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Clinical Trial Results:
A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin Alfa in Adult Subjects With Steroid Refractory Chronic Graft Versus Host Disease

Summary
EudraCT number	2017-000763-33
Trial protocol	BE
Global end of trial date	13 Oct 2022

Results information
Results version number	v1(current)
This version publication date	21 Oct 2023
First version publication date	21 Oct 2023
Other versions

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

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Trial information

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Sponsor protocol code

20160283

ISRCTN number

US NCT number

NCT03422627

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States,

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

Study Director, Amgen Inc., medinfo@amgen.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

13 Oct 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Oct 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of the trial was to evaluate the safety and tolerability of multiple ascending doses of efavaleukin alfa in participants with steroid refractory chronic graft versus host disease (cGVHD) in order to estimate the maximum tolerated dose (MTD) and establish the recommended phase 2 dose (RP2D). Only the Phase 1b portion of this trial was completed. Phase 2 never opened.

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. All participants provided written informed consent before undergoing any study-related procedures, including screening procedures.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Apr 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Japan: 7

Country: Number of subjects enrolled

United States: 16

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled into this study at sites in Belgium, France, Japan, and the United States.

Screening details

Screening tests and procedures were performed up to 28 days preceding treatment. The study was planned to have a Phase 1b part and a Phase 2 part. The study was cancelled before enrolling participants into the Phase 2 part. Therefore, results presented only include data for the Phase 1b part.

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

Cohort 1

Arm description

Participants in Cohort 1 received efavaleukin alfa subcutaneously (SC) once every 2 weeks (Q2W) plus protocol permitted background therapy for 52 weeks. Four ascending dose levels of efavaleukin alfa were administered between the 5 cohorts as follows. Dose 1 (low dose), dose 2 (low-mid dose), dose 3 (high-mid dose), dose 4 (high dose). Participants in Cohort 1 received dose 2. At the discretion of the sponsor, following discussion and agreement between the principal investigator and medical monitor, participants that responded to efavaleukin alfa were permitted to continue to receive efavaleukin alfa treatment at their current dosing regimen for up to a maximum of 258 weeks (Q2W dose), if they remained eligible for extended dosing. Participants then completed the 6-week safety follow up after their last dose of efavaleukin alfa.

Arm type

Experimental

Investigational medicinal product name

Efavaleukin alfa

Investigational medicinal product code

Other name

AMG 592

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received efavaleukin alfa subcutaneously (SC) plus protocol permitted background therapy for 52 weeks.

Cohort 2

Arm description

Participants in Cohort 2 received efavaleukin alfa SC once every week (QW) plus protocol permitted background therapy for 52 weeks. Four ascending dose levels of efavaleukin alfa were administered between the 5 cohorts as follows. Dose 1 (low dose), dose 2 (low-mid dose), dose 3 (high-mid dose), dose 4 (high dose). Participants in Cohort 2 received dose 1. At the discretion of the sponsor, following discussion and agreement between the principal investigator and medical monitor, participants that responded to efavaleukin alfa were permitted to continue to receive efavaleukin alfa treatment at their current dosing regimen for up to a maximum of 259 weeks (QW dose), if they remained eligible for extended dosing. Participants then completed the 6-week safety follow up after their last dose of efavaleukin alfa.

Arm type

Experimental

Investigational medicinal product name

Efavaleukin alfa

Investigational medicinal product code

Other name

AMG 592

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received efavaleukin alfa subcutaneously (SC) plus protocol permitted background therapy for 52 weeks.

Cohort 3

Arm description

Participants in Cohort 3 received efavaleukin alfa SC Q2W plus protocol permitted background therapy for 52 weeks. Four ascending dose levels of efavaleukin alfa were administered between the 5 cohorts as follows. Dose 1 (low dose), dose 2 (low-mid dose), dose 3 (high-mid dose), dose 4 (high dose). Participants in Cohort 3 received dose 3. At the discretion of the sponsor, following discussion and agreement between the principal investigator and medical monitor, participants that responded to efavaleukin alfa were permitted to continue to receive efavaleukin alfa treatment at their current dosing regimen for up to a maximum of 258 weeks (Q2W dose), if they remained eligible for extended dosing. Participants then completed the 6-week safety follow up after their last dose of efavaleukin alfa.

Arm type

Experimental

Investigational medicinal product name

Efavaleukin alfa

Investigational medicinal product code

Other name

AMG 592

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received efavaleukin alfa subcutaneously (SC) plus protocol permitted background therapy for 52 weeks.

Cohort 4

Arm description

Participants in Cohort 4 received efavaleukin alfa SC QW plus protocol permitted background therapy for 52 weeks. Four ascending dose levels of efavaleukin alfa were administered between the 5 cohorts as follows. Dose 1 (low dose), dose 2 (low-mid dose), dose 3 (high-mid dose), dose 4 (high dose). Participants in Cohort 4 received dose 2. At the discretion of the sponsor, following discussion and agreement between the principal investigator and medical monitor, participants that responded to efavaleukin alfa were permitted to continue to receive efavaleukin alfa treatment at their current dosing regimen for up to a maximum of 259 weeks (QW dose), if they remained eligible for extended dosing. Participants then completed the 6-week safety follow up after their last dose of efavaleukin alfa.

Arm type

Experimental

Investigational medicinal product name

Efavaleukin alfa

Investigational medicinal product code

Other name

AMG 592

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received efavaleukin alfa subcutaneously (SC) plus protocol permitted background therapy for 52 weeks.

Cohort 5

Arm description

Participants in Cohort 5 received efavaleukin alfa SC Q2W plus protocol permitted background therapy for 52 weeks. Four ascending dose levels of efavaleukin alfa were administered between the 5 cohorts as follows. Dose 1 (low dose), dose 2 (low-mid dose), dose 3 (high-mid dose), dose 4 (high dose). Participants in Cohort 5 received dose 4. At the discretion of the sponsor, following discussion and agreement between the principal investigator and medical monitor, participants that responded to efavaleukin alfa were permitted to continue to receive efavaleukin alfa treatment at their current dosing regimen for up to a maximum of 258 weeks (Q2W dose), if they remained eligible for extended dosing. Participants then completed the 6-week safety follow up after their last dose of efavaleukin alfa.

Arm type

Experimental

Investigational medicinal product name

Efavaleukin alfa

Investigational medicinal product code

Other name

AMG 592

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received efavaleukin alfa subcutaneously (SC) plus protocol permitted background therapy for 52 weeks.

Number of subjects in period 1	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Started	7	7	7	6	5
Completed Wk52 Opted for Extended Dosing	2	1 ^[1]	2 ^[2]	3	0 ^[3]
Completed Wk52 Didn't Opt Extend Dosing	0 ^[4]	1 ^[5]	1 ^[6]	0 ^[7]	1
Completed	2	2	3	3	1
Not completed	5	5	4	3	4
Adverse event, serious fatal	-	1	1	-	-
Consent withdrawn by subject	-	-	-	1	-
Ineligibility Determined	-	1	-	-	-
Adverse event, non-fatal	2	1	-	-	2
Requirement for Alternative Therapy	1	1	2	-	-
Protocol-specified Criteria	1	1	-	-	2
Disease Progression	1	-	1	2	-

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed Week 52 who did not opt for extended dosing.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed Week 52 who did not opt for extended dosing.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed Week 52 who did not opt for extended dosing.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed Week 52 who did not opt for extended dosing.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed Week 52 who did not opt for extended dosing.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed Week 52 who did not opt for extended dosing.
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Number of participants who completed Week 52 who did not opt for extended dosing.

Baseline characteristics

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Reporting group title

Cohort 1

Reporting group description

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Reporting group title

Cohort 4

Reporting group description

Reporting group title

Cohort 5

Reporting group description

Reporting group values	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Total
Number of subjects	7	7	7	6	5	32
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	6	5	7	6	2	26
From 65-84 years	1	2	0	0	3	6
85 years and over	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	48.9 ± 12.5	52.9 ± 17.4	49.4 ± 12.2	55.3 ± 7.6	64.6 ± 5.9	-
Sex: Female, Male
Units: participants
Female	3	3	2	3	1	12
Male	4	4	5	3	4	20
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	0	0	0	1
Not Hispanic or Latino	1	5	6	6	5	23
Unknown or Not Reported	5	2	1	0	0	8
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	1	2	2	2	7
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0
White	2	4	4	4	3	17
More than one race	0	0	0	0	0	0
Unknown or Not Reported	5	2	1	0	0	8

End points

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Reporting group title

Cohort 1

Reporting group description

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Reporting group title

Cohort 4

Reporting group description

Reporting group title

Cohort 5

Reporting group description

Primary: Phase 1b: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)

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End point title

Phase 1b: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) ^[1]

End point description

A DLT was defined as a: - Non-hematological toxicity ≥grade-4(per common terminology criteria for adverse events [CTCAE] v4.03) related to efavaleukin alfa. Non-hematological lab abnormalities without clinical significance weren't considered DLTs. - Hematological toxicity ≥grade 4 related to efavaleukin alfa defined as decreases in peripheral counts (absolute neutrophil count or platelets) persisting longer than 72 hrs, as measured by 2 separate results, that were not related to malignant disease relapse, infection, or other etiologies. - Constitutional events (ie, fever, fatigue) ≥grade 3 that were classified as serious adverse events by the investigator and related to efavaleukin alfa. - Infection is considered an expected complication of chronic graft versus host disease (cGVHD) and its treatment. Only grade 4 or 5 infections considered by the investigator to be related to efavaleukin alfa were reviewed by the dose level review meeting to determine whether it was considered a DLT.

End point type

Primary

End point timeframe

Up to 4 weeks after first dose of study drug administration

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 analysis was planned for this endpoint.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Number of subjects analysed	6	7	6	6	3
Units: participants	0	0	0	0	0

No statistical analyses for this end point

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-related Adverse Event (AE)

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End point title

Phase 1b: Number of Participants Who Experienced a Treatment-related Adverse Event (AE) ^[2]

End point description

A treatment-related AE was any untoward medical occurrence in a clinical study participant deemed to have a possibly causal relationship to the study treatment as determined by the investigator. Measured in the safety analysis set, which included all participants who received at least 1 dose of efavaleukin alfa.

End point type

Primary

End point timeframe

Day 1 until the end of study; median (min, max) duration was 38.01 (3.27, 139.81) weeks

Notes
[2] - 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 analysis was planned for this endpoint.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Number of subjects analysed	7	7	7	6	5
Units: participants	5	5	6	6	4

No statistical analyses for this end point

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-emergent AE

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End point title

Phase 1b: Number of Participants Who Experienced a Treatment-emergent AE ^[3]

End point description

A treatment-emergent AE was any untoward medical occurrence in a clinical study participant that occurred after first dose. Measured in the safety analysis set, which included all participants who received at least 1 dose of efavaleukin alfa.

End point type

Primary

End point timeframe

Day 1 until the end of study; median (min, max) duration was 38.01 (3.27, 139.81) weeks

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 analysis was planned for this endpoint.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Number of subjects analysed	7	7	7	6	5
Units: participants	6	6	7	6	4

No statistical analyses for this end point

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-emergent Serious AE

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End point title

Phase 1b: Number of Participants Who Experienced a Treatment-emergent Serious AE ^[4]

End point description

A treatment-emergent serious AE was any untoward medical occurrence in a clinical study participant that occurred after first dose that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or another medically important serious event. Measured in the safety analysis set, which included all participants who received at least 1 dose of efavaleukin alfa.

End point type

Primary

End point timeframe

Day 1 until the end of study; median (min, max) duration was 38.01 (3.27, 139.81) weeks

Notes
[4] - 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 analysis was planned for this endpoint.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Number of subjects analysed	7	7	7	6	5
Units: participants	5	3	3	4	3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Mortality: from enrollment until the end of study; median (min, max) duration was 38.44 (3.56, 140.09) weeks. Serious and non-serious adverse events: from Day 1 until the end of study; median (min, max) duration was 38.01 (3.27, 139.81) weeks.

Adverse event reporting additional description

All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Cohort 1

Reporting group description

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Reporting group title

Cohort 4

Reporting group description

Reporting group title

Cohort 5

Reporting group description

Serious adverse events	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 7 (71.43%)	3 / 7 (42.86%)	3 / 7 (42.86%)	4 / 6 (66.67%)	3 / 5 (60.00%)
number of deaths (all causes)	0	1	1	0	0
number of deaths resulting from adverse events
Investigations
Liver function test increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vena cava thrombosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Nervous system disorders
Seizure
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Chronic graft versus host disease
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Graft versus host disease in skin
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic graft versus host disease in skin
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Large intestine polyp
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Klebsiella bacteraemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Candida sepsis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia parainfluenzae viral
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 7 (85.71%)	6 / 7 (85.71%)	7 / 7 (100.00%)	6 / 6 (100.00%)	3 / 5 (60.00%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	1	0	0	1
Vena cava thrombosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Hypotension
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	0
Haematoma
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Venous thrombosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
General disorders and administration site conditions
Injection site swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	7
Asthenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Disease progression
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Face oedema
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	0	0	0
Fatigue
subjects affected / exposed	1 / 7 (14.29%)	3 / 7 (42.86%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	1	4	0	2	0
Gait disturbance
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Injection site erythema
subjects affected / exposed	3 / 7 (42.86%)	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	4	1	0	4	0
Injection site pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Injection site pruritus
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Injection site rash
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	1	1	1	0
Injection site reaction
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	4 / 7 (57.14%)	2 / 6 (33.33%)	2 / 5 (40.00%)
occurrences all number	0	9	6	2	2
Localised oedema
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Oedema peripheral
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 5 (40.00%)
occurrences all number	5	1	0	1	2
Pyrexia
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	7	3	4	0	1
Malaise
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Immune system disorders
Graft versus host disease in skin
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Acute graft versus host disease oral
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Chronic graft versus host disease
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	1	0	0	0
Chronic graft versus host disease in skin
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	1	1	0	1	0
Drug hypersensitivity
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Graft versus host disease
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Graft versus host disease in eye
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Graft versus host disease in gastrointestinal tract
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Reproductive system and breast disorders
Cervix oedema
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Wheezing
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Vasomotor rhinitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Pulmonary thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Pulmonary embolism
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Productive cough
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	2	0	0	2
Pneumonitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Pharyngeal enanthema
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Nasal congestion
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	2	0	0	0
Laryngeal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Dyspnoea
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	2	1	0	0
Dysphonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Cough
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	2	2	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	0	0
Depression
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	1	0	0
Delirium
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Agitation
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	0	1	1	2	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	0	1	0	2	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
C-reactive protein increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Enterovirus test positive
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Eosinophil count increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Human rhinovirus test positive
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Weight increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Injury, poisoning and procedural complications
Joint injury
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Ligament sprain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Pelvic fracture
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Procedural nausea
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Procedural pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Skin laceration
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Spinal compression fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Congenital, familial and genetic disorders
Arteriovenous malformation
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Cardiac disorders
Cardiac disorder
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Palpitations
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	1	0	1
Tachycardia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Nervous system disorders
Migraine
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Monoparesis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Headache
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	2	2	1	0
Facial paresis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Dizziness
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Aphasia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Lethargy
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Motor dysfunction
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Presyncope
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Nervous system disorder
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	1	3	1	1	0
Eosinophilia
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	2	0	0	0
Neutropenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Thrombocytopenia
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Iron deficiency anaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Ear and labyrinth disorders
Deafness unilateral
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Eye disorders
Blepharitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Ocular hypertension
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Dry eye
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	1	1	0	1
Eye pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	1	0	0
Keratitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Meibomianitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Ocular hyperaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Cataract
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	1	0	0
Vision blurred
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	2	0	0	0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	0	0	1
Abdominal pain lower
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Constipation
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	2	1	0	0	1
Diarrhoea
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	2	0	0
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Dysphagia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0
Large intestine polyp
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Melaena
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Nausea
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	1	1	1	0
Odynophagia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Oral lichen planus
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Oral pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Abdominal pain
subjects affected / exposed	3 / 7 (42.86%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	4	1	0	1	0
Periodontal disease
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Vomiting
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	1	2	1	2	0
Toothache
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Hepatic cytolysis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Hepatomegaly
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	0
Erythema
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	2	2	0	1	0
Dermatitis acneiform
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Drug eruption
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	0
Hyperhidrosis
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	0	0
Ingrowing nail
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	1	0	0
Skin lesion
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	2	0	0	0
Skin induration
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Rash pruritic
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Rash papular
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Rash maculo-papular
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	1	2	0	2	0
Rash
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	3 / 7 (42.86%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	3	0	0
Pruritus
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 5 (0.00%)
occurrences all number	0	3	0	2	0
Lichenoid keratosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Night sweats
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Palmar erythema
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Plantar erythema
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Urticaria
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	2	0	0
Skin ulcer
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	1	0	0	0	1
Renal and urinary disorders
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Renal failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Nephrolithiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Incontinence
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Chronic kidney disease
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Acute kidney injury
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	1	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	2 / 7 (28.57%)	1 / 6 (16.67%)	2 / 5 (40.00%)
occurrences all number	0	2	2	1	2
Trismus
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Scleroderma
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	1	0	0	0
Pain in extremity
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	5	0	1	0	0
Myalgia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Muscle spasms
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	1	2	0	1	0
Back pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	1	1	1	0
Infections and infestations
Bacterial infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Catheter site infection
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	2
Clostridium difficile colitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Cytomegalovirus infection reactivation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Ear infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Enterococcal sepsis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Escherichia urinary tract infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Fungal disease carrier
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Herpes simplex
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Influenza
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	1	0	0
Keratitis bacterial
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Lip infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Localised infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Mastitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Onychomycosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Pathogen resistance
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Pharyngitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Rhinitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Skin infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Subcutaneous abscess
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Tinea pedis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Tracheitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	1	0	0	1
Vascular device infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Viral infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Oral herpes
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	2	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 7 (42.86%)	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	3	2	0	0	0
Zinc deficiency
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Steroid diabetes
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)
occurrences all number	0	0	0	0	2
Hypophosphataemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	3	0	1	1	0
Hyponatraemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 5 (40.00%)
occurrences all number	0	0	1	0	2
Hypocalcaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	1	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Hyperuricaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Diabetes mellitus
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Dehydration
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0

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Were there any global substantial amendments to the protocol? Yes

22 Aug 2017

- Key Sponsor Contact and supporting information was updated - The primary objective for the phase 1b portion of the study was updated to clarify the intent to use the phase 1 data to determine the maximum tolerated dose and support the determination of the recommended phase 2 dose. - Updated the phase 2 primary endpoint and all related descriptions to reflect a change to analyze the best overall response rate (ORR) during the study. In addition, week 8 is included in the secondary endpoint analysis. - Updated the maximum dose to be administered in the study. - To accommodate the change in formulation, the information regarding product packaging was updated to indicate that AMG 592 is a liquid formulation that was provided in glass vials. - Updated the cGVHD response assessment - Updated Schedule of Activities and eligibility - Clarified that pharmacokinetics was determined using serum samples rather than plasma samples. - Subgroup analyses were updated to include prior radiation status and conditioning regimen (myeloablative versus non-myeloablative). - The Safety Follow-Up Visit was updated to require in-clinic assessment of the participants rather than a phone call assessment. Urine pregnancy testing was also added for women of childbearing potential to confirm pregnancy status up to 6 weeks posttreatment.

04 Dec 2018

- Changes to study design: Increased Phase 1b cohort size of future dosing cohorts from n = 3 to up to n = 6, clarified that dosing cohorts may be added or removed at any time after completion of the first cohorts, removed optional cohorts 1b/2b,a dded 1a/2a dose expansion cohorts to align with DLRM decision, made final dose expansion cohort of n = 10 participants optional. - Clarified entry criteria and study conduct rules - Revised entry criterion 104, definition of moderate to severe steroid refractory cGVHD: o Removed requirement for diagnosis within the past 2 years o Removed requirement to be steroid refractory within the past 12 months - Modified alcohol restrictions after the 4-week DLT evaluation period in eligible participants - Increased visit window duration after the week 16 visit - Clarified that direct genital exams are not require as part of the Staging and National Institutes of Health (NIH) Form A evaluations. - Miscellaneous changes made to schedule of assessments - Changed to 1-sided test with a significance level of 0.025

26 Aug 2019

- Updated the phase 1b part of the study to allow for continued access to AMG 592 for up to an additional 52 weeks following week 50 (Q2W dose) or week 51 (QW dose) at the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, for participants who were responding to AMG 592 (as assessed by week 50) and who wished to continue on treatment. - Clarified that phase 1b participants who were still receiving or planned to receive AMG 592 treatment at the time that the RP2D was established may change their AMG 592 dose to the RP2D dose at the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, and may continue study treatment until completion of the week104/EOT visit. - Corrected inconsistencies in the Schedules of Assessments for the phase 1b part of the study with regard to corticosteroid use, adverse events, serious adverse events, and disease-related events. - Clarified requirements for recording and reporting disease-related events

08 Dec 2020

- Added cohort 5 for the purpose of exploring the safety, pharmacokinetics (PK), pharmacodynamics (PD) of higher efavaleukin alfa (AMG 592) doses in participants with steroid refractory chronic graft versus host disease. - Included description of cohort 5 and enrollment to cohort 5 to study design - Removed statement regarding efavaleukin alfa dose level weekly limit - Updated study schema phase 1b to include cohort 5 - Increased the sample size from up to 34 participants to approximately 40 participants sample size to reflect the addition of cohort 5 - Updated human exposure and justification for investigational product dose sections to support the cohort 5 dose - Edited a secondary PK endpoint to be consistent to evaluate PK parameters on week 4 instead of week 16 - Updated risk assessment - Updated footnotes and timing windows for assessments - Updated eligibility criteria - Clarified that the medical monitor was to be informed when efavaleukin alfa was withheld for acute clinical events - Minor corrections to statistical considerations section to provide additional clarity - Provided more details for serious adverse event reporting via the electronic data collection tool - Clarified that the disease-related events table presented in Appendix 11 was not inclusive

22 Jun 2021

- Updated the phase 1b part of the study to allow for continued access to efavaleukin alfa for up to an additional 156 weeks following week 102 (Q2W dose) or week 103 (QW dose) at the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, for participants who were responding to efavaleukin alfa (as assessed by week 104) and who wished to continue on treatment.

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 Trial Results:
A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin Alfa in Adult Subjects With Steroid Refractory Chronic Graft Versus Host Disease

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Clinical Trial Results: A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin Alfa in Adult Subjects With Steroid Refractory Chronic Graft Versus Host Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)

Primary: Phase 1b: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-related Adverse Event (AE)

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-related Adverse Event (AE)

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-emergent AE

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-emergent AE

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-emergent Serious AE

Primary: Phase 1b: Number of Participants Who Experienced a Treatment-emergent Serious AE

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin Alfa in Adult Subjects With Steroid Refractory Chronic Graft Versus Host Disease