Safety Management Study): Cohort 4

Phase 2 (Safety Management Study): Cohort 5

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5

Retreatment Axicabtagene Ciloleucel: Phase 1

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4

Phase 2 (Safety Management Study): Cohort 6

Total subjects affected by serious adverse events

subjects affected / exposed

5 / 7 (71.43%)

40 / 77 (51.95%)

14 / 24 (58.33%)

26 / 38 (68.42%)

24 / 41 (58.54%)

27 / 50 (54.00%)

0 / 2 (0.00%)

1 / 1 (100.00%)

5 / 9 (55.56%)

1 / 2 (50.00%)

2 / 2 (100.00%)

0 / 2 (0.00%)

25 / 40 (62.50%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

B-cell lymphoma

subjects affected / exposed

1 / 7 (14.29%)

4 / 77 (5.19%)

0 / 24 (0.00%)

3 / 38 (7.89%)

3 / 41 (7.32%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

2 / 9 (22.22%)

0 / 2 (0.00%)

1 / 2 (50.00%)

0 / 2 (0.00%)

2 / 40 (5.00%)

occurrences causally related to treatment / all

0 / 1

0 / 4

0 / 0

0 / 3

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 1

0 / 4

0 / 0

0 / 3

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 2

Myelodysplastic syndrome

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

2 / 24 (8.33%)

2 / 38 (5.26%)

0 / 41 (0.00%)

2 / 50 (4.00%)

0 / 2 (0.00%)

1 / 1 (100.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

1 / 2

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

Squamous cell carcinoma

subjects affected / exposed

0 / 7 (0.00%)

2 / 77 (2.60%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute myeloid leukaemia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Diffuse large B-cell lymphoma

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Carcinoma in situ

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cancer pain

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Basal cell carcinoma

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Central nervous system lymphoma

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lung neoplasm malignant

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Prostate cancer

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Hypotension

subjects affected / exposed

0 / 7 (0.00%)

2 / 77 (2.60%)

1 / 24 (4.17%)

4 / 38 (10.53%)

2 / 41 (4.88%)

3 / 50 (6.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

2 / 40 (5.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 2

3 / 4

2 / 2

3 / 3

0 / 0

2 / 2

deaths causally related to treatment / all

0 / 0

Hypertension

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Embolism

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Shock

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Gait disturbance

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fatigue

subjects affected / exposed

1 / 7 (14.29%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Asthenia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 7 (0.00%)

5 / 77 (6.49%)

1 / 24 (4.17%)

3 / 38 (7.89%)

2 / 41 (4.88%)

5 / 50 (10.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

4 / 40 (10.00%)

occurrences causally related to treatment / all

0 / 0

1 / 5

0 / 1

1 / 4

2 / 2

3 / 5

0 / 0

0 / 1

0 / 0

2 / 4

deaths causally related to treatment / all

0 / 0

General physical health ~ deterioration

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oedema peripheral

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Immune system disorders

Haemophagocytic lymphohistiocytosis

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Respiratory, thoracic and mediastinal disorders

Hypoxia

subjects affected / exposed

0 / 7 (0.00%)

4 / 77 (5.19%)

0 / 24 (0.00%)

2 / 38 (5.26%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

4 / 4

0 / 0

1 / 2

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

2 / 41 (4.88%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 2 (50.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

1 / 1

Acute respiratory failure

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspiration

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pneumonitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chronic obstructive pulmonary ~ disease

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Pulmonary oedema

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Reexpansion pulmonary oedema

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory distress

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Confusional state

subjects affected / exposed

0 / 7 (0.00%)

3 / 77 (3.90%)

2 / 24 (8.33%)

3 / 38 (7.89%)

1 / 41 (2.44%)

5 / 50 (10.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

5 / 40 (12.50%)

occurrences causally related to treatment / all

0 / 0

3 / 3

1 / 1

4 / 5

0 / 0

5 / 5

deaths causally related to treatment / all

0 / 0

Agitation

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

2 / 24 (8.33%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Disorientation

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Depression

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Anxiety

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Delirium

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mental status changes

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

2 / 40 (5.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

Hallucination

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Restlessness

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ejection fraction decreased

subjects affected / exposed

0 / 7 (0.00%)

3 / 77 (3.90%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

3 / 3

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gamma-glutamyltransferase increased

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Platelet count decreased

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutrophil count decreased

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Troponin T increased

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Hip fracture

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Brain herniation

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Radius fracture

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Seroma

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Cardiac arrest

subjects affected / exposed

0 / 7 (0.00%)

2 / 77 (2.60%)

2 / 24 (8.33%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 7 (0.00%)

3 / 77 (3.90%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 3

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial flutter

subjects affected / exposed

0 / 7 (0.00%)

2 / 77 (2.60%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac failure

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tachycardia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Arrhythmia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute left ventricular failure

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiomyopathy

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pericarditis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sinus tachycardia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Somnolence

subjects affected / exposed

0 / 7 (0.00%)

3 / 77 (3.90%)

0 / 24 (0.00%)

2 / 38 (5.26%)

3 / 41 (7.32%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

3 / 3

0 / 0

2 / 2

3 / 3

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Encephalopathy

subjects affected / exposed

1 / 7 (14.29%)

16 / 77 (20.78%)

3 / 24 (12.50%)

9 / 38 (23.68%)

1 / 41 (2.44%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

1 / 1

17 / 17

5 / 5

10 / 10

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aphasia

subjects affected / exposed

0 / 7 (0.00%)

3 / 77 (3.90%)

1 / 24 (4.17%)

1 / 38 (2.63%)

0 / 41 (0.00%)

3 / 50 (6.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

3 / 40 (7.50%)

occurrences causally related to treatment / all

0 / 0

3 / 3

1 / 1

2 / 2

0 / 0

3 / 3

0 / 0

2 / 3

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

3 / 40 (7.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

2 / 3

deaths causally related to treatment / all

0 / 0

Tremor

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

4 / 50 (8.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

4 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Immune effector cell-associated ~ neurotoxicity syndrome

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

2 / 41 (4.88%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

2 / 2

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysgraphia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Headache

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 2 (50.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Depressed level of consciousness

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysarthria

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhage intracranial

subjects affected / exposed

1 / 7 (14.29%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 1

0 / 0

Leukoencephalopathy

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

1 / 1

Presyncope

subjects affected / exposed

1 / 7 (14.29%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Apraxia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Ataxia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Brain injury

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Cerebral venous sinus thrombosis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebellar infarction

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Brain oedema

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Cognitive disorder

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Disturbance in attention

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspraxia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hemiparesis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lethargy

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Memory impairment

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Migraine with aura

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Toxic encephalopathy

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

1 / 1

Seizure like phenomena

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Quadriplegia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Febrile neutropenia

subjects affected / exposed

1 / 7 (14.29%)

4 / 77 (5.19%)

0 / 24 (0.00%)

2 / 38 (5.26%)

1 / 41 (2.44%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

2 / 40 (5.00%)

occurrences causally related to treatment / all

0 / 1

1 / 5

0 / 0

0 / 2

1 / 1

0 / 0

2 / 2

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

1 / 38 (2.63%)

2 / 41 (4.88%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

2 / 2

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Anaemia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bone marrow failure

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pancytopenia

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

2 / 50 (4.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

2 / 40 (5.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 3

0 / 0

2 / 2

deaths causally related to treatment / all

0 / 0

Febrile bone marrow aplasia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Leukopenia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Visual impairment

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Vomiting

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

2 / 38 (5.26%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ascites

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enteritis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tongue ulceration

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Rectal haemorrhage

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholecystitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Toxic skin eruption

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

0 / 7 (0.00%)

3 / 77 (3.90%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal failure

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Anuria

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cystitis haemorrhagic

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haematuria

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

1 / 7 (14.29%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Muscular weakness

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

2 / 50 (4.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Pain in extremity

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Amyotrophy

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Arthralgia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bone pain

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal pain

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Pneumonia

subjects affected / exposed

2 / 7 (28.57%)

7 / 77 (9.09%)

3 / 24 (12.50%)

1 / 38 (2.63%)

3 / 41 (7.32%)

3 / 50 (6.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

3 / 40 (7.50%)

occurrences causally related to treatment / all

1 / 2

1 / 9

1 / 3

1 / 1

2 / 3

1 / 3

0 / 0

3 / 3

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Sepsis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

1 / 41 (2.44%)

2 / 50 (4.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

1 / 2 (50.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

1 / 2

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Covid-19

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

3 / 40 (7.50%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

0 / 4

deaths causally related to treatment / all

0 / 0

0 / 1

Urinary tract infection

subjects affected / exposed

0 / 7 (0.00%)

3 / 77 (3.90%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Herpes zoster

subjects affected / exposed

0 / 7 (0.00%)

2 / 77 (2.60%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Septic shock

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

3 / 50 (6.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

3 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

3 / 3

0 / 0

Bacteraemia

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

1 / 38 (2.63%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Cellulitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

2 / 50 (4.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumocystis jirovecii pneumonia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Escherichia bacteraemia

subjects affected / exposed

0 / 7 (0.00%)

2 / 77 (2.60%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Clostridium difficile infection

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Clostridium difficile colitis

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rhinovirus infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Covid-19 pneumonia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Cytomegalovirus colitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Adenovirus infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Anal abscess

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atypical pneumonia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cytomegalovirus enteritis

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Device related sepsis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Encephalitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia sepsis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Human herpesvirus 6 encephalitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Influenza

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Klebsiella infection

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Meningitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myelitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oral herpes

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Parainfluenzae virus infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumococcal sepsis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peritonitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumocystis jirovecii infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia necrotising

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pneumonia influenzal

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pneumonia respiratory syncytial ~ viral

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia staphylococcal

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pseudomonal sepsis

subjects affected / exposed

1 / 7 (14.29%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rhinitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rotavirus infection

subjects affected / exposed

1 / 7 (14.29%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sinusitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Soft tissue infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urosepsis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

Upper respiratory tract infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

1 / 50 (2.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Viral upper respiratory tract ~ infection

subjects affected / exposed

1 / 7 (14.29%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 7 (0.00%)

2 / 77 (2.60%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acidosis

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

1 / 24 (4.17%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Decreased appetite

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

1 / 41 (2.44%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypercalcaemia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

1 / 9 (11.11%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypoglycaemia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

1 / 38 (2.63%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 7 (0.00%)

0 / 77 (0.00%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

1 / 40 (2.50%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Lactic acidosis

subjects affected / exposed

0 / 7 (0.00%)

1 / 77 (1.30%)

0 / 24 (0.00%)

0 / 38 (0.00%)

0 / 41 (0.00%)

0 / 50 (0.00%)

0 / 2 (0.00%)

0 / 1 (0.00%)

0 / 9 (0.00%)

0 / 2 (0.00%)

0 / 40 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemot	Phase 2 (Pivotal Study): Cohort 1	Phase 2 (Pivotal Study): Cohort 2	Phase 2 (Safety Management Study): Cohort 3	Phase 2 (Safety Management Study): Cohort 4	Phase 2 (Safety Management Study): Cohort 5	Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5	Retreatment Axicabtagene Ciloleucel: Phase 1	Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1	Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2	Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3	Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4	Phase 2 (Safety Management Study): Cohort 6
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	77 / 77 (100.00%)	23 / 24 (95.83%)	38 / 38 (100.00%)	41 / 41 (100.00%)	50 / 50 (100.00%)	2 / 2 (100.00%)	1 / 1 (100.00%)	9 / 9 (100.00%)	2 / 2 (100.00%)	2 / 2 (100.00%)	2 / 2 (100.00%)	40 / 40 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Myelodysplastic syndrome
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	1	2	0	0	0	0	0	1	0
Cancer pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	3 / 7 (42.86%)	44 / 77 (57.14%)	14 / 24 (58.33%)	22 / 38 (57.89%)	24 / 41 (58.54%)	25 / 50 (50.00%)	1 / 2 (50.00%)	1 / 1 (100.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	21 / 40 (52.50%)
occurrences all number	3	49	22	30	30	28	1	3	1	1	0	1	30
Hypertension
subjects affected / exposed	1 / 7 (14.29%)	9 / 77 (11.69%)	4 / 24 (16.67%)	2 / 38 (5.26%)	2 / 41 (4.88%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	1	14	8	2	2	3	0	0	0	1	0	0	8
Capillary leak syndrome
subjects affected / exposed	1 / 7 (14.29%)	2 / 77 (2.60%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	2	0	0	1	0	0	0	0	0	0	0	0
Deep vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	2	0	2	0	0	0	0	0	0	0	0	3
Hot flush
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	2
Subclavian vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
General disorders and administration site conditions
Chills
subjects affected / exposed	1 / 7 (14.29%)	32 / 77 (41.56%)	7 / 24 (29.17%)	11 / 38 (28.95%)	11 / 41 (26.83%)	14 / 50 (28.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	2 / 9 (22.22%)	2 / 2 (100.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	8 / 40 (20.00%)
occurrences all number	1	34	7	16	13	15	0	1	2	3	0	0	8
Fatigue
subjects affected / exposed	2 / 7 (28.57%)	34 / 77 (44.16%)	12 / 24 (50.00%)	18 / 38 (47.37%)	19 / 41 (46.34%)	12 / 50 (24.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	3 / 9 (33.33%)	0 / 2 (0.00%)	1 / 2 (50.00%)	1 / 2 (50.00%)	18 / 40 (45.00%)
occurrences all number	3	41	15	21	20	13	0	0	3	0	1	1	25
Pyrexia
subjects affected / exposed	7 / 7 (100.00%)	66 / 77 (85.71%)	21 / 24 (87.50%)	35 / 38 (92.11%)	39 / 41 (95.12%)	40 / 50 (80.00%)	2 / 2 (100.00%)	1 / 1 (100.00%)	9 / 9 (100.00%)	2 / 2 (100.00%)	1 / 2 (50.00%)	2 / 2 (100.00%)	33 / 40 (82.50%)
occurrences all number	9	81	32	48	49	60	2	1	13	3	1	2	41
Asthenia
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	2 / 24 (8.33%)	3 / 38 (7.89%)	2 / 41 (4.88%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	5 / 40 (12.50%)
occurrences all number	0	5	2	3	2	5	0	0	1	1	0	0	5
Pain
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	1 / 24 (4.17%)	5 / 38 (13.16%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	5	1	5	0	0	0	0	1	0	0	0	1
Malaise
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	0 / 24 (0.00%)	1 / 38 (2.63%)	1 / 41 (2.44%)	2 / 50 (4.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	4	0	1	1	2	1	0	1	0	0	0	2
Non-cardiac chest pain
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	2 / 24 (8.33%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	5	2	2	0	0	0	0	0	0	0	0	1
Gait disturbance
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	4 / 38 (10.53%)	0 / 41 (0.00%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2	0	4	0	2	0	0	0	0	0	0	1
Influenza like illness
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	2 / 38 (5.26%)	2 / 41 (4.88%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	1	0	0	3	2	0	2	0	0	0	0	0	3
Oedema
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	1 / 40 (2.50%)
occurrences all number	0	1	0	0	1	2	0	0	1	0	0	1	2
Oedema peripheral
subjects affected / exposed	1 / 7 (14.29%)	12 / 77 (15.58%)	2 / 24 (8.33%)	6 / 38 (15.79%)	2 / 41 (4.88%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	1	14	2	7	2	3	0	0	1	1	0	0	3
Chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	1 / 38 (2.63%)	3 / 41 (7.32%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	1	3	0	0	0	0	1	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	2	0	0	1	0	0	0	0	0	0	0	2
Swelling
subjects affected / exposed	1 / 7 (14.29%)	1 / 77 (1.30%)	1 / 24 (4.17%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	1	1	1	0	0	0	0	0	0	0	0	0
Puncture site pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	3 / 41 (7.32%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0	0	0	0
Catheter site pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 40 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	0
Hernia
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Immune system disorders
Hypogammaglobulinaemia
subjects affected / exposed	3 / 7 (42.86%)	10 / 77 (12.99%)	3 / 24 (12.50%)	2 / 38 (5.26%)	6 / 41 (14.63%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	8 / 40 (20.00%)
occurrences all number	3	10	3	2	6	1	0	0	0	0	0	2	11
Graft versus host disease
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	2	0	0	0
Reproductive system and breast disorders
Scrotal oedema
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0	0	0	0
Perineal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	4 / 7 (57.14%)	24 / 77 (31.17%)	5 / 24 (20.83%)	9 / 38 (23.68%)	6 / 41 (14.63%)	5 / 50 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	1 / 2 (50.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	7 / 40 (17.50%)
occurrences all number	5	27	5	10	6	5	0	0	2	2	0	1	8
Cough
subjects affected / exposed	2 / 7 (28.57%)	18 / 77 (23.38%)	6 / 24 (25.00%)	9 / 38 (23.68%)	11 / 41 (26.83%)	6 / 50 (12.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	5 / 9 (55.56%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	6 / 40 (15.00%)
occurrences all number	4	20	12	11	12	6	0	0	5	0	0	0	8
Nasal congestion
subjects affected / exposed	1 / 7 (14.29%)	4 / 77 (5.19%)	1 / 24 (4.17%)	2 / 38 (5.26%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	2	4	1	2	1	0	0	0	0	1	0	0	4
Oropharyngeal pain
subjects affected / exposed	1 / 7 (14.29%)	4 / 77 (5.19%)	2 / 24 (8.33%)	2 / 38 (5.26%)	1 / 41 (2.44%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	1	5	2	2	1	2	0	0	0	1	0	0	2
Pleural effusion
subjects affected / exposed	3 / 7 (42.86%)	9 / 77 (11.69%)	1 / 24 (4.17%)	5 / 38 (13.16%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	3	9	1	5	3	0	0	0	0	1	0	0	0
Dyspnoea
subjects affected / exposed	3 / 7 (42.86%)	11 / 77 (14.29%)	4 / 24 (16.67%)	5 / 38 (13.16%)	3 / 41 (7.32%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	8 / 40 (20.00%)
occurrences all number	4	11	5	5	3	5	0	0	0	1	0	0	12
Wheezing
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	0 / 24 (0.00%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	4	0	1	0	0	0	0	0	1	0	0	0
Pulmonary oedema
subjects affected / exposed	2 / 7 (28.57%)	5 / 77 (6.49%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	2	6	0	0	0	0	0	0	0	0	0	0	1
Upper-airway cough syndrome
subjects affected / exposed	1 / 7 (14.29%)	4 / 77 (5.19%)	1 / 24 (4.17%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	4	1	1	0	0	0	0	0	0	0	0	0
Tachypnoea
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	1 / 24 (4.17%)	3 / 38 (7.89%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	2	1	3	0	0	0	0	0	0	0	0	0
Hiccups
subjects affected / exposed	0 / 7 (0.00%)	3 / 77 (3.90%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	3	1	0	0	1	0	0	0	0	0	0	5
Laryngeal haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Rhinitis allergic
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	1	0	0	0
Atelectasis
subjects affected / exposed	1 / 7 (14.29%)	2 / 77 (2.60%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	2	0	0	1	0	0	0	0	0	0	0	0
Paranasal cyst
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 7 (0.00%)	9 / 77 (11.69%)	3 / 24 (12.50%)	4 / 38 (10.53%)	0 / 41 (0.00%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	0	9	3	4	0	2	0	0	2	0	0	0	5
Insomnia
subjects affected / exposed	1 / 7 (14.29%)	7 / 77 (9.09%)	2 / 24 (8.33%)	4 / 38 (10.53%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	6 / 40 (15.00%)
occurrences all number	1	7	4	4	2	0	0	1	3	1	1	0	6
Confusional state
subjects affected / exposed	1 / 7 (14.29%)	19 / 77 (24.68%)	8 / 24 (33.33%)	16 / 38 (42.11%)	4 / 41 (9.76%)	6 / 50 (12.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	12 / 40 (30.00%)
occurrences all number	1	20	10	19	6	8	0	0	2	1	0	0	14
Agitation
subjects affected / exposed	1 / 7 (14.29%)	5 / 77 (6.49%)	3 / 24 (12.50%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	1	6	3	0	1	0	0	0	0	0	0	0	4
Hallucination
subjects affected / exposed	1 / 7 (14.29%)	4 / 77 (5.19%)	0 / 24 (0.00%)	1 / 38 (2.63%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	4	0	1	2	0	0	0	0	0	0	0	1
Mental status changes
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	1 / 24 (4.17%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	4	1	1	0	0	0	0	0	0	0	0	2
Delirium
subjects affected / exposed	1 / 7 (14.29%)	1 / 77 (1.30%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	2	0	2	0	2	0	0	0	0	0	0	1
Bradyphrenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	2	0	0	0	0	0	0	0	0	0
Disorientation
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	1 / 24 (4.17%)	1 / 38 (2.63%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	1	1	1	0	0	0	0	2	0	0	0
Depression
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	1 / 24 (4.17%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	1	1	0	1	0	0	0	0	0	0	0	3
Restlessness
subjects affected / exposed	1 / 7 (14.29%)	2 / 77 (2.60%)	1 / 24 (4.17%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	2	1	1	0	0	0	0	0	0	1	0	1
Mood altered
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0
Investigations
White blood cell count decreased
subjects affected / exposed	2 / 7 (28.57%)	23 / 77 (29.87%)	8 / 24 (33.33%)	10 / 38 (26.32%)	6 / 41 (14.63%)	14 / 50 (28.00%)	1 / 2 (50.00%)	1 / 1 (100.00%)	3 / 9 (33.33%)	2 / 2 (100.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	10 / 40 (25.00%)
occurrences all number	7	63	15	13	13	24	1	1	9	6	0	2	24
Platelet count decreased
subjects affected / exposed	2 / 7 (28.57%)	25 / 77 (32.47%)	5 / 24 (20.83%)	9 / 38 (23.68%)	10 / 41 (24.39%)	17 / 50 (34.00%)	1 / 2 (50.00%)	1 / 1 (100.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	6 / 40 (15.00%)
occurrences all number	6	46	10	16	17	20	1	1	8	2	0	1	6
Neutrophil count decreased
subjects affected / exposed	2 / 7 (28.57%)	27 / 77 (35.06%)	7 / 24 (29.17%)	11 / 38 (28.95%)	13 / 41 (31.71%)	25 / 50 (50.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	4 / 9 (44.44%)	2 / 2 (100.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	14 / 40 (35.00%)
occurrences all number	9	63	16	18	29	49	0	0	11	2	0	2	25
Lymphocyte count decreased
subjects affected / exposed	2 / 7 (28.57%)	12 / 77 (15.58%)	6 / 24 (25.00%)	4 / 38 (10.53%)	4 / 41 (9.76%)	8 / 50 (16.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	3 / 9 (33.33%)	2 / 2 (100.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	7 / 40 (17.50%)
occurrences all number	2	24	9	4	4	12	0	3	8	2	0	1	11
C-reactive protein increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	2 / 38 (5.26%)	5 / 41 (12.20%)	7 / 50 (14.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	1 / 40 (2.50%)
occurrences all number	0	0	0	2	6	7	0	0	0	0	0	1	1
Weight decreased
subjects affected / exposed	2 / 7 (28.57%)	11 / 77 (14.29%)	4 / 24 (16.67%)	1 / 38 (2.63%)	0 / 41 (0.00%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	3	18	9	1	0	4	0	0	6	2	0	0	2
Aspartate aminotransferase increased
subjects affected / exposed	2 / 7 (28.57%)	11 / 77 (14.29%)	5 / 24 (20.83%)	7 / 38 (18.42%)	4 / 41 (9.76%)	7 / 50 (14.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	2	14	7	10	4	9	0	0	0	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	3 / 7 (42.86%)	13 / 77 (16.88%)	5 / 24 (20.83%)	8 / 38 (21.05%)	5 / 41 (12.20%)	7 / 50 (14.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	3	14	8	12	6	8	0	0	1	1	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	2 / 24 (8.33%)	0 / 38 (0.00%)	3 / 41 (7.32%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	1 / 40 (2.50%)
occurrences all number	0	5	2	0	3	1	0	0	0	0	0	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 7 (14.29%)	3 / 77 (3.90%)	1 / 24 (4.17%)	4 / 38 (10.53%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	3	3	4	1	1	0	0	2	0	0	0	0
Serum ferritin increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	1 / 24 (4.17%)	2 / 38 (5.26%)	3 / 41 (7.32%)	5 / 50 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1	1	2	3	5	0	0	0	0	0	0	1
Weight increased
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	0 / 24 (0.00%)	1 / 38 (2.63%)	4 / 41 (9.76%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 40 (0.00%)
occurrences all number	0	6	0	1	4	4	0	0	1	0	0	1	0
Blood bilirubin increased
subjects affected / exposed	0 / 7 (0.00%)	3 / 77 (3.90%)	1 / 24 (4.17%)	2 / 38 (5.26%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	4	1	5	0	1	0	0	0	0	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	3 / 41 (7.32%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	5	6	0	0	0	0	0	0	0
Blood immunoglobulin G decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	1 / 38 (2.63%)	0 / 41 (0.00%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	3	0	1	0	3	0	0	0	0	0	0	0
Blood potassium decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	6	0	0	0	0	0	0	0
Urine output decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	1	0	0	0
Immunoglobulins decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	3 / 41 (7.32%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0	0	0	0
Blood fibrinogen decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	0	5	0	0	0	0	0	0	0	0	1
Oxygen saturation decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	0	3	0	0	0	0	0	0	0
Blood albumin decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	0	0	0
Blood magnesium decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Skin abrasion
subjects affected / exposed	1 / 7 (14.29%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	1
Infusion related reaction
subjects affected / exposed	2 / 7 (28.57%)	1 / 77 (1.30%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	2	1	1	0	0	0	0	0	0	0	0	0	0
Fall
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	2 / 24 (8.33%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	5	2	0	0	1	0	0	0	0	0	0	4
Head injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Procedural pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	1 / 24 (4.17%)	1 / 38 (2.63%)	1 / 41 (2.44%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	5	1	1	1	2	0	0	0	0	0	0	1
Sinus bradycardia
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	2 / 24 (8.33%)	1 / 38 (2.63%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	5	8	1	1	0	0	0	0	1	0	0	1
Ventricular arrhythmia
subjects affected / exposed	1 / 7 (14.29%)	3 / 77 (3.90%)	2 / 24 (8.33%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	3	2	0	0	0	0	0	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 7 (0.00%)	19 / 77 (24.68%)	2 / 24 (8.33%)	4 / 38 (10.53%)	2 / 41 (4.88%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	4 / 9 (44.44%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	5 / 40 (12.50%)
occurrences all number	0	25	11	5	2	3	0	0	11	1	0	0	6
Tachycardia
subjects affected / exposed	3 / 7 (42.86%)	29 / 77 (37.66%)	8 / 24 (33.33%)	6 / 38 (15.79%)	7 / 41 (17.07%)	7 / 50 (14.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	6 / 40 (15.00%)
occurrences all number	3	35	9	7	8	8	0	0	1	0	0	0	8
Bradycardia
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	4	0	2	0	0	0	0	0	0	0	0	1
Acute left ventricular failure
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Ventricular tachycardia
subjects affected / exposed	0 / 7 (0.00%)	3 / 77 (3.90%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	4	0	2	0	0	0	0	0	0	0	0	0
Nervous system disorders
Tremor
subjects affected / exposed	4 / 7 (57.14%)	23 / 77 (29.87%)	6 / 24 (25.00%)	16 / 38 (42.11%)	5 / 41 (12.20%)	11 / 50 (22.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	4 / 9 (44.44%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	9 / 40 (22.50%)
occurrences all number	4	23	7	16	5	12	0	0	5	1	0	0	12
Headache
subjects affected / exposed	3 / 7 (42.86%)	34 / 77 (44.16%)	12 / 24 (50.00%)	19 / 38 (50.00%)	16 / 41 (39.02%)	17 / 50 (34.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	2 / 2 (100.00%)	13 / 40 (32.50%)
occurrences all number	4	39	14	21	20	20	2	0	4	2	0	4	16
Encephalopathy
subjects affected / exposed	4 / 7 (57.14%)	20 / 77 (25.97%)	6 / 24 (25.00%)	9 / 38 (23.68%)	5 / 41 (12.20%)	5 / 50 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	5	22	7	10	6	5	0	0	2	0	0	0	4
Dysarthria
subjects affected / exposed	0 / 7 (0.00%)	3 / 77 (3.90%)	1 / 24 (4.17%)	3 / 38 (7.89%)	2 / 41 (4.88%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	3	1	3	4	1	0	0	0	0	0	0	2
Somnolence
subjects affected / exposed	3 / 7 (42.86%)	10 / 77 (12.99%)	4 / 24 (16.67%)	3 / 38 (7.89%)	5 / 41 (12.20%)	5 / 50 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	5 / 40 (12.50%)
occurrences all number	3	12	5	6	5	5	0	0	1	1	0	0	5
Aphasia
subjects affected / exposed	1 / 7 (14.29%)	13 / 77 (16.88%)	4 / 24 (16.67%)	8 / 38 (21.05%)	4 / 41 (9.76%)	9 / 50 (18.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	4 / 40 (10.00%)
occurrences all number	1	14	5	10	4	9	0	0	0	1	0	1	4
Dizziness
subjects affected / exposed	1 / 7 (14.29%)	12 / 77 (15.58%)	9 / 24 (37.50%)	5 / 38 (13.16%)	7 / 41 (17.07%)	8 / 50 (16.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	6 / 40 (15.00%)
occurrences all number	1	13	10	6	8	9	2	0	1	1	0	0	7
Memory impairment
subjects affected / exposed	0 / 7 (0.00%)	6 / 77 (7.79%)	2 / 24 (8.33%)	0 / 38 (0.00%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	6	2	0	1	1	0	0	0	0	0	0	1
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	4 / 38 (10.53%)	2 / 41 (4.88%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	1	0	5	3	1	0	0	0	0	0	0	2
Dysgeusia
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	2 / 24 (8.33%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 40 (0.00%)
occurrences all number	0	5	2	0	0	0	0	0	1	0	0	1	0
Dyskinesia
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	2	0	0	0	0	0	1	0	0	0
Dysgraphia
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	0	0	0	3	0	0	0	0	0	0	1
Seizure
subjects affected / exposed	0 / 7 (0.00%)	3 / 77 (3.90%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	6	0	2	0	0	0	0	0	0	0	0	1
Disturbance in attention
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	2 / 24 (8.33%)	0 / 38 (0.00%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1	3	0	1	1	0	0	0	0	0	0	1
Post herpetic neuralgia
subjects affected / exposed	1 / 7 (14.29%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	1	0	0	0	1	0	0	0	0	0	0	1
Head discomfort
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0
Dementia
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Peripheral sensory neuropathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	1	0	0	0
Apraxia
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	2
Muscle contractions involuntary
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Poor sucking reflex
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Peripheral motor neuropathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Presyncope
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	0	0	0
Sensory loss
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 7 (57.14%)	47 / 77 (61.04%)	13 / 24 (54.17%)	22 / 38 (57.89%)	19 / 41 (46.34%)	19 / 50 (38.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	13 / 40 (32.50%)
occurrences all number	7	75	20	34	27	47	0	1	9	1	0	1	16
Neutropenia
subjects affected / exposed	3 / 7 (42.86%)	26 / 77 (33.77%)	12 / 24 (50.00%)	18 / 38 (47.37%)	16 / 41 (39.02%)	16 / 50 (32.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	20 / 40 (50.00%)
occurrences all number	5	41	20	30	24	25	0	0	1	1	0	0	43
Thrombocytopenia
subjects affected / exposed	2 / 7 (28.57%)	24 / 77 (31.17%)	6 / 24 (25.00%)	12 / 38 (31.58%)	7 / 41 (17.07%)	9 / 50 (18.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	10 / 40 (25.00%)
occurrences all number	2	30	7	21	9	10	0	0	0	0	0	0	18
Febrile neutropenia
subjects affected / exposed	4 / 7 (57.14%)	21 / 77 (27.27%)	8 / 24 (33.33%)	10 / 38 (26.32%)	3 / 41 (7.32%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	4	22	9	10	3	2	0	0	4	1	0	0	2
Pancytopenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	1 / 24 (4.17%)	0 / 38 (0.00%)	4 / 41 (9.76%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	1	0	4	3	0	0	0	0	0	0	0
Leukopenia
subjects affected / exposed	0 / 7 (0.00%)	13 / 77 (16.88%)	3 / 24 (12.50%)	4 / 38 (10.53%)	7 / 41 (17.07%)	8 / 50 (16.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	7 / 40 (17.50%)
occurrences all number	0	19	7	4	14	11	0	0	0	0	0	0	15
Lymphopenia
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	0 / 24 (0.00%)	0 / 38 (0.00%)	3 / 41 (7.32%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	0	6	0	0	7	0	0	0	0	0	0	0	6
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	1 / 38 (2.63%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	1	1	0	0	1	0	0	0	0	0
Ear pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0	0	0	0
Hypoacusis
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Eye disorders
Vision blurred
subjects affected / exposed	1 / 7 (14.29%)	2 / 77 (2.60%)	2 / 24 (8.33%)	2 / 38 (5.26%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	1	2	2	2	1	1	0	0	0	0	0	0	2
Vitreous floaters
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	0	2
Eyelid function disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 7 (14.29%)	17 / 77 (22.08%)	11 / 24 (45.83%)	9 / 38 (23.68%)	6 / 41 (14.63%)	7 / 50 (14.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 2 (100.00%)	8 / 40 (20.00%)
occurrences all number	1	18	12	10	8	7	1	0	1	0	0	2	9
Constipation
subjects affected / exposed	2 / 7 (28.57%)	15 / 77 (19.48%)	5 / 24 (20.83%)	7 / 38 (18.42%)	6 / 41 (14.63%)	8 / 50 (16.00%)	1 / 2 (50.00%)	1 / 1 (100.00%)	3 / 9 (33.33%)	2 / 2 (100.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	15 / 40 (37.50%)
occurrences all number	3	17	9	7	6	8	1	1	3	2	0	0	19
Nausea
subjects affected / exposed	1 / 7 (14.29%)	22 / 77 (28.57%)	12 / 24 (50.00%)	15 / 38 (39.47%)	12 / 41 (29.27%)	12 / 50 (24.00%)	2 / 2 (100.00%)	1 / 1 (100.00%)	4 / 9 (44.44%)	0 / 2 (0.00%)	1 / 2 (50.00%)	2 / 2 (100.00%)	14 / 40 (35.00%)
occurrences all number	1	27	13	18	17	14	2	1	4	0	1	2	20
Diarrhoea
subjects affected / exposed	5 / 7 (71.43%)	29 / 77 (37.66%)	8 / 24 (33.33%)	16 / 38 (42.11%)	25 / 41 (60.98%)	11 / 50 (22.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	2 / 2 (100.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	11 / 40 (27.50%)
occurrences all number	5	32	9	25	29	11	0	0	2	3	0	1	14
Abdominal pain
subjects affected / exposed	1 / 7 (14.29%)	8 / 77 (10.39%)	3 / 24 (12.50%)	3 / 38 (7.89%)	2 / 41 (4.88%)	5 / 50 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	5 / 40 (12.50%)
occurrences all number	1	8	3	3	2	5	0	0	0	0	0	0	5
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 7 (14.29%)	2 / 77 (2.60%)	0 / 24 (0.00%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	2	0	1	0	0	0	1	0	0	0	0	1
Anal incontinence
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	1 / 24 (4.17%)	0 / 38 (0.00%)	2 / 41 (4.88%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	1	1	0	2	1	0	0	0	0	0	0	2
Stomatitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	2 / 38 (5.26%)	1 / 41 (2.44%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1	0	2	1	4	0	0	0	0	0	0	1
Dry mouth
subjects affected / exposed	2 / 7 (28.57%)	7 / 77 (9.09%)	3 / 24 (12.50%)	3 / 38 (7.89%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	2	7	3	3	5	0	0	0	2	0	0	0	3
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	1 / 24 (4.17%)	0 / 38 (0.00%)	2 / 41 (4.88%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2	1	0	2	3	0	0	0	0	0	0	1
Abdominal distension
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	2 / 24 (8.33%)	1 / 38 (2.63%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	6	2	1	0	1	0	0	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	1 / 24 (4.17%)	3 / 38 (7.89%)	1 / 41 (2.44%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2	1	3	1	2	0	0	0	0	0	0	5
Dysphagia
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	0 / 24 (0.00%)	5 / 38 (13.16%)	3 / 41 (7.32%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	4	0	5	3	2	0	0	0	0	0	0	1
Toothache
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	0	0	1	0	1	0	0	1	0	0	1
Rectal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	2
Flatulence
subjects affected / exposed	1 / 7 (14.29%)	3 / 77 (3.90%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	3	1	0	0	0	0	0	0	0	0	0	0
Ascites
subjects affected / exposed	1 / 7 (14.29%)	2 / 77 (2.60%)	0 / 24 (0.00%)	1 / 38 (2.63%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	2	0	1	1	0	0	0	0	0	0	0	0
Odynophagia
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	2 / 38 (5.26%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	2	0	2	2	0	0	0	0	0	0	0	2
Rash
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	1 / 24 (4.17%)	2 / 38 (5.26%)	1 / 41 (2.44%)	2 / 50 (4.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2	1	2	1	2	1	0	1	0	0	0	1
Pruritus
subjects affected / exposed	0 / 7 (0.00%)	6 / 77 (7.79%)	2 / 24 (8.33%)	1 / 38 (2.63%)	1 / 41 (2.44%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	6	2	1	1	3	0	0	0	0	0	0	2
Hyperhidrosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	2 / 38 (5.26%)	2 / 41 (4.88%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	1	2	2	2	0	0	0	0	0	0	1
Alopecia
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	2	0	0	1	1	0	0	0	0	0	0	2
Erythema
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0	0	4
Night sweats
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	0 / 38 (0.00%)	0 / 41 (0.00%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	1	0	0	2	0	0	1	0	0	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	2 / 24 (8.33%)	3 / 38 (7.89%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2	2	3	1	0	0	0	0	0	0	0	1
Pollakiuria
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	2 / 38 (5.26%)	2 / 41 (4.88%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	0	2	0	2	2	1	0	0	0	0	0	0	4
Acute kidney injury
subjects affected / exposed	1 / 7 (14.29%)	6 / 77 (7.79%)	0 / 24 (0.00%)	2 / 38 (5.26%)	2 / 41 (4.88%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	7	0	2	2	1	0	0	0	0	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 7 (0.00%)	7 / 77 (9.09%)	1 / 24 (4.17%)	4 / 38 (10.53%)	1 / 41 (2.44%)	3 / 50 (6.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	7	1	4	1	3	0	0	0	0	0	0	3
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	0	4	0	0	1	0	0	0	0	0	0	0	3
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	4	0	0	1	0	0	0	0	0	0	0	2
Urinary tract obstruction
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	2	0	0	0	0	0	0	0	0	0
Bladder spasm
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	2 / 7 (28.57%)	10 / 77 (12.99%)	3 / 24 (12.50%)	5 / 38 (13.16%)	2 / 41 (4.88%)	1 / 50 (2.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	2	10	3	6	4	1	1	0	1	0	0	0	1
Pain in extremity
subjects affected / exposed	1 / 7 (14.29%)	7 / 77 (9.09%)	4 / 24 (16.67%)	1 / 38 (2.63%)	4 / 41 (9.76%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	1	7	4	1	4	1	0	0	0	1	0	0	3
Muscular weakness
subjects affected / exposed	3 / 7 (42.86%)	11 / 77 (14.29%)	2 / 24 (8.33%)	4 / 38 (10.53%)	1 / 41 (2.44%)	2 / 50 (4.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	6 / 40 (15.00%)
occurrences all number	4	11	2	4	1	2	1	0	3	1	0	0	6
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	12 / 77 (15.58%)	2 / 24 (8.33%)	1 / 38 (2.63%)	4 / 41 (9.76%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	9 / 40 (22.50%)
occurrences all number	0	13	2	1	4	4	0	0	0	0	0	0	12
Back pain
subjects affected / exposed	1 / 7 (14.29%)	13 / 77 (16.88%)	2 / 24 (8.33%)	1 / 38 (2.63%)	5 / 41 (12.20%)	4 / 50 (8.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	2 / 40 (5.00%)
occurrences all number	1	14	2	1	5	4	1	0	1	0	0	1	2
Muscle spasms
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	2 / 38 (5.26%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2	0	3	1	1	0	0	0	0	0	0	1
Flank pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	2	0	2	0	0	0	0	0	0	0	0	0
Bone pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	2 / 38 (5.26%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	3 / 9 (33.33%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	2	0	3	1	0	0	0	3	0	0	0	2
Neck pain
subjects affected / exposed	2 / 7 (28.57%)	3 / 77 (3.90%)	1 / 24 (4.17%)	1 / 38 (2.63%)	2 / 41 (4.88%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	2	3	1	1	2	0	1	0	0	0	0	0	2
Tenosynovitis stenosans
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Groin pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	1	0	0	0	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	2 / 7 (28.57%)	5 / 77 (6.49%)	4 / 24 (16.67%)	7 / 38 (18.42%)	3 / 41 (7.32%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	3	5	4	7	3	1	0	0	0	0	0	0	4
Herpes zoster
subjects affected / exposed	2 / 7 (28.57%)	3 / 77 (3.90%)	3 / 24 (12.50%)	1 / 38 (2.63%)	4 / 41 (9.76%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	2	3	3	1	5	1	0	0	0	0	0	0	1
Sinusitis
subjects affected / exposed	2 / 7 (28.57%)	3 / 77 (3.90%)	2 / 24 (8.33%)	2 / 38 (5.26%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	2	3	3	2	2	0	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	1 / 7 (14.29%)	3 / 77 (3.90%)	1 / 24 (4.17%)	0 / 38 (0.00%)	1 / 41 (2.44%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 40 (7.50%)
occurrences all number	1	3	1	0	1	3	0	0	0	0	0	0	3
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	4 / 77 (5.19%)	0 / 24 (0.00%)	1 / 38 (2.63%)	6 / 41 (14.63%)	4 / 50 (8.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	4	0	1	7	4	0	0	1	0	0	0	1
Candida infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	1 / 24 (4.17%)	4 / 38 (10.53%)	0 / 41 (0.00%)	2 / 50 (4.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	1	4	0	2	0	0	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	1 / 7 (14.29%)	1 / 77 (1.30%)	0 / 24 (0.00%)	1 / 38 (2.63%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	2 / 40 (5.00%)
occurrences all number	1	1	0	1	2	0	0	0	0	0	0	1	2
Clostridium difficile infection
subjects affected / exposed	0 / 7 (0.00%)	5 / 77 (6.49%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	5	0	0	1	0	0	0	0	0	0	0	0
Covid-19
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	1 / 38 (2.63%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0	4
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	0 / 38 (0.00%)	3 / 41 (7.32%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	1	0	3	0	0	0	0	0	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	2 / 24 (8.33%)	0 / 38 (0.00%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	3	0	1	0	0	0	0	0	0	0	1
Clostridium difficile colitis
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	1 / 24 (4.17%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	2	1	2	0	0	0	0	0	0	0	0	0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	2
Tooth infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	0	0	0
Oral herpes
subjects affected / exposed	1 / 7 (14.29%)	1 / 77 (1.30%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	0
Folliculitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	1 / 38 (2.63%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 7 (0.00%)	2 / 77 (2.60%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	2
Ear infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Tinea versicolour
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Wound infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	2 / 7 (28.57%)	23 / 77 (29.87%)	8 / 24 (33.33%)	6 / 38 (15.79%)	6 / 41 (14.63%)	10 / 50 (20.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	11 / 40 (27.50%)
occurrences all number	2	28	11	9	7	13	0	0	5	0	0	1	14
Decreased appetite
subjects affected / exposed	3 / 7 (42.86%)	31 / 77 (40.26%)	12 / 24 (50.00%)	10 / 38 (26.32%)	3 / 41 (7.32%)	6 / 50 (12.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	4 / 9 (44.44%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	8 / 40 (20.00%)
occurrences all number	3	33	14	10	4	6	0	0	5	0	0	0	13
Hypophosphataemia
subjects affected / exposed	3 / 7 (42.86%)	19 / 77 (24.68%)	6 / 24 (25.00%)	5 / 38 (13.16%)	6 / 41 (14.63%)	5 / 50 (10.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	11 / 40 (27.50%)
occurrences all number	5	29	10	5	7	7	0	1	3	3	0	0	12
Hyponatraemia
subjects affected / exposed	4 / 7 (57.14%)	20 / 77 (25.97%)	10 / 24 (41.67%)	2 / 38 (5.26%)	2 / 41 (4.88%)	1 / 50 (2.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	6 / 40 (15.00%)
occurrences all number	4	26	11	3	3	1	0	1	4	4	0	0	8
Hypoalbuminaemia
subjects affected / exposed	2 / 7 (28.57%)	22 / 77 (28.57%)	9 / 24 (37.50%)	4 / 38 (10.53%)	2 / 41 (4.88%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	2	24	16	4	2	0	0	0	7	2	0	0	2
Hypocalcaemia
subjects affected / exposed	2 / 7 (28.57%)	23 / 77 (29.87%)	11 / 24 (45.83%)	4 / 38 (10.53%)	1 / 41 (2.44%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	2	25	11	4	1	2	0	0	0	0	0	0	2
Hypernatraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 77 (0.00%)	1 / 24 (4.17%)	2 / 38 (5.26%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	2	2	0	0	0	0	1	0	0	0	3
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	12 / 77 (15.58%)	6 / 24 (25.00%)	2 / 38 (5.26%)	1 / 41 (2.44%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	0	23	26	3	2	0	0	0	9	2	0	0	6
Hypomagnesaemia
subjects affected / exposed	2 / 7 (28.57%)	5 / 77 (6.49%)	4 / 24 (16.67%)	6 / 38 (15.79%)	2 / 41 (4.88%)	5 / 50 (10.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	4 / 40 (10.00%)
occurrences all number	3	5	4	7	3	9	1	0	0	0	0	0	6
Dehydration
subjects affected / exposed	2 / 7 (28.57%)	5 / 77 (6.49%)	4 / 24 (16.67%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 40 (5.00%)
occurrences all number	2	6	4	0	0	0	0	1	5	0	0	0	2
Hyperkalaemia
subjects affected / exposed	0 / 7 (0.00%)	6 / 77 (7.79%)	1 / 24 (4.17%)	1 / 38 (2.63%)	0 / 41 (0.00%)	1 / 50 (2.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	10	3	1	0	1	0	0	1	0	0	0	1
Hypermagnesaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 77 (1.30%)	2 / 24 (8.33%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	2	0	0	0	0	0	2	0	0	0	0
Malnutrition
subjects affected / exposed	0 / 7 (0.00%)	4 / 77 (5.19%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	4	0	0	0	0	0	0	0	0	0	0	0
Metabolic acidosis
subjects affected / exposed	1 / 7 (14.29%)	3 / 77 (3.90%)	0 / 24 (0.00%)	0 / 38 (0.00%)	0 / 41 (0.00%)	0 / 50 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 9 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	3	0	0	0	0	0	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Jan 2015

• Visit windows for screening, leukapheresis, and Month 1 imaging were expanded to provide greater logistical flexibility for the subjects and study sites. • Additional toxicity assessments prior to the infusion of axicabtagene ciloleucel were added. • Recovery criteria for discharge of subject from hospital after Day 7 were expanded. • Grade 3 or higher CRS was designated for expedited safety reporting.

27 Feb 2015

• Total sample size of the study was increased from approximately 118–124 to 118– 136 subjects based upon the contingency for additional cohort assessment in Phase 1. • Exclusion criterion was added for subjects with a history of aminoglycoside hypersensitivity. • Cyclophosphamide dose for the initial A1 cohort in Phase 1 was increased from 300 to 500 mg/m2/day. • Contingency for an additional cohort (B1) added in the event that a more intensive lymphodepletion therapy is deemed warranted. Subjects would receive 30 mg/kg cyclophosphamide Days –7 and -6 and 25 mg/m2 fludarabine Days –5 through –1. • Objective response rate, the primary endpoint of Phase 2, was specified to be based on investigator assessment; response rate according to the central reviewer was designated as a secondary endpoint.

27 Oct 2015

• Enrollment was aligned with the day of leukapheresis. • Eligibility criteria governing renal, hepatic, cardiac, pulmonary function were revised (adding oxygen saturation of > 92%, adding cardiac and pleural effusion criteria). • Deep vein thrombosis and pulmonary embolism were added as exclusion criteria. • Clarification that indwelling line or drain were exclusion criteria but Ommaya reservoir and dedicated central venous access catheters were permitted. • Clarifications were made for the concomitant use of corticosteroids and other agents with immunosuppressive potential for the management of CRS and neurologic events. • Expanded instructions were given for management of possible hypotension and renal insufficiency arising from CRS; specifically, use of IV saline was detailed. • Blood samples were added for measurement of cytokine levels, CRP, and antibodies to axicabtagene ciloleucel or bovine serum albumin. • Expanded instructions were given about subject requirements prior to initiating leukapheresis; namely, no significant infection before proceeding with leukapheresis. • Instructions were added for subjects eligible to receive a second treatment with axicabtagene ciloleucel.

18 Apr 2016

• IND and EudraCT numbers added to title page. • Several eligibility criteria in Section 5 were clarified as related to prior radiation or systemic therapy, history of hepatitis B or C, history of CNS lymphoma, and history of autoimmune disease. • Section 6 was updated with additional toxicity management guidance to include specific treatments for CRS, management of cardiac toxicity, management of neurologic events, deep vein thrombosis prophylaxis. • Description of histiocytosis haematophagic/hemophagocytic lymphohistiocytosis (HLH) was added. • Lumbar puncture when expect expansion, infiltration of the CAR T cells, and neurologic events were added. • Confirmation of eligibility with PET-CT. • Recommendation that CRP, ferritin, and LDH (if elevated at baseline) be monitored daily starting at Day 0 through hospitalization.

05 Jan 2022

• A Long-term Follow-up (LTFU) protocol, KT-US-982-5968 has been developed to allow for rollover of subjects to complete the 15-year follow-up after infusion of KTE-C19 on the KTE-C19-101/ZUMA-1 study. Subjects will be provided the opportunity to rollover to the LTFU protocol after a minimum of 24-months follow-up for safety follow-up and reduced burden of study-specific assessments.

22 Jun 2022

• References to availability of retreatment with axicabtagene ciloleucel in the KT-US-982-5968 long-term follow-up (LTFU) have been removed following a separate amendment to the LTFU protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults with Refractory Aggressive Non-Hodgkin Lymphoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma

Primary: Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma

Primary: Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) defined as Dose Limiting Toxicities (DLTs)

Primary: Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) defined as Dose Limiting Toxicities (DLTs)

Primary: Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades

Primary: Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades

Primary: Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

Primary: Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

Primary: Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

Primary: Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

Primary: Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

Primary: Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades

Secondary: Phase 2: Duration of Response (DOR) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 2: Duration of Response (DOR) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): ORR per Independent Radiological Review Committee (IRRC)

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): ORR per Independent Radiological Review Committee (IRRC)

Secondary: Phase 1 Study: ORR as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 1 Study: ORR as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator per Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator per the Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator per the Revised IWG Response Criteria for Malignant Lymphoma

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC per Cheson 2007

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC per Cheson 2007

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC per Cheson 2007

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC per Cheson 2007

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC per Cheson 2007

Secondary: Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC per Cheson 2007

Secondary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)

Secondary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)

Secondary: Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs

Secondary: Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs

Secondary: Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood

Secondary: Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood

Secondary: Percentage of Participants with Anti-Axicabtagene Ciloleucel Antibodies

Secondary: Percentage of Participants with Anti-Axicabtagene Ciloleucel Antibodies

Secondary: Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)

Secondary: Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)

Secondary: Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6)

Secondary: Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6)

Secondary: Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)

Secondary: Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)

Secondary: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)

Secondary: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)

Secondary: Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum

Secondary: Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum

Secondary: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)

Secondary: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)

Secondary: Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score

Secondary: Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score

Secondary: Percentage of Participants With Positive Replication Competent Retrovirus (RCR)

Secondary: Percentage of Participants With Positive Replication Competent Retrovirus (RCR)

Secondary: Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score

Secondary: Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults with Refractory Aggressive Non-Hodgkin Lymphoma