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Clinical Trial Results:
A Phase 3, Randomized, Open-Label, Active-Controlled Study of ALXN1210 Versus Eculizumab in Complement Inhibitor-Naïve Adult Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Summary
EudraCT number	2016-002025-11
Trial protocol	GB DE SE BE CZ DK PT FI ES NL AT EE PL IT
Global end of trial date	28 Feb 2023

Results information
Results version number	v3(current)
This version publication date	20 Jun 2024
First version publication date	08 Jul 2020
Other versions	v1 , v2
Version creation reason

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

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Trial information

Top of page

Sponsor protocol code

ALXN1210-PNH-301

ISRCTN number

-

US NCT number

NCT02946463

WHO universal trial number (UTN)

-

Sponsor organisation name

Alexion Pharmaceuticals Inc.

Sponsor organisation address

121 Seaport Boulevard, Boston, MA, United States, 02210

Public contact

European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 147100606, clinicaltrials.eu@alexion.com

Scientific contact

European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 147100606, clinicaltrials.eu@alexion.com

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

No

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

No

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

Yes

Analysis stage

Final

Date of interim/final analysis

28 Feb 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Jan 2018

Global end of trial reached?

Yes

Global end of trial date

28 Feb 2023

Was the trial ended prematurely?

No

Main objective of the trial

The primary purpose of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult participants with PNH who had never been treated with a complement inhibitor (treatment-naïve).

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the countries in which the study was conducted.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

20 Dec 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 5

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Czechia: 2

Country: Number of subjects enrolled

Estonia: 2

Country: Number of subjects enrolled

France: 28

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Argentina: 4

Country: Number of subjects enrolled

Australia: 1

Country: Number of subjects enrolled

Brazil: 16

Country: Number of subjects enrolled

Canada: 4

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Japan: 34

Country: Number of subjects enrolled

Malaysia: 30

Country: Number of subjects enrolled

Mexico: 2

Country: Number of subjects enrolled

Russian Federation: 46

Country: Number of subjects enrolled

Singapore: 2

Country: Number of subjects enrolled

Korea, Republic of: 40

Country: Number of subjects enrolled

Taiwan: 9

Country: Number of subjects enrolled

Thailand: 8

Country: Number of subjects enrolled

Türkiye: 1

Country: Number of subjects enrolled

United States: 5

Worldwide total number of subjects

272

EEA total number of subjects

65

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

2

Adults (18-64 years)

234

From 65 to 84 years

35

85 years and over

1

Subject disposition

Top of page

Recruitment details

24 adult and 2 peadiatric participants rolled over from other Alexion ongoing studies of ravulizumab intravenous in participants with PNH into the extension period of this study and received weight-based doses of ravulizumab for up to 5 years.

Screening details

Due to database limitations, data for the 26 rolled over participants are reported under "Ravulizumab: Extension Period" and data are reported under separate columns in the Adverse Event module.

Period 1 title

Primary Evaluation

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ravulizumab: Primary Evaluation

Arm description

Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

Arm type

Experimental

Investigational medicinal product name

Ravulizumab

Investigational medicinal product code

Other name

Ultomiris, ALXN1210

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received weight-based loading doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

Eculizumab: Primary Evaluation

Arm description

Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

Arm type

Experimental

Investigational medicinal product name

Eculizumab

Investigational medicinal product code

Other name

Soliris

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 600-mg induction doses of eculizumab on Days 1, 8, 15, and 22, followed by 900-mg maintenance doses of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

Number of subjects in period 1 ^[1]	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation
Started	125	121
Received at Least 1 Dose of Study Drug	125	121
Completed	125	119
Not completed	0	2
Physician decision	-	1
Consent withdrawn by subject	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 24 adult and 2 peadiatric participants rolled over from other Alexion ongoing studies of ravulizumab intravenous in participants with PNH into the extension period of this study. The worldwide number enrolled includes the 26 participants that rolled into the extension period.

Period 2 title

Extension Period

Is this the baseline period?

No

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ravulizumab: Extension Period

Arm description

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years.

Arm type

Experimental

Investigational medicinal product name

Ravulizumab

Investigational medicinal product code

Other name

Ultomiris, ALXN1210

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered every 8 weeks for up to 5 years.

Eculizumab/Ravulizumab: Extension Period

Arm description

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years.

Arm type

Experimental

Investigational medicinal product name

Ravulizumab

Investigational medicinal product code

Other name

Ultomiris, ALXN1210

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received weight-based loading doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based maintenance doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 5 years.

Number of subjects in period 2 ^[2]	Ravulizumab: Extension Period	Eculizumab/Ravulizumab: Extension Period
Started	124	119
Received at Least 1 Dose of Study Drug	150	119
Completed	132	102
Not completed	18	17
Physician decision	1	4
Consent withdrawn by subject	4	3
Adverse event, non-fatal	1	2
Death during the study	4	4
Pregnancy	3	1
Unspecified	4	3
Lost to follow-up	1	-
Joined	26	0
Rolled over from other Alexion studies	26	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 1 patient in the Ravulizumab group discontinued treatment but completed Week 26. The participant did not continue to the Extension Period but did not discontinue the study.

Baseline characteristics

Top of page

Reporting group title

Ravulizumab: Primary Evaluation

Reporting group description

Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

Reporting group title

Eculizumab: Primary Evaluation

Reporting group description

Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

Reporting group values	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation	Total
Number of subjects	125	121	246
Age categorical
Measure Description: Age at first infusion of study drug
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	110	102	212
From 65-84 years	15	18	33
85 years and over	0	1	1
Age continuous
Measure Description: Age at first infusion of study drug
Units: years
arithmetic mean (standard deviation)	44.8 ± 15.16	46.2 ± 16.24	-
Gender categorical
Units: Subjects
Female	60	52	112
Male	65	69	134
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	5	13	18
Not Hispanic or Latino	116	102	218
Unknown or Not Reported	4	6	10
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1	1	2
Asian	72	57	129
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	2	4	6
White	43	51	94
More than one race	0	0	0
Unknown or Not Reported	7	8	15

End points

Top of page

Reporting group title

Ravulizumab: Primary Evaluation

Reporting group description

Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

Reporting group title

Eculizumab: Primary Evaluation

Reporting group description

Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

Reporting group title

Ravulizumab: Extension Period

Reporting group description

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years.

Reporting group title

Eculizumab/Ravulizumab: Extension Period

Reporting group description

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years.

Primary: Proportion Of Participants With Normalization Of LDH Levels

Top of page

End point title

Proportion Of Participants With Normalization Of LDH Levels

End point description

Lactate dehydrogenase is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH was 246 units/liter.

End point type

Primary

End point timeframe

Day 29 through Day 183

End point values	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation
Number of subjects analysed	125	121
Units: Proportion of Participants
number (confidence interval 95%)	0.536 (0.459 to 0.612)	0.494 (0.417 to 0.570)

Analysis of Normalization Of LDH

Statistical analysis description

A minimum of 142 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab.

Comparison groups

Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.187

Confidence interval

level

95%

sides

2-sided

lower limit

0.796

upper limit

1.769

Notes
[1] - LDH-N was analyzed using a generalized estimating equation approach. The model included the following terms: treatment group, history of transfusion (as a categorical variable based on the stratification factor levels), and baseline LDH level (as a continuous variable). Noninferiority margin was based on the lower bound of the 95% confidence interval (CI) for the OR of ravulizumab versus eculizumab for LDH normalization being greater than an OR of 0.39.

Primary: Percentage Of Participants Who Achieved Transfusion Avoidance

Top of page

End point title

Percentage Of Participants Who Achieved Transfusion Avoidance

End point description

The co-primary end point of transfusion avoidance (TA) was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines through Day 183.

End point type

Primary

End point timeframe

Baseline through Day 183

End point values	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation
Number of subjects analysed	125	121
Units: Percentage of Participants
number (confidence interval 95%)	73.6 (65.87 to 81.33)	66.1 (57.68 to 74.55)

Analysis of TA

Statistical analysis description

A minimum of 193 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab. The difference of percentages were calculated using stratified Newcombe CI method. Stratification factors were: observed stratification groups of packed red blood cells (pRBC)/whole blood units transfused in the 1 year prior to first dose of study drug and screening LDH levels.

Comparison groups

Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Parameter type

Treatment difference

Point estimate

6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.66

upper limit

18.14

Notes
[2] - Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -20%.

Secondary: Percentage Of Participants With Breakthrough Hemolysis

Top of page

End point title

Percentage Of Participants With Breakthrough Hemolysis

End point description

Breakthrough hemolysis (BTH) was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 gram/deciliter (g/dL)], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥ 2 × ULN, after prior LDH reduction to < 1.5 × ULN on therapy.

End point type

Secondary

End point timeframe

Baseline through Day 183

End point values	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation
Number of subjects analysed	125	121
Units: Percentage Of Participants
number (confidence interval 95%)	4.0 (0.56 to 7.44)	10.7 (5.23 to 16.26)

Analysis of BTH

Statistical analysis description

The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.

Comparison groups

Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Treatment Difference

Point estimate

-6.7

Confidence interval

level

95%

sides

2-sided

lower limit

-14.21

upper limit

0.18

Notes
[3] - Noninferiority margin was based on the upper bound of the 95% CI. Noninferiority margin was 20%.

Secondary: Percent Change From Baseline In LDH Levels

Top of page

End point title

Percent Change From Baseline In LDH Levels

End point description

Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on mixed model for repeated measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.

End point type

Secondary

End point timeframe

Baseline, Day 183

End point values	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation
Number of subjects analysed	125	121
Units: Percent Change
least squares mean (confidence interval 95%)	-76.84 (-79.96 to -73.73)	-76.02 (-79.20 to -72.83)

Analysis of LDH

Comparison groups

Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Parameter type

Treatment Difference

Point estimate

-0.83

Confidence interval

level

95%

sides

2-sided

lower limit

-5.21

upper limit

3.56

Notes
[4] - Noninferiority margin was based on the upper bound of the 95% CI. Noninferiority margin was 20%.

Secondary: Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy-Fatigue

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End point title

Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy-Fatigue

End point description

The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.

End point type

Secondary

End point timeframe

Baseline, Day 183

End point values	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation
Number of subjects analysed	125	121
Units: Units On A Scale
least squares mean (confidence interval 95%)	7.07 (5.55 to 8.60)	6.40 (4.85 to 7.96)

Analysis of FACIT-Fatigue

Comparison groups

Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

Parameter type

Treatment Difference

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

-1.21

upper limit

2.55

Notes
[5] - Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -5%.

Secondary: Percentage Of Participants With Stabilized Hemoglobin Levels

Top of page

End point title

Percentage Of Participants With Stabilized Hemoglobin Levels

End point description

Stabilized hemoglobin was defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through Day 183.

End point type

Secondary

End point timeframe

Baseline through Day 183

End point values	Ravulizumab: Primary Evaluation	Eculizumab: Primary Evaluation
Number of subjects analysed	125	121
Units: Percentage of Participants
number (confidence interval 95%)	68.0 (59.82 to 76.18)	64.5 (55.93 to 72.99)

Analysis of Stabilized Hemoglobin Levels

Statistical analysis description

The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.

Comparison groups

Ravulizumab: Primary Evaluation v Eculizumab: Primary Evaluation

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

Treatment Difference

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-8.8

upper limit

14.64

Notes
[6] - Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -20%.

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline up to Day 2045

Adverse event reporting additional description

TEAEs reported below include those that occurred during or after first infusion of study treatment up to Day 2045 (end of study). All cause mortality and number of participants who discontinued due to AEs in the AE section reports number of participants during study and number of participants who died after they were discontinued from study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Ravulizumab: Primary Evaluation

Reporting group description

Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

Reporting group title

Ravulizumab-Pediatrics

Reporting group description

Participants in this group rolled over from other ongoing studies of ravulizumab intravenous in participants with PNH into the extension period of this study and received weight-based doses of ravulizumab for up to 5 years.

Reporting group title

Eculizumab/Ravulizumab: Extension Period

Reporting group description

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years.

Reporting group title

Ravulizumab-Adults

Reporting group description

Participants in this group rolled over from other ongoing studies of ravulizumab intravenous in participants with PNH into the extension period of this study and received weight-based doses of ravulizumab for up to 5 years.

Reporting group title

Eculizumab: Primary Evaluation

Reporting group description

Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

Reporting group title

Ravulizumab/Ravulizumab: Extension Period

Reporting group description

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants received weight-based doses of ravulizumab for up to 5 years.

Serious adverse events	Ravulizumab: Primary Evaluation	Ravulizumab-Pediatrics	Eculizumab/Ravulizumab: Extension Period	Ravulizumab-Adults	Eculizumab: Primary Evaluation	Ravulizumab/Ravulizumab: Extension Period
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 125 (8.80%)	0 / 2 (0.00%)	43 / 119 (36.13%)	2 / 24 (8.33%)	9 / 121 (7.44%)	52 / 124 (41.94%)
number of deaths (all causes)	0	0	4	0	0	4
number of deaths resulting from adverse events	0	0	4	0	0	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	1 / 121 (0.83%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Adenocarcinoma gastric
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Sinonasal papilloma
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	2 / 119 (1.68%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	2 / 121 (1.65%)	4 / 124 (3.23%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 3	0 / 0	0 / 2	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Immune system disorders
Allergy to vaccine
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	1 / 1
Pulmonary embolism
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Nasal septum deviation
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Injury, poisoning and procedural complications
Skin laceration
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Femur fracture
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	2 / 119 (1.68%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Road traffic accident
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Congenital, familial and genetic disorders
Branchial cyst
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cardiac disorders
Myocardial ischaemia
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Angina unstable
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Nervous system disorders
Migraine
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cerebral venous thrombosis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Headache
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	2 / 119 (1.68%)	0 / 24 (0.00%)	0 / 121 (0.00%)	7 / 124 (5.65%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 2	0 / 0	0 / 0	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aplastic anaemia
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	1 / 119 (0.84%)	1 / 24 (4.17%)	0 / 121 (0.00%)	5 / 124 (4.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 1	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolysis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	2 / 119 (1.68%)	0 / 24 (0.00%)	0 / 121 (0.00%)	4 / 124 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breakthrough haemolysis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Gastrointestinal disorders
Neutropenic colitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	1 / 121 (0.83%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal discomfort
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Ileus
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Obstructive pancreatitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Gastric varices
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	1 / 24 (4.17%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	4 / 119 (3.36%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Renal and urinary disorders
Renal colic
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paroxysmal nocturnal haemoglobinuria
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	1 / 121 (0.83%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Musculoskeletal and connective tissue disorders
Osteonecrosis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	1 / 121 (0.83%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	1 / 121 (0.83%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	1 / 121 (0.83%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Leptospirosis
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	6 / 119 (5.04%)	0 / 24 (0.00%)	1 / 121 (0.83%)	5 / 124 (4.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 8	0 / 0	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic infection
subjects affected / exposed	1 / 125 (0.80%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	1 / 121 (0.83%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	2 / 119 (1.68%)	0 / 24 (0.00%)	0 / 121 (0.00%)	3 / 124 (2.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	0 / 121 (0.00%)	6 / 124 (4.84%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Coronavirus infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Dengue fever
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Chikungunya virus infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Appendicitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Influenza
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningococcal sepsis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	1 / 1
Intracranial infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	1 / 1
Urinary tract infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	2 / 119 (1.68%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Furuncle
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Fungal endocarditis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Endophthalmitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Endometritis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cystitis escherichia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Sinusitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Haemochromatosis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	1 / 119 (0.84%)	0 / 24 (0.00%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0

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

Non-serious adverse events	Ravulizumab: Primary Evaluation	Ravulizumab-Pediatrics	Eculizumab/Ravulizumab: Extension Period	Ravulizumab-Adults	Eculizumab: Primary Evaluation	Ravulizumab/Ravulizumab: Extension Period
Total subjects affected by non serious adverse events
subjects affected / exposed	87 / 125 (69.60%)	0 / 2 (0.00%)	100 / 119 (84.03%)	13 / 24 (54.17%)	86 / 121 (71.07%)	102 / 124 (82.26%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	4 / 119 (3.36%)	0 / 24 (0.00%)	0 / 121 (0.00%)	7 / 124 (5.65%)
occurrences all number	0	0	4	0	0	10
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	6 / 125 (4.80%)	0 / 2 (0.00%)	18 / 119 (15.13%)	2 / 24 (8.33%)	11 / 121 (9.09%)	22 / 124 (17.74%)
occurrences all number	6	0	22	2	14	27
Chest pain
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	0 / 121 (0.00%)	8 / 124 (6.45%)
occurrences all number	0	0	3	0	0	10
Fatigue
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	10 / 119 (8.40%)	0 / 24 (0.00%)	0 / 121 (0.00%)	5 / 124 (4.03%)
occurrences all number	0	0	11	0	0	5
Asthenia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	0 / 119 (0.00%)	4 / 24 (16.67%)	0 / 121 (0.00%)	0 / 124 (0.00%)
occurrences all number	0	0	0	4	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 125 (3.20%)	0 / 2 (0.00%)	18 / 119 (15.13%)	0 / 24 (0.00%)	8 / 121 (6.61%)	14 / 124 (11.29%)
occurrences all number	4	0	21	0	11	21
Oropharyngeal pain
subjects affected / exposed	8 / 125 (6.40%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	6 / 121 (4.96%)	0 / 124 (0.00%)
occurrences all number	10	0	0	0	6	0
Epistaxis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	7 / 119 (5.88%)	0 / 24 (0.00%)	0 / 121 (0.00%)	4 / 124 (3.23%)
occurrences all number	0	0	9	0	0	4
Psychiatric disorders
Insomnia
subjects affected / exposed	2 / 125 (1.60%)	0 / 2 (0.00%)	6 / 119 (5.04%)	0 / 24 (0.00%)	6 / 121 (4.96%)	11 / 124 (8.87%)
occurrences all number	2	0	6	0	7	14
Investigations
C-reactive protein increased
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	6 / 119 (5.04%)	0 / 24 (0.00%)	0 / 121 (0.00%)	2 / 124 (1.61%)
occurrences all number	0	0	7	0	0	4
Alanine aminotransferase increased
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	8 / 119 (6.72%)	0 / 24 (0.00%)	0 / 121 (0.00%)	9 / 124 (7.26%)
occurrences all number	0	0	18	0	0	12
Cardiac disorders
Palpitations
subjects affected / exposed	7 / 125 (5.60%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	2 / 121 (1.65%)	0 / 124 (0.00%)
occurrences all number	10	0	0	0	2	0
Nervous system disorders
Headache
subjects affected / exposed	45 / 125 (36.00%)	0 / 2 (0.00%)	20 / 119 (16.81%)	2 / 24 (8.33%)	40 / 121 (33.06%)	16 / 124 (12.90%)
occurrences all number	70	0	26	3	71	30
Dizziness
subjects affected / exposed	9 / 125 (7.20%)	0 / 2 (0.00%)	9 / 119 (7.56%)	0 / 24 (0.00%)	7 / 121 (5.79%)	4 / 124 (3.23%)
occurrences all number	9	0	9	0	10	10
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 125 (2.40%)	0 / 2 (0.00%)	10 / 119 (8.40%)	0 / 24 (0.00%)	6 / 121 (4.96%)	4 / 124 (3.23%)
occurrences all number	3	0	17	0	9	5
Neutropenia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	0 / 121 (0.00%)	9 / 124 (7.26%)
occurrences all number	0	0	3	0	0	12
Leukopenia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	0 / 121 (0.00%)	7 / 124 (5.65%)
occurrences all number	0	0	3	0	0	12
Thrombocytopenia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	4 / 119 (3.36%)	0 / 24 (0.00%)	0 / 121 (0.00%)	8 / 124 (6.45%)
occurrences all number	0	0	8	0	0	15
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	7 / 125 (5.60%)	0 / 2 (0.00%)	12 / 119 (10.08%)	2 / 24 (8.33%)	7 / 121 (5.79%)	10 / 124 (8.06%)
occurrences all number	7	0	17	3	7	13
Diarrhoea
subjects affected / exposed	10 / 125 (8.00%)	0 / 2 (0.00%)	13 / 119 (10.92%)	0 / 24 (0.00%)	5 / 121 (4.13%)	14 / 124 (11.29%)
occurrences all number	12	0	19	0	7	16
Nausea
subjects affected / exposed	11 / 125 (8.80%)	0 / 2 (0.00%)	11 / 119 (9.24%)	0 / 24 (0.00%)	10 / 121 (8.26%)	8 / 124 (6.45%)
occurrences all number	14	0	17	0	14	9
Dyspepsia
subjects affected / exposed	5 / 125 (4.00%)	0 / 2 (0.00%)	10 / 119 (8.40%)	0 / 24 (0.00%)	6 / 121 (4.96%)	8 / 124 (6.45%)
occurrences all number	7	0	20	0	7	12
Vomiting
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	4 / 119 (3.36%)	0 / 24 (0.00%)	0 / 121 (0.00%)	7 / 124 (5.65%)
occurrences all number	0	0	5	0	0	7
Constipation
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	5 / 119 (4.20%)	0 / 24 (0.00%)	0 / 121 (0.00%)	10 / 124 (8.06%)
occurrences all number	0	0	5	0	0	11
Abdominal pain upper
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	5 / 119 (4.20%)	0 / 24 (0.00%)	0 / 121 (0.00%)	10 / 124 (8.06%)
occurrences all number	0	0	5	0	0	14
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	4 / 125 (3.20%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	6 / 121 (4.96%)	0 / 124 (0.00%)
occurrences all number	4	0	0	0	6	0
Rash
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	7 / 119 (5.88%)	0 / 24 (0.00%)	0 / 121 (0.00%)	1 / 124 (0.81%)
occurrences all number	0	0	7	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 125 (8.80%)	0 / 2 (0.00%)	12 / 119 (10.08%)	0 / 24 (0.00%)	11 / 121 (9.09%)	17 / 124 (13.71%)
occurrences all number	17	0	14	0	12	19
Pain in extremity
subjects affected / exposed	9 / 125 (7.20%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	6 / 121 (4.96%)	0 / 124 (0.00%)
occurrences all number	10	0	0	0	7	0
Myalgia
subjects affected / exposed	9 / 125 (7.20%)	0 / 2 (0.00%)	7 / 119 (5.88%)	0 / 24 (0.00%)	9 / 121 (7.44%)	4 / 124 (3.23%)
occurrences all number	14	0	7	0	12	9
Back pain
subjects affected / exposed	8 / 125 (6.40%)	0 / 2 (0.00%)	11 / 119 (9.24%)	2 / 24 (8.33%)	6 / 121 (4.96%)	12 / 124 (9.68%)
occurrences all number	9	0	12	2	6	13
Infections and infestations
Nasopharyngitis
subjects affected / exposed	11 / 125 (8.80%)	0 / 2 (0.00%)	26 / 119 (21.85%)	0 / 24 (0.00%)	20 / 121 (16.53%)	14 / 124 (11.29%)
occurrences all number	14	0	47	0	22	28
Viral upper respiratory tract infection
subjects affected / exposed	9 / 125 (7.20%)	0 / 2 (0.00%)	0 / 119 (0.00%)	0 / 24 (0.00%)	8 / 121 (6.61%)	0 / 124 (0.00%)
occurrences all number	10	0	0	0	10	0
Upper respiratory tract infection
subjects affected / exposed	13 / 125 (10.40%)	0 / 2 (0.00%)	25 / 119 (21.01%)	0 / 24 (0.00%)	7 / 121 (5.79%)	30 / 124 (24.19%)
occurrences all number	15	0	36	0	7	68
Influenza
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	11 / 119 (9.24%)	0 / 24 (0.00%)	0 / 121 (0.00%)	9 / 124 (7.26%)
occurrences all number	0	0	12	0	0	10
COVID-19
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	16 / 119 (13.45%)	9 / 24 (37.50%)	0 / 121 (0.00%)	19 / 124 (15.32%)
occurrences all number	0	0	17	10	0	22
Cystitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	4 / 119 (3.36%)	0 / 24 (0.00%)	0 / 121 (0.00%)	8 / 124 (6.45%)
occurrences all number	0	0	8	0	0	8
Gastroenteritis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	9 / 119 (7.56%)	0 / 24 (0.00%)	0 / 121 (0.00%)	3 / 124 (2.42%)
occurrences all number	0	0	9	0	0	5
Bronchitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	7 / 119 (5.88%)	0 / 24 (0.00%)	0 / 121 (0.00%)	3 / 124 (2.42%)
occurrences all number	0	0	8	0	0	3
Urinary tract infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	3 / 119 (2.52%)	0 / 24 (0.00%)	0 / 121 (0.00%)	8 / 124 (6.45%)
occurrences all number	0	0	4	0	0	10
Oral herpes
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	6 / 119 (5.04%)	0 / 24 (0.00%)	0 / 121 (0.00%)	5 / 124 (4.03%)
occurrences all number	0	0	8	0	0	6
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 125 (0.00%)	0 / 2 (0.00%)	4 / 119 (3.36%)	0 / 24 (0.00%)	0 / 121 (0.00%)	12 / 124 (9.68%)
occurrences all number	0	0	4	0	0	18

More information

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Were there any global substantial amendments to the protocol? Yes

28 Sep 2016

• Modified the weight-based dosing for ravulizumab. The initial dosing regimen was designed to achieve complete inhibition of terminal complement activity over the entire dosing interval in all participants. After discussion with the United States Food and Drug Administration, it was determined that these slightly lower dosing levels also met the initially established trough exposure levels to ensure complete inhibition of complement component 5 activity in all participants. Changes were as follows: − For participants weighing ≥ 40 to < 60 kilograms (kg): Loading dose changed from 2700 mg to 2400 mg and maintenance dose changed from 3300 mg to 3000 mg − For participants weighing ≥ 60 to < 100 kg: Loading dose changed from 3000 mg to 2700 mg and maintenance dose changed from 3600 mg to 3300 mg − For participants weighing ≥ 100 kg: Loading dose unchanged and maintenance dose changed from 3900 mg to 3600 mg • The Dosing Reference Chart for ravulizumab Dose Preparation also was modified accordingly.

25 Jan 2017

• Clarified that all safety data, including those in the Extension Period, would be reported. • Text added to address recommendations from regulatory authorities to incorporate a benefit-risk assessment summary in the study protocol. This included addition of a reference. • An additional secondary objective was added to gain an understanding of the benefit-risk of switching participants from eculizumab to ravulizumab. • Text was added as follows to minimize participant discomfort: To minimize needle sticks to the participant, the predose sample may be drawn through the venous access created for the dose infusion, prior to administration of the dose. • A study visit on Day 225 was added globally to the Extension Period for participants who received eculizumab during the Primary Evaluation Period, to allow for assessment 4 weeks after their first maintenance dose of ravulizumab. • Text added to ensure independent review of meningococcal infection cases.

23 Oct 2017

• Revised the statistical analysis description regarding control of Type I error when testing the primary and secondary end points for noninferiority and superiority. • Clarified that the last recorded study visit body weight should be used for determination of weight-based dose, and if study drug is prepared the night before a visit, the weight from the most recent study visit should be used. • Indicated the maximum permitted duration of an eculizumab infusion. • In order to reduce the incidence of ex vivo hemolyzed blood samples, it was specified that draws should not be made via a heparinized tube. • To reduce the participant data collection burden, removed the exploratory end points of Patient-Reported PNH Symptoms and Healthcare Resource Utilization, their description, and the questionnaires. • Clarified that transfusions administered in the inpatient or outpatient setting should not be captured as adverse events or serious adverse events unless identified as such by the Investigator.

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

http://www.ncbi.nlm.nih.gov/pubmed/30510080

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