Download PDF

Clinical Trial Results:
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WITHOUT A RECENT HISTORY OF BLOOD TRANSFUSION

Summary
EudraCT number	2017-003539-12
Trial protocol	AT GB DE NO ES BE NL IT
Global end of trial date	03 Dec 2021

Results information
Results version number	v1(current)
This version publication date	16 Dec 2022
First version publication date	16 Dec 2022
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

EFC16216

ISRCTN number

US NCT number

NCT03347422

WHO universal trial number (UTN)

Other trial identifiers

IND #: 128,190, STUDY NAME: Cadenza

Sponsor organisation name

Sanofi-aventis Recherche & Développement

Sponsor organisation address

1, Avenue Pierre Brossolette, Chilly Mazarin, France, 91385

Public contact

Trial Transparency Team, Bioverativ, a Sanofi company, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Bioverativ, a Sanofi company, Contact-US@sanofi.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

25 Jan 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Dec 2021

Was the trial ended prematurely?

Main objective of the trial

The purpose of Part A was to determine whether sutimlimab administration results in a greater than or equal to (>=)1.5 grams per decilitre (g/dL) increase in hemoglobin (Hgb) level and avoidance of transfusion in subjects with primary cold agglutinin disease (CAD) without a recent history of blood transfusion. The purpose of Part B was to evaluate the long-term safety and tolerability of sutimlimab in subjects with primary CAD.

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Mar 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

Australia: 2

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

Israel: 1

Country: Number of subjects enrolled

Japan: 5

Country: Number of subjects enrolled

United States: 5

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

Top of page

Recruitment details

The study was conducted at 27 sites in 13 countries. Out of 66 screened subjects, a total of 42 subjects were enrolled and randomised from 17 March 2018 to 30 March 2020. This study consisted of 2 Parts: Part A and Part B.

Screening details

Subjects were stratified based on baseline body weight to receive BIVV009 6.5 grams (g) (if <75 kg) or 7.5 g (if >=75 kg). As planned, data presented as: 1) Dose-wise (2 dose cohorts: BIVV009 6.5 g and BIVV009 7.5 g) for safety endpoints and adverse events (AEs). 2) combined population (BIVV009 at any dose) for efficacy endpoints.

Period 1 title

Part A (26 Weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

BIVV009

Arm description

Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an intravenous (IV) infusion of BIVV009 6.5 g (for subjects less than [<]75 kilograms [kg]) or 7.5 g dose (for subjects >=75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

Arm type

Experimental

Investigational medicinal product name

BIVV009

Investigational medicinal product code

Other name

Sutimlimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received fixed doses of BIVV009 6.5 g or 7.5 g based on body weight, as IV infusion on Day 0 and Day 7 and every 14 days thereafter up to Week 25.

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received fixed doses of placebo matched to BIVV009 (6.5 g or 7.5 g) as IV infusion on Day 0 and Day 7 and every 14 days thereafter up to Week 25.

Number of subjects in period 1	BIVV009	Placebo
Started	22	20
Completed	19	20
Not completed	3	0
Adverse event, non-fatal	3	-

Period 2 title

Part B (149 Weeks)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

BIVV009/BIVV009

Arm description

Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of BIVV009 6.5 g (for subjects <75 kg) or 7.5 g dose (for subjects >=75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Subjects who completed Part A per protocol through the end of treatment visit (Week 26), received placebo on Week 26 and continued to receive BIVV009 6.5 or 7.5 g in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g). All subjects who completed Part A elected to continue in Part B.

Arm type

Experimental

Investigational medicinal product name

BIVV009

Investigational medicinal product code

Other name

Sutimlimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with body weight <75 kg (for 6.5 g) and body weight >=75 kg (for 7.5 g) received placebo on Week 26 and continued to receive fixed doses of BIVV009 6.5 g or 7.5 g as IV infusion every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g).

Placebo/BIVV009

Arm description

Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Subjects who completed Part A per protocol through the end of treatment visit (Week 26) received BIVV009 6.5 (if <75 kg) or 7.5 g (if >=75 kg) in Part B, on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g). All subjects who completed Part A elected to continue in Part B.

Arm type

Experimental

Investigational medicinal product name

BIVV009

Investigational medicinal product code

Other name

Sutimlimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with body weight <75 kg (for 6.5 g) and body weight >=75 kg (for 7.5 g) received fixed doses of BIVV009 6.5 g or 7.5 g as IV infusion on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g).

Number of subjects in period 2	BIVV009/BIVV009	Placebo/BIVV009
Started	19	20
Completed	16	16
Not completed	3	4
Consent withdrawn by subject	1	1
Adverse event, non-fatal	-	1
Unspecified	1	-
Lack of efficacy	1	2

Baseline characteristics

Top of page

Reporting group title

BIVV009

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	BIVV009	Placebo	Total
Number of subjects	22	20	42
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	65.3 ( 10.9 )	68.2 ( 10.1 )	-
Gender categorical
Units: Subjects
Female	17	16	33
Male	5	4	9
Race
Units: Subjects
Asian	5	2	7
White	0	4	4
Black or African American	0	0	0
American Indian or Alaska Native	0	0	0
Native Hawaiian or other Pacific Islander	0	0	0
More than one race	0	0	0
Unknown or Not Reported	17	14	31

End points

Top of page

Reporting group title

BIVV009

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

BIVV009/BIVV009

Reporting group description

Reporting group title

Placebo/BIVV009

Reporting group description

Subject analysis set title

Part B: BIVV009 6.5 g

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed Part A per protocol through the end of treatment visit (Week 26) were eligible to be enrolled in Part B where they were treated for up to an additional 149 weeks. Subjects who received placebo in Part A received BIVV009 6.5 g on Week 26, Week 27 and every 2 weeks thereafter; subjects who received BIVV009 6.5 g in Part A received placebo on Week 26, BIVV009 6.5 g on Week 27 and every 2 weeks thereafter for up to an additional 149 weeks.

Subject analysis set title

Part B: BIVV009 7.5 g

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed Part A per protocol through the end of treatment visit (Week 26) were eligible to be enrolled in Part B where they were treated for up to an additional 137 weeks. Subjects who received placebo in Part A received BIVV009 7.5 g on Week 26, Week 27 and every 2 weeks thereafter; subjects who received BIVV009 7.5 g in Part A received placebo on Week 26, BIVV009 7.5 g on Week 27 and every 2 weeks thereafter for up to an additional 137 weeks.

Primary: Part A: Percentage of Subjects With Response to Treatment

Top of page

End point title

Part A: Percentage of Subjects With Response to Treatment

End point description

A subject was considered a responder: if he or she did not receive blood transfusion from Week 5 through Week 26 (end of treatment) and did not receive treatment for CAD beyond what was permitted per protocol. Additionally, subject’s hemoglobin (Hgb) level must have increased to >=1.5 g/dL from baseline (defined as last Hgb value before administration of first dose of study drug) at treatment assessment timepoint (defined as average of values from the Week 23, 25, and 26 visits). Percentage of responders was calculated together with 95% exact Clopper-Pearson confidence interval (CI). Analysed on Part A-full analysis set (FAS) which included all subjects who received at least 1 dose (including partial dose) of study drug (BIVV009 or placebo). Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either at 6.5 or 7.5 g] and placebo in Part A.

End point type

Primary

End point timeframe

From Week 5 through Week 26

End point values	BIVV009	Placebo
Number of subjects analysed	22	20
Units: percentage of subjects
number (confidence interval 95%)	72.7 (49.8 to 89.3)	15.0 (3.2 to 37.9)

BIVV009 versus Placebo

Statistical analysis description

A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints were reported and continued when primary endpoint was statistically significant at two-sided 0.05 level.

Comparison groups

BIVV009 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.001 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

15.94

Confidence interval

level

95%

sides

2-sided

lower limit

2.88

upper limit

88.04

Notes
[1] - Stratified by baseline hemoglobin (< median versus >=median) and geographic region (Asia/Other, North America, and Europe).
[2] - Threshold for significance was 0.05.

Primary: Part B: Number of Subjects With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs)

Top of page

End point title

Part B: Number of Subjects With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs) ^[3]

End point description

Adverse Event (AE): any untoward medical occurrence in a subject who received study drug and did not necessarily have to have a causal relationship with the treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect, was medically important event. TEAEs: AEs that developed, worsened or became serious during the treatment-emergent (TE) period (from first investigational medicinal product [IMP] administration in Part B to last IMP administration + 9 weeks follow-up period). Analysed on Part B safety analysis set (SAS) which included all subjects who received at least 1 dose (including partial dose) of study drug in Part B. Data for this endpoint was planned to be collected and analysed separately for each dose (BIVV009 6.5 g and 7.5 g).

End point type

Primary

End point timeframe

Part B, 6.5 g cohort: From first dose (Week 26) up to 149 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 184); Part B, 7.5 g cohort: From first dose (Week 26) up to 137 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 172)

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: As the endpoint was descriptive in nature, no statistical analysis was provided.

End point values	Part B: BIVV009 6.5 g	Part B: BIVV009 7.5 g
Number of subjects analysed	32	7
Units: subjects
TEAEs	29	7
TESAEs	6	1

No statistical analyses for this end point

Secondary: Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint

Top of page

End point title

Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint

End point description

Mean change from baseline (Week 0) in Hemoglobin (Hgb) at the treatment assessment timepoint is reported in this endpoint. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Least squares (LS) mean and 95 % confidence interval (CI) was assessed by Mixed Model for Repeated Measures (MMRM) approach using heterogeneous Toeplitz (TOEPH) covariance matrix with change from baseline as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.

End point type

Secondary

End point timeframe

Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

End point values	BIVV009	Placebo
Number of subjects analysed	22	20
Units: gram per decilitre
least squares mean (confidence interval 95%)	2.66 (2.09 to 3.22)	0.09 (-0.50 to 0.68)

BIVV009 versus Placebo

Statistical analysis description

A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoint were reported and continued when previous endpoint was statistically significant at two-sided 0.05 level.

Comparison groups

BIVV009 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[4]

Method

Mixed model for repeated measures

Parameter type

LS Mean Difference

Point estimate

2.56

Confidence interval

level

95%

sides

2-sided

lower limit

1.75

upper limit

3.38

Variability estimate

Standard error of the mean

Dispersion value

0.408

Notes
[4] - Threshold of significance at 0.05 level.

Secondary: Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint

Top of page

End point title

Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint

End point description

Mean change from baseline (Week 0) in total bilirubin at the treatment assessment timepoint is reported in this endpoint. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.

End point type

Secondary

End point timeframe

Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

End point values	BIVV009	Placebo
Number of subjects analysed	19	20
Units: micromoles per litre
arithmetic mean (standard deviation)	-22.881 ( 10.401 )	-1.388 ( 13.901 )

No statistical analyses for this end point

Secondary: Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint

Top of page

End point title

Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint

End point description

FACIT-Fatigue scale consists of 13 questions assessed using a 5-point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added to obtain a total score. Total score ranged from 0 to 52, with higher score indicating more fatigue. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. LS mean and 95 % CI was assessed by MMRM approach using TOEPH covariance matrix with change from baseline (Week 0) as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.

End point type

Secondary

End point timeframe

Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

End point values	BIVV009	Placebo
Number of subjects analysed	22	20
Units: score on a scale
least squares mean (confidence interval 95%)	10.83 (7.45 to 14.22)	1.91 (-1.65 to 5.46)

BIVV009 versus Placebo

Statistical analysis description

Comparison groups

BIVV009 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[5]

Method

Mixed model for repeated measures

Parameter type

LS Mean Difference

Point estimate

8.93

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

13.85

Variability estimate

Standard error of the mean

Dispersion value

2.45

Notes
[5] - Threshold of significance at 0.05 level.

Secondary: Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint

Top of page

End point title

Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint

End point description

Mean change from baseline (Week 0) in LDH at the treatment assessment timepoint is reported in this endpoint. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.

End point type

Secondary

End point timeframe

Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

End point values	BIVV009	Placebo
Number of subjects analysed	19	20
Units: units per litre
arithmetic mean (standard deviation)	-150.833 ( 160.824 )	7.600 ( 212.690 )

No statistical analyses for this end point

Secondary: Part A: Percentage of Subjects With Solicited Symptomatic Anemia at Week 26

Top of page

End point title

Part A: Percentage of Subjects With Solicited Symptomatic Anemia at Week 26

End point description

Symptomatic anemia was defined as having following symptoms: i. Fatigue; ii. Weakness; iii. Shortness of breath; iv. Palpitations, fast heart beat; v. Light headedness and/or vi. Chest pain. Percentage of subjects with solicited symptomatic anemia symptoms was reported in this endpoint. Analysis was performed on Part A-FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.

End point type

Secondary

End point timeframe

Week 26

End point values	BIVV009	Placebo
Number of subjects analysed	19	19
Units: percentage of subjects
number (not applicable)
Fatigue	31.6	68.4
Weakness	5.3	31.6
Shortness of breath	5.3	36.8
Palpitations	0	15.8
Light headedness	5.3	15.8
Chest pain	0	5.3

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points

Top of page

End point title

Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points

End point description

Change from baseline (Week 0) in Hgb levels at each specified time points is reported in this endpoint. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. Early Termination (ET) visit/safety follow up (SFU) visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS which included all subjects who enrolled in Part B and received at least 1 dose (including partial dose) of study drug (BIVV009). Here, 'n' = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as space filler which denotes that standard deviation (SD) was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: grams per decilitre
arithmetic mean (standard deviation)
Week 27 (n=19,20)	2.647 ( 1.348 )	1.125 ( 1.545 )
Week 29 (n=17,18)	2.507 ( 1.669 )	1.947 ( 1.467 )
Week 31 (n=18,19)	2.490 ( 1.550 )	2.358 ( 1.471 )
Week 33 (n=18,19)	2.519 ( 1.520 )	1.987 ( 2.054 )
Week 35 (n=17,19)	2.611 ( 1.522 )	1.977 ( 2.010 )
Week 37 (n=18,19)	2.197 ( 1.461 )	2.469 ( 1.550 )
Week 39 (n=17,18)	2.528 ( 1.607 )	2.368 ( 1.835 )
Week 41 (n=19,19)	2.162 ( 1.636 )	2.074 ( 1.825 )
Week 43 (n=17,19)	2.436 ( 1.103 )	2.182 ( 1.643 )
Week 45 (n=18,20)	2.644 ( 1.688 )	2.249 ( 1.858 )
Week 47 (n=16,19)	2.335 ( 1.108 )	2.315 ( 2.129 )
Week 49 (n=16,18)	2.531 ( 1.280 )	2.121 ( 1.883 )
Week 51 (n=16,19)	2.349 ( 1.260 )	2.394 ( 1.870 )
Week 53 (n=16,18)	2.346 ( 1.182 )	2.411 ( 1.786 )
Week 55 (n=17,18)	2.438 ( 1.396 )	2.539 ( 1.403 )
Week 57 (n=16,17)	2.531 ( 1.446 )	2.250 ( 1.774 )
Week 59 (n=17,17)	2.590 ( 1.397 )	2.008 ( 2.615 )
Week 61 (n=17,18)	4.073 ( 6.761 )	2.059 ( 1.911 )
Week 63 (n=17,17)	2.382 ( 1.546 )	2.102 ( 1.780 )
Week 65 (n=16,17)	2.925 ( 1.447 )	2.311 ( 1.986 )
Week 67 (n=17,17)	4.170 ( 6.509 )	2.534 ( 2.036 )
Week 69 (n=16,17)	2.777 ( 1.411 )	2.505 ( 2.093 )
Week 71 (n=14,15)	2.654 ( 1.495 )	2.357 ( 1.758 )
Week 73 (n=15,16)	2.800 ( 2.132 )	2.197 ( 1.989 )
Week 75 (n=15,16)	2.391 ( 1.700 )	2.175 ( 2.151 )
Week 77 (n=14,16)	3.074 ( 2.088 )	2.451 ( 1.878 )
Week 79 (n=13,15)	2.614 ( 1.874 )	2.419 ( 2.247 )
Week 81 (n=14,17)	2.598 ( 1.801 )	2.458 ( 1.579 )
Week 83 (n=14,13)	2.469 ( 1.777 )	2.762 ( 1.539 )
Week 85 (n=12,15)	2.755 ( 1.942 )	2.489 ( 1.375 )
Week 87 (n=13,15)	2.477 ( 1.779 )	2.765 ( 1.605 )
Week 89 (n=12,13)	2.551 ( 1.835 )	2.482 ( 2.004 )
Week 91 (n=11,12)	2.380 ( 2.084 )	2.556 ( 1.538 )
Week 93 (n=11,12)	2.931 ( 2.386 )	2.655 ( 2.033 )
Week 95 (n=11,12)	2.262 ( 2.014 )	2.578 ( 1.970 )
Week 97 (n=11,12)	2.413 ( 2.262 )	2.551 ( 1.544 )
Week 99 (n=11,13)	2.019 ( 1.799 )	2.412 ( 1.822 )
Week 101 (n=11,12)	2.276 ( 1.986 )	2.171 ( 1.852 )
Week 103 (n=11,13)	2.378 ( 2.342 )	2.527 ( 1.807 )
Week 105 (n=11,12)	2.291 ( 1.719 )	2.321 ( 1.805 )
Week 107 (n=11,13)	2.319 ( 1.511 )	2.560 ( 1.858 )
Week 109 (n=11,11)	2.509 ( 1.772 )	2.645 ( 1.608 )
Week 111 (n=11,12)	2.416 ( 1.908 )	2.750 ( 1.707 )
Week 113 (n=11,12)	2.860 ( 1.832 )	2.268 ( 1.497 )
Week 115 (n=10,10)	2.622 ( 1.986 )	2.326 ( 1.809 )
Week 117 (n=9,11)	3.135 ( 1.598 )	2.474 ( 1.808 )
Week 119 (n=9,10)	3.106 ( 1.493 )	2.608 ( 2.045 )
Week 121 (n=9,8)	3.388 ( 1.616 )	2.325 ( 2.223 )
Week 123 (n=9,9)	3.255 ( 1.346 )	2.878 ( 2.667 )
Week 125 (n=8,7)	3.197 ( 1.366 )	1.700 ( 2.684 )
Week 127 (n=7,8)	3.371 ( 1.551 )	2.102 ( 3.211 )
Week 129 (n=7,7)	3.171 ( 1.566 )	2.129 ( 2.739 )
Week 131 (n=6,6)	3.453 ( 1.823 )	1.423 ( 3.184 )
Week 133 (n=5,4)	3.520 ( 1.707 )	2.025 ( 1.167 )
Week 135 (n=5,5)	3.611 ( 1.458 )	3.048 ( 1.620 )
Week 137 (n=4,3)	4.074 ( 2.392 )	2.400 ( 1.808 )
Week 139 (n=5,3)	3.929 ( 1.889 )	3.334 ( 2.669 )
Week 141 (n=3,3)	3.500 ( 0.656 )	2.733 ( 1.674 )
Week 143 (n=4,3)	3.220 ( 1.064 )	2.985 ( 1.904 )
Week 145 (n=2,3)	3.350 ( 0.636 )	3.467 ( 2.108 )
Week 147 (n=3,2)	3.202 ( 0.591 )	2.300 ( 0.566 )
Week 149 (n=1,2)	2.900 ( 99999 )	2.550 ( 0.778 )
Week 151 (n=2,1)	2.961 ( 0.370 )	3.000 ( 99999 )
Week 153 (n=1,1)	2.800 ( 99999 )	2.800 ( 99999 )
Week 155 (n=1,1)	2.700 ( 99999 )	3.600 ( 99999 )
Week 157 (n=1,1)	2.700 ( 99999 )	3.000 ( 99999 )
Week 159 (n=1,1)	3.300 ( 99999 )	2.300 ( 99999 )
Week 161 (n=1,1)	4.100 ( 99999 )	2.400 ( 99999 )
Week 163 (n=1,1)	4.100 ( 99999 )	2.600 ( 99999 )
Week 165 (n=1,0)	3.800 ( 99999 )	9999 ( 99999 )
Week 167 (n=1,0)	4.700 ( 99999 )	9999 ( 99999 )
Week 169 (n=1,0)	4.300 ( 99999 )	9999 ( 99999 )
Week 171 (n=1,0)	4.200 ( 99999 )	9999 ( 99999 )
Week 173 (n=1,0)	4.000 ( 99999 )	9999 ( 99999 )
Week 175 (n=1,0)	2.500 ( 99999 )	9999 ( 99999 )
ET/SFU Visit (n=17,18)	0.149 ( 2.073 )	0.359 ( 1.872 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points

Top of page

End point title

Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points

End point description

Change from baseline (Week 0) in total bilirubin levels at each specified time point is reported in this endpoint. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	17	18
Units: micromoles per litre
arithmetic mean (standard deviation)
Week 27 (n=17,18)	-22.965 ( 9.899 )	-18.761 ( 13.353 )
Week 29 (n=16,18)	-20.119 ( 12.170 )	-19.889 ( 14.500 )
Week 31 (n=16,17)	-21.675 ( 11.025 )	-22.153 ( 14.962 )
Week 33 (n=15,16)	-19.860 ( 11.527 )	-24.263 ( 15.169 )
Week 35 (n=15,16)	-20.540 ( 10.557 )	-21.888 ( 13.930 )
Week 37 (n=16,15)	-21.350 ( 13.234 )	-22.527 ( 16.315 )
Week 39 (n=15,15)	-23.493 ( 11.425 )	-21.173 ( 15.901 )
Week 41 (n=16,16)	-18.694 ( 12.189 )	-21.138 ( 16.150 )
Week 43 (n=15,16)	-20.593 ( 11.449 )	-21.544 ( 16.603 )
Week 45 (n=16,18)	-18.556 ( 11.213 )	-20.156 ( 16.757 )
Week 47 (n=14,18)	-20.400 ( 9.803 )	-20.250 ( 15.536 )
Week 49 (n=14,17)	-21.450 ( 10.271 )	-21.024 ( 13.630 )
Week 51 (n=14,16)	-19.686 ( 11.072 )	-19.444 ( 15.942 )
Week 53 (n=15,17)	-19.107 ( 11.267 )	-20.335 ( 17.126 )
Week 55 (n=13,16)	-19.354 ( 12.209 )	-23.481 ( 12.300 )
Week 57 (n=13,15)	-21.708 ( 10.467 )	-18.953 ( 15.825 )
Week 59 (n=14,15)	-19.979 ( 9.706 )	-19.820 ( 16.209 )
Week 61 (n=13,15)	-18.254 ( 10.541 )	-21.073 ( 17.457 )
Week 63 (n=15,15)	-21.587 ( 9.680 )	-21.753 ( 16.663 )
Week 65 (n=14,14)	-20.400 ( 9.866 )	-20.950 ( 19.833 )
Week 67 (n=15,14)	-22.680 ( 10.317 )	-20.150 ( 20.250 )
Week 69 (n=14,15)	-21.279 ( 9.423 )	-17.827 ( 22.194 )
Week 71 (n=12,13)	-19.008 ( 8.255 )	-20.585 ( 21.125 )
Week 73 (n=12,15)	-23.058 ( 7.766 )	-20.080 ( 17.803 )
Week 75 (n=12,14)	-21.492 ( 7.453 )	-20.771 ( 20.261 )
Week 77 (n=12,14)	-23.267 ( 8.972 )	-19.814 ( 19.337 )
Week 79 (n=12,15)	-21.125 ( 12.701 )	-21.027 ( 19.830 )
Week 81 (n=11,13)	-19.255 ( 9.478 )	-22.331 ( 20.117 )
Week 83 (n=12,11)	-16.567 ( 12.565 )	-25.091 ( 13.838 )
Week 85 (n=11,13)	-18.045 ( 12.183 )	-23.292 ( 12.976 )
Week 87 (n=10,11)	-19.990 ( 12.043 )	-21.473 ( 14.444 )
Week 89 (n=10,11)	-17.790 ( 11.036 )	-24.782 ( 13.390 )
Week 91 (n=9,11)	-16.944 ( 13.476 )	-23.091 ( 14.949 )
Week 93 (n=9,10)	-18.300 ( 11.132 )	-24.970 ( 13.852 )
Week 95 (n=8,11)	-18.613 ( 12.265 )	-23.564 ( 11.122 )
Week 97 (n=9,9)	-18.656 ( 11.462 )	-26.122 ( 11.870 )
Week 99 (n=9,11)	-17.389 ( 10.932 )	-23.700 ( 12.919 )
Week 101 (n=9,10)	-18.411 ( 10.175 )	-25.940 ( 12.309 )
Week 103 (n=9,11)	-18.178 ( 11.156 )	-22.655 ( 11.308 )
Week 105 (n=9,10)	-19.422 ( 8.444 )	-26.920 ( 10.996 )
Week 107 (n=9,11)	-18.100 ( 9.955 )	-23.018 ( 12.755 )
Week 109 (n=9,9)	-18.456 ( 10.606 )	-25.422 ( 14.100 )
Week 111 (n=9,10)	-19.767 ( 9.992 )	-24.380 ( 12.298 )
Week 113 (n=9,10)	-19.389 ( 9.192 )	-23.940 ( 15.514 )
Week 115 (n=9,9)	-19.622 ( 8.194 )	-21.533 ( 14.215 )
Week 117 (n=8,8)	-22.088 ( 10.247 )	-22.225 ( 15.256 )
Week 119 (n=8,8)	-20.038 ( 8.529 )	-22.713 ( 14.859 )
Week 121 (n=8,6)	-22.063 ( 7.215 )	-21.183 ( 10.750 )
Week 123 (n=8,7)	-21.438 ( 8.058 )	-22.029 ( 12.421 )
Week 125 (n=7,5)	-20.657 ( 8.889 )	-19.560 ( 12.997 )
Week 127 (n=6,6)	-20.550 ( 9.782 )	-21.433 ( 15.850 )
Week 129 (n=6,5)	-22.883 ( 11.291 )	-19.020 ( 11.749 )
Week 131 (n=5,5)	-19.420 ( 12.936 )	-23.100 ( 15.797 )
Week 133 (n=4,4)	-27.600 ( 7.477 )	-17.450 ( 16.917 )
Week 135 (n=4,5)	-29.500 ( 7.816 )	-21.900 ( 19.552 )
Week 137 (n=3,2)	-28.833 ( 8.615 )	-11.650 ( 18.173 )
Week 139 (n=4,3)	-25.800 ( 9.081 )	-24.733 ( 17.470 )
Week 141 (n=2,3)	-34.400 ( 2.404 )	-13.833 ( 16.669 )
Week 143 (n=3,3)	-26.967 ( 9.235 )	-20.033 ( 22.861 )
Week 145 (n=2,3)	-32.900 ( 3.677 )	-18.100 ( 27.217 )
Week 147 (n=3,2)	-29.300 ( 7.418 )	-3.300 ( 34.083 )
Week 149 (n=1,2)	-31.700 ( 99999 )	-7.300 ( 28.284 )
Week 151 (n=2,1)	-21.500 ( 0.566 )	0.300 ( 99999 )
Week 153 (n=1,1)	-30.800 ( 99999 )	-11.400 ( 99999 )
Week 155 (n=1,1)	-35.300 ( 99999 )	0.700 ( 99999 )
Week 157 (n=1,1)	-32.400 ( 99999 )	-0.100 ( 99999 )
Week 159 (n=1,1)	-32.500 ( 99999 )	4.700 ( 99999 )
Week 161 (n=1,1)	-36.800 ( 99999 )	5.500 ( 99999 )
Week 163 (n=1,1)	-37.100 ( 99999 )	13.000 ( 99999 )
Week 165 (n=1,0)	-36.300 ( 99999 )	9999 ( 99999 )
Week 167 (n=1,0)	-34.300 ( 99999 )	9999 ( 99999 )
Week 169 (n=1,0)	-32.700 ( 99999 )	9999 ( 99999 )
Week 171 (n=1,0)	-33.100 ( 99999 )	9999 ( 99999 )
Week 173 (n=1,0)	-32.100 ( 99999 )	9999 ( 99999 )
Week 175 (n=1,0)	-28.400 ( 99999 )	9999 ( 99999 )
ET/SFU Visit (n=17,17)	1.976 ( 9.444 )	1.165 ( 18.773 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points

Top of page

End point title

Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points

End point description

FACIT-Fatigue scale consists of 13 questions assessed using a 5-point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added to obtain a total score. The Total score ranged from 0 to 52, with higher score indicating more fatigue. Baseline (Week 0) was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS. Here, ‘n’ = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable due to only one subject being available for analysis and "9999 & 99999" denotes no subject was available for analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: score on a scale
arithmetic mean (standard deviation)
Week 39 (n=18,18)	11.048 ( 12.333 )	7.958 ( 12.003 )
Week 51 (n=15,16)	10.080 ( 11.506 )	6.354 ( 9.680 )
Week 63 (n=16,16)	10.672 ( 13.225 )	8.499 ( 11.146 )
Week 75 (n=13,14)	9.861 ( 12.953 )	10.304 ( 9.722 )
Week 87 (n=13,15)	11.015 ( 13.972 )	8.483 ( 11.323 )
Week 99 (n=11,13)	12.109 ( 14.786 )	8.788 ( 10.985 )
Week 111 (n=11,12)	11.563 ( 13.411 )	10.688 ( 11.768 )
Week 123 (n=9,9)	10.806 ( 13.736 )	6.583 ( 16.613 )
Week 135 (n=5,5)	16.683 ( 18.953 )	12.650 ( 15.243 )
Week 147 (n=2,2)	9.208 ( 1.120 )	0.500 ( 2.121 )
Week 159 (n=1,1)	20.000 ( 99999 )	10.000 ( 99999 )
Week 171 (n=1,0)	15.000 ( 99999 )	9999 ( 99999 )
ET/SFU Visit (n=19,18)	-1.257 ( 10.399 )	-1.551 ( 12.840 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points

Top of page

End point title

Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points

End point description

SF-12: 12 item-questionnaire contained 12 items, categorised into 8 domains (subscales) of functioning and well-being: physical functioning, role-physical, role emotional, mental health, bodily pain, general health, vitality and social functioning, with each domain score ranged from 0 (poor health) to 100 (better health). Higher scores = good health condition. The 8 domains were further summarised into 2 summary scores, PCS and MCS that ranged from 0 (poor health) to 100 (better health). Higher scores = better HRQOL. Baseline (Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184). Part B-FAS. Here, 'n' = subjects with available data. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., either 6.5 g or 7.5 g). '99999'=1 subject thus SD was not estimable & '99999' & '9999' = no subject was available for analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and ET Visit/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: score on a scale
arithmetic mean (standard deviation)
Week 39-PCS (n=18,18)	4.814 ( 8.830 )	6.745 ( 11.255 )
Week 39-MCS (n=18,18)	8.543 ( 9.155 )	1.151 ( 11.591 )
Week 51-PCS (n=14,16)	5.320 ( 6.913 )	5.654 ( 8.527 )
Week 51-MCS (n=14,16)	8.461 ( 6.754 )	1.704 ( 8.813 )
Week 63-PCS (n=16,16)	5.840 ( 6.916 )	6.216 ( 9.514 )
Week 63-MCS (n=16,16)	8.117 ( 9.955 )	1.722 ( 10.175 )
Week 75-PCS (n=12,15)	5.723 ( 7.563 )	7.661 ( 10.418 )
Week 75-MCS (n=12,15)	7.932 ( 9.279 )	3.519 ( 7.891 )
Week 87-PCS (n=12,15)	5.226 ( 8.196 )	8.778 ( 12.405 )
Week 87-MCS (n=12,15)	6.058 ( 10.981 )	2.219 ( 9.111 )
Week 99-PCS (n=10,13)	3.945 ( 7.463 )	8.262 ( 12.534 )
Week 99-MCS (n=10,13)	7.136 ( 11.850 )	4.682 ( 7.698 )
Week 111-PCS (n=10,12)	4.800 ( 7.985 )	8.080 ( 12.302 )
Week 111-MCS (n=10,12)	8.705 ( 7.777 )	4.411 ( 10.249 )
Week 123-PCS (n=9,9)	4.147 ( 7.110 )	7.973 ( 13.200 )
Week 123-MCS (n=9,9)	8.650 ( 8.323 )	-2.538 ( 13.136 )
Week 135-PCS (n=5,4)	6.660 ( 9.096 )	6.070 ( 13.819 )
Week 135-MCS (n=5,4)	8.860 ( 9.817 )	2.790 ( 6.170 )
Week 147-PCS (n=2,2)	-1.655 ( 3.769 )	-3.740 ( 1.824 )
Week 147-MCS (n=2,2)	11.220 ( 6.095 )	-1.110 ( 0.679 )
Week 159-PCS (n=1,1)	5.620 ( 99999 )	-10.410 ( 99999 )
Week 159-MCS (n=1,1)	16.400 ( 99999 )	9.590 ( 99999 )
Week 171-PCS (n=1,0)	11.980 ( 99999 )	9999 ( 99999 )
Week 171-MCS (n=1,0)	0.250 ( 99999 )	9999 ( 99999 )
ET/SFU Visit-PCS (n=18,18)	-3.478 ( 10.875 )	-0.429 ( 10.922 )
ET/SFU Visit-MCS (n=18,18)	1.835 ( 11.882 )	-2.137 ( 10.148 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in 5-level European Quality of Life 5- Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Each Specified Time Points

Top of page

End point title

Part B: Change From Baseline in 5-level European Quality of Life 5- Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Each Specified Time Points

End point description

EQ-5D-5L included 2 components: health state utility index (descriptive system) & Visual Analog Scale (VAS). EQ-5D descriptive system comprises 5 dimensions:mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response option: no, slight, moderate, severe & extreme problems measured with Likert scale. EQ-5D-5L responses converted into single index utility score between 0 to 1. Higher score=better health. EQ-5D-5L VAS rated subject’s current health state on scale from 0(worst imaginable health) to 100 (best imaginable health). Baseline(Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184). Part B FAS. Data was planned to be collected & analysed for combined population of BIVV009(6.5g or 7.5g). 'n'=subjects with available data. '99999'=only 1 subject SD was not estimable and 9999 and 99999=no subject available for analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: score on a scale
arithmetic mean (standard deviation)
Week 39 - Index score (n=17,18)	0.020 ( 0.165 )	0.054 ( 0.135 )
Week 51 - Index score (n=15,16)	0.075 ( 0.173 )	-0.008 ( 0.197 )
Week 63 - Index score (n=16,16)	0.060 ( 0.214 )	0.015 ( 0.157 )
Week 75 - Index score (n=13,15)	-0.004 ( 0.144 )	0.063 ( 0.152 )
Week 87 - Index score (n=13,15)	-0.034 ( 0.240 )	0.059 ( 0.158 )
Week 99 - Index score (n=11,13)	-0.058 ( 0.216 )	0.058 ( 0.146 )
Week 111 - Index score (n=11,12)	-0.033 ( 0.205 )	0.050 ( 0.194 )
Week 123- Index score (n=9,9)	-0.020 ( 0.235 )	0.031 ( 0.221 )
Week 135- Index score (n=5,5)	0.008 ( 0.351 )	0.094 ( 0.245 )
Week 147- Index score (n=2,2)	0.054 ( 0.037 )	-0.087 ( 0.222 )
Week 159- Index score (n=1,1)	0.174 ( 99999 )	0.087 ( 99999 )
Week 171- Index score (n=1,0)	0.053 ( 99999 )	-9999 ( 99999 )
ET/SFU - Index score (n=19,18)	-0.108 ( 0.238 )	-0.077 ( 0.169 )
Week 39 - VAS score (n=17,18)	20.647 ( 16.871 )	12.000 ( 17.146 )
Week 51 - VAS score (n=15,16)	14.800 ( 27.589 )	9.125 ( 21.112 )
Week 63 - VAS score (n=15,16)	19.867 ( 21.603 )	14.375 ( 15.573 )
Week 75 - VAS score (n=13,15)	16.846 ( 22.120 )	18.933 ( 20.243 )
Week 87 - VAS score (n=13,15)	14.077 ( 25.221 )	16.867 ( 17.912 )
Week 99 - VAS score (n=11,13)	19.364 ( 20.796 )	18.385 ( 20.706 )
Week 111 - VAS score (n=11,12)	18.273 ( 19.463 )	22.833 ( 20.621 )
Week 123- VAS score (n=9,9)	21.667 ( 18.371 )	18.000 ( 30.389 )
Week 135- VAS score (n=5,5)	26.000 ( 20.433 )	23.400 ( 27.574 )
Week 147- VAS score (n=2,2)	17.500 ( 17.678 )	3.500 ( 26.163 )
Week 159- VAS score (n=1,1)	40.000 ( 99999 )	27.000 ( 99999 )
Week 171- VAS score (n=1,0)	35.000 ( 99999 )	-9999 ( 99999 )
ET/SFU - VAS score (n=19,18)	1.526 ( 17.976 )	-2.056 ( 14.957 )

No statistical analyses for this end point

Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points

Top of page

End point title

Part B: Number of Subjects With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points

End point description

The PGIS is a self-reported scale. The PGIS is a 1-item questionnaire designed to assess subject’s impression of disease severity using a 5-point scale ranging from 1 to 5, where 1=none, 2=mild, 3=moderate, 4=severe, 5=very severe. Higher scores indicated greater severity. Analysis was performed on Part B-FAS population. Here, ‘n’ = subjects with available data for each specified category. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, n=0 denotes no subject was available for analysis.

End point type

Secondary

End point timeframe

At Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: subjects
Week 39 - None (n=17,17)	7	5
Week 39 - Mild (n=17,17)	8	7
Week 39 - Moderate (n=17,17)	1	5
Week 39 - Severe (n=17,17)	1	0
Week 39 - Very Severe (n=17,17)	0	0
Week 51 - None (n=15,16)	5	4
Week 51 - Mild (n=15,16)	8	7
Week 51 - Moderate (n=15,16)	2	5
Week 51 - Severe (n=15,16)	0	0
Week 51 - Very Severe (n=15,16)	0	0
Week 63 - None (n=17,16)	6	4
Week 63 - Mild (n=17,16)	8	7
Week 63 - Moderate (n=17,16)	3	5
Week 63 - Severe (n=17,16)	0	0
Week 63 - Very Severe (n=17,16)	0	0
Week 75 - None (n=13,15)	5	6
Week 75 - Mild (n=13,15)	6	6
Week 75 - Moderate (n=13,15)	2	3
Week 75 - Severe (n=13,15)	0	0
Week 75 - Very Severe (n=13,15)	0	0
Week 87 - None (n=13,15)	6	7
Week 87 - Mild (n=13,15)	5	4
Week 87 - Moderate (n=13,15)	1	3
Week 87 - Severe (n=13,15)	1	1
Week 87 - Very Severe (n=13,15)	0	0
Week 99 - None (n=11,13)	5	8
Week 99 - Mild (n=11,13)	5	3
Week 99 - Moderate (n=11,13)	1	2
Week 99 - Severe (n=11,13)	0	0
Week 99 - Very Severe (n=11,13)	0	0
Week 111 - None (n=11,12)	5	7
Week 111 - Mild (n=11,12)	4	3
Week 111 - Moderate (n=11,12)	2	2
Week 111 - Severe (n=11,12)	0	0
Week 111 - Very Severe (n=11,12)	0	0
Week 123 - None (n=9,9)	2	5
Week 123 - Mild (n=9,9)	6	2
Week 123 - Moderate (n=9,9)	1	2
Week 123 - Severe (n=9,9)	0	0
Week 123 - Very Severe (n=9,9)	0	0
Week 135 - None (n=5,5)	0	2
Week 135 - Mild (n=5,5)	3	1
Week 135 - Moderate (n=5,5)	2	2
Week 135 - Severe (n=5,5)	0	0
Week 135 - Very Severe (n=5,5)	0	0
Week 147 - None (n=2,2)	0	1
Week 147 - Mild (n=2,2)	1	0
Week 147 - Moderate (n=2,2)	1	1
Week 147 - Severe (n=2,2)	0	0
Week 147 - Very Severe (n=2,2)	0	0
Week 159 - None (n=1,1)	0	0
Week 159 - Mild (n=1,1)	0	0
Week 159 - Moderate (n=1,1)	1	1
Week 159 - Severe (n=1,1)	0	0
Week 159 - Very Severe (n=1,1)	0	0
Week 171 - None (n=1,0)	0	0
Week 171 - Mild (n=1,0)	1	0
Week 171 - Moderate (n=1,0)	0	0
Week 171 - Severe (n=1,0)	0	0
Week 171 - Very Severe (n=1,0)	0	0
ET/SFU - None (n=19,18)	2	4
ET/SFU - Mild (n=19,18)	5	3
ET/SFU - Moderate (n=19,18)	7	5
ET/SFU - Severe (n=19,18)	3	5
ET/SFU - Very Severe (n=19,18)	2	1

No statistical analyses for this end point

Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points

Top of page

End point title

Part B: Number of Subjects With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points

End point description

PGIC is a self-administered questionnaire to evaluate the improvement or worsening compared to the start of the study. PGIC was assessed on a 7-point Likert scale ranged from 1 (greatly improved) to 7 (greatly worsened). Categories were defined based on the PGIC scores as follows: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worsen. Higher scores indicated greater severity. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS. Here, 'n' =subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, n=0 denotes no subject was available for analysis.

End point type

Secondary

End point timeframe

At Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: subjects
Week 39 - Very much improved (n=17,16)	4	3
Week 39 - Much improved (n=17,16)	8	6
Week 39 - Minimally improved (n=17,16)	2	6
Week 39 - No Change (n=17,16)	2	1
Week 39 - Minimally worse (n=17,16)	1	0
Week 39 - Much worse (n=17,16)	0	0
Week 39 - Very much worse (n=17,16)	0	0
Week 51 - Very much improved (n=15,16)	5	3
Week 51 - Much improved (n=15,16)	3	6
Week 51 - Minimally improved (n=15,16)	2	4
Week 51 - No Change (n=15,16)	5	2
Week 51 - Minimally worse (n=15,16)	0	0
Week 51 - Much worse (n=15,16)	0	1
Week 51 - Very much worse (n=15,16)	0	0
Week 63 - Very much improved (n=17,16)	5	3
Week 63 - Much improved (n=17,16)	8	4
Week 63 - Minimally improved (n=17,16)	0	5
Week 63 - No change (n=17,16)	4	3
Week 63 - Minimally worse (n=17,16)	0	0
Week 63 - Much worse (n=17,16)	0	1
Week 63 - Very much worse (n=17,16)	0	0
Week 75 - Very much improved (n=13,15)	6	6
Week 75 - Much improved (n=13,15)	2	3
Week 75 - Minimally improved (n=13,15)	1	5
Week 75 - No Change (n=13,15)	4	1
Week 75 - Minimally worse (n=13,15)	0	0
Week 75 - Much worse (n=13,15)	0	0
Week 75 - Very much worse (n=13,15)	0	0
Week 87 - Very much improved (n=13,15)	7	7
Week 87 - Much improved (n=13,15)	0	3
Week 87 - Minimally improved (n=13,15)	2	1
Week 87 - No Change (n=13,15)	2	3
Week 87 - Minimally worse (n=13,15)	1	1
Week 87 - Much worse (n=13,15)	1	0
Week 87 - Very much worse (n=13,15)	0	0
Week 99 - Very much improved (n=11,13)	3	8
Week 99 - Much improved (n=11,13)	3	2
Week 99 - Minimally improved (n=11,13)	1	3
Week 99 - No change (n=11,13)	3	0
Week 99 - Minimally worse (n=11,13)	1	0
Week 99 - Much worse (n=11,13)	0	0
Week 99 - Very much worse (n=11,13)	0	0
Week 111 - Very much improved (n=11,12)	3	6
Week 111 - Much improved (n=11,12)	5	4
Week 111 - Minimally improved (n=11,12)	1	1
Week 111 - No Change (n=11,12)	2	1
Week 111 - Minimally worse (n=11,12)	0	0
Week 111 - Much worse (n=11,12)	0	0
Week 111 - Very much worse (n=11,12)	0	0
Week 123 - Very much improved (n=9,9)	3	4
Week 123 - Much improved (n=9,9)	3	3
Week 123 - Minimally improved (n=9,9)	2	1
Week 123 - No Change (n=9,9)	1	1
Week 123 - Minimally worse (n=9,9)	0	0
Week 123 - Much worse (n=9,9)	0	0
Week 123 - Very much worse (n=9,9)	0	0
Week 135 - Very much improved (n=5,5)	2	2
Week 135 - Much improved (n=5,5)	2	1
Week 135 - Minimally improved (n=5,5)	0	1
Week 135 - No Change (n=5,5)	0	1
Week 135 - Minimally worse (n=5,5)	1	0
Week 135 - Much worse (n=5,5)	0	0
Week 135 - Very much worse (n=5,5)	0	0
Week 147 - Very much improved (n=2,2)	1	0
Week 147 - Much improved (n=2,2)	0	1
Week 147 - Minimally improved (n=2,2)	0	1
Week 147 - No Change (n=2,2)	1	0
Week 147 - Minimally worse (n=2,2)	0	0
Week 147 - Much worse (n=2,2)	0	0
Week 147 - Very much worse (n=2,2)	0	0
Week 159 - Very much improved (n=1,1)	1	0
Week 159 - Much improved (n=1,1)	0	0
Week 159 - Minimally improved (n=1,1)	0	1
Week 159 - No Change (n=1,1)	0	0
Week 159 - Minimally worse (n=1,1)	0	0
Week 159 - Much worse (n=1,1)	0	0
Week 159 - Very much worse (n=1,1)	0	0
Week 171- Very much improved (n=1,0)	1	0
Week 171- Much improved (n=1,0)	0	0
Week 171- Minimally improved (n=1,0)	0	0
Week 171- No Change (n=1,0)	0	0
Week 171- Minimally worse (n=1,0)	0	0
Week 171- Much worse (n=1,0)	0	0
Week 171- Very much worse (n=1,0)	0	0
ET/SFU Visit- Very much improved (n=19,18)	3	3
ET/SFU Visit- Much improved (n=19,18)	5	6
ET/SFU Visit- Minimally improved (n=19,18)	4	1
ET/SFU Visit- No Change (n=19,18)	3	3
ET/SFU Visit- Minimally worse (n=19,18)	1	2
ET/SFU Visit- Much worse (n=19,18)	3	3
ET/SFU Visit- Very much worse (n=19,18)	0	0

No statistical analyses for this end point

Secondary: Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points

Top of page

End point title

Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points

End point description

Mean change from baseline (Week 0) in LDH levels at each specified time points is reported in this endpoint. Baseline was defined as last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysed on Part B-FAS. Here, 'n' = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: units per litre
arithmetic mean (standard deviation)
Week 27 (n=19,20)	-151.000 ( 184.640 )	0.650 ( 208.051 )
Week 29 (n=18,19)	-115.944 ( 226.913 )	11.000 ( 222.383 )
Week 31 (n=18,17)	-85.111 ( 247.506 )	38.882 ( 211.386 )
Week 33 (n=17,16)	-66.176 ( 324.145 )	4.813 ( 203.939 )
Week 35 (n=18,16)	-64.667 ( 261.431 )	-19.313 ( 142.989 )
Week 37 (n=16,17)	4.438 ( 398.843 )	25.765 ( 219.679 )
Week 39 (n=16,16)	-88.500 ( 271.941 )	27.313 ( 210.705 )
Week 41 (n=18,17)	23.778 ( 342.195 )	-6.000 ( 173.810 )
Week 43 (n=17,17)	-22.118 ( 310.381 )	-21.706 ( 181.668 )
Week 45 (n=17,18)	26.529 ( 329.717 )	-13.500 ( 190.460 )
Week 47 (n=15,18)	-22.600 ( 302.511 )	-24.944 ( 153.580 )
Week 49 (n=16,18)	-29.250 ( 289.392 )	15.722 ( 193.630 )
Week 51 (n=16,18)	-12.563 ( 290.489 )	-9.556 ( 155.646 )
Week 53 (n=16,17)	-16.938 ( 299.788 )	12.529 ( 206.642 )
Week 55 (n=14,16)	-89.500 ( 219.634 )	-11.250 ( 177.647 )
Week 57 (n=15,16)	-78.200 ( 285.140 )	64.188 ( 266.395 )
Week 59 (n=16,17)	-84.438 ( 220.376 )	31.647 ( 226.128 )
Week 61 (n=17,17)	-74.353 ( 215.414 )	20.588 ( 263.984 )
Week 63 (n=17,17)	-98.235 ( 185.259 )	38.059 ( 325.329 )
Week 65 (n=16,15)	-97.438 ( 212.335 )	-16.467 ( 246.765 )
Week 67 (n=17,15)	-127.824 ( 192.148 )	29.667 ( 269.918 )
Week 69 (n=16,16)	-113.625 ( 197.270 )	36.563 ( 303.550 )
Week 71 (n=13,15)	-101.692 ( 320.348 )	4.067 ( 307.924 )
Week 73 (n=14,16)	-174.500 ( 177.153 )	7.063 ( 245.723 )
Week 75 (n=14,15)	-157.429 ( 184.525 )	7.067 ( 285.183 )
Week 77 (n=14,15)	-142.857 ( 199.169 )	-24.867 ( 291.754 )
Week 79 (n=13,16)	-98.077 ( 271.632 )	-20.063 ( 265.761 )
Week 81 (n=13,15)	-127.846 ( 233.663 )	7.200 ( 219.952 )
Week 83 (n=13,11)	-59.000 ( 346.917 )	8.818 ( 250.068 )
Week 85 (n=13,15)	-72.000 ( 350.021 )	28.400 ( 282.626 )
Week 87 (n=13,13)	-101.385 ( 285.590 )	83.385 ( 288.731 )
Week 89 (n=12,12)	-78.667 ( 351.059 )	10.833 ( 323.647 )
Week 91 (n=9,13)	-143.000 ( 273.540 )	0.846 ( 288.451 )
Week 93 (n=10,11)	-133.500 ( 254.332 )	10.818 ( 268.308 )
Week 95 (n=11,13)	-59.364 ( 368.708 )	18.231 ( 241.354 )
Week 97 (n=11,10)	-53.364 ( 343.820 )	-38.500 ( 188.403 )
Week 99 (n=11,12)	-80.909 ( 312.405 )	-12.917 ( 183.844 )
Week 101 (n=11,11)	-90.273 ( 293.680 )	-17.182 ( 249.134 )
Week 103 (n=11,13)	-50.273 ( 331.072 )	5.692 ( 211.233 )
Week 105 (n=11,12)	-96.455 ( 276.907 )	-34.250 ( 147.738 )
Week 107 (n=11,13)	-28.091 ( 354.244 )	20.769 ( 222.772 )
Week 109 (n=11,11)	-50.727 ( 335.078 )	-2.000 ( 243.243 )
Week 111 (n=10,12)	-83.000 ( 303.258 )	-5.583 ( 219.850 )
Week 113 (n=10,12)	-80.700 ( 319.283 )	0.667 ( 294.904 )
Week 115 (n=10,10)	-109.500 ( 256.395 )	44.700 ( 295.946 )
Week 117 (n=9,10)	-140.444 ( 280.944 )	12.700 ( 254.786 )
Week 119 (n=9,10)	-149.556 ( 237.771 )	-26.500 ( 274.168 )
Week 121 (n=9,8)	-195.778 ( 225.978 )	-42.375 ( 211.840 )
Week 123 (n=9,9)	-185.000 ( 231.489 )	22.222 ( 278.037 )
Week 125 (n=7,7)	-99.429 ( 285.513 )	-85.143 ( 265.374 )
Week 127 (n=7,8)	-154.714 ( 231.922 )	-28.875 ( 312.483 )
Week 129 (n=7,7)	-136.429 ( 234.954 )	-18.571 ( 354.584 )
Week 131 (n=6,6)	-120.833 ( 300.454 )	-2.000 ( 270.245 )
Week 133 (n=5,4)	-179.000 ( 298.811 )	-47.500 ( 367.639 )
Week 135 (n=5,5)	-211.800 ( 265.438 )	58.000 ( 449.233 )
Week 137 (n=4,2)	-252.500 ( 264.591 )	46.500 ( 768.625 )
Week 139 (n=5,3)	-181.800 ( 284.966 )	-48.667 ( 373.339 )
Week 141 (n=3,3)	-259.667 ( 362.136 )	30.667 ( 372.889 )
Week 143 (n=4,2)	-160.250 ( 357.021 )	-7.500 ( 21.920 )
Week 145 (n=2,2)	-340.500 ( 458.912 )	290.000 ( 562.857 )
Week 147 (n=3,2)	-248.667 ( 355.136 )	311.000 ( 547.301 )
Week 149 (n=1,2)	-78.000 ( 99999 )	116.000 ( 175.362 )
Week 151 (n=2,1)	58.000 ( 32.527 )	295.000 ( 99999 )
Week 153 (n=1,1)	7.000 ( 99999 )	75.000 ( 99999 )
Week 155 (n=1,0)	-50.000 ( 99999 )	9999 ( 99999 )
Week 157 (n=1,1)	-50.000 ( 99999 )	369.000 ( 99999 )
Week 159 (n=1,1)	-155.000 ( 99999 )	365.000 ( 99999 )
Week 161 (n=1,0)	-175.000 ( 99999 )	9999 ( 99999 )
Week 163 (n=1,1)	-149.000 ( 99999 )	782.000 ( 99999 )
Week 165 (n=1,0)	-155.000 ( 99999 )	9999 ( 99999 )
Week 167 (n=1,0)	-162.000 ( 99999 )	9999 ( 99999 )
Week 169 (n=1,0)	-180.000 ( 99999 )	9999 ( 99999 )
Week 171 (n=1,0)	-167.000 ( 99999 )	9999 ( 99999 )
Week 173 (n=1,0)	-171.000 ( 99999 )	9999 ( 99999 )
Week 175 (n=1,0)	-121.000 ( 99999 )	9999 ( 99999 )
ET/SFU Visit (n=16,17)	-2.500 ( 195.967 )	-11.706 ( 206.321 )

No statistical analyses for this end point

Secondary: Part B: Number of Blood Transfusions Per Subject

Top of page

End point title

Part B: Number of Blood Transfusions Per Subject

End point description

A subject was to receive a transfusion if his or her Hgb level met either of the following criteria: Hgb was <9 g/dL and the subject had symptoms of anemia or Hgb was <7 g/dL and the subject was asymptomatic. Analysis was performed on Part B-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]).

End point type

Secondary

End point timeframe

From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: blood transfusions per subject
arithmetic mean (standard deviation)	0.4 ( 0.8 )	0.3 ( 0.4 )

No statistical analyses for this end point

Secondary: Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points

Top of page

End point title

Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points

End point description

Change from baseline (Week 0) in haptoglobin values at each specified time points is reported in this endpoint. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Haptoglobin values <0.2 were imputed as 0.2. Analysis was performed on Part B-FAS. Here, 'n' =subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either at 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: grams per litre
arithmetic mean (standard deviation)
Week 27 (n=19,19)	0.219 ( 0.380 )	0.082 ( 0.197 )
Week 29 (n=18,20)	0.240 ( 0.317 )	0.182 ( 0.482 )
Week 31 (n=19,20)	0.183 ( 0.311 )	0.256 ( 0.516 )
Week 33 (n=19,17)	0.212 ( 0.423 )	0.229 ( 0.379 )
Week 35 (n=18,19)	0.207 ( 0.355 )	0.151 ( 0.280 )
Week 37 (n=18,18)	0.232 ( 0.419 )	0.187 ( 0.291 )
Week 39 (n=16,16)	0.213 ( 0.330 )	0.165 ( 0.295 )
Week 41 (n=19,18)	0.119 ( 0.238 )	0.082 ( 0.168 )
Week 43 (n=18,18)	0.100 ( 0.224 )	0.161 ( 0.234 )
Week 45 (n=18,20)	0.114 ( 0.205 )	0.189 ( 0.275 )
Week 47 (n=15,20)	0.135 ( 0.243 )	0.255 ( 0.416 )
Week 49 (n=16,18)	0.139 ( 0.205 )	0.172 ( 0.345 )
Week 51 (n=15,17)	0.083 ( 0.197 )	0.207 ( 0.369 )
Week 53 (n=16,19)	0.045 ( 0.137 )	0.122 ( 0.296 )
Week 55 (n=17,18)	0.149 ( 0.251 )	0.179 ( 0.343 )
Week 57 (n=16,17)	0.158 ( 0.234 )	0.158 ( 0.362 )
Week 59 (n=17,17)	0.132 ( 0.229 )	0.131 ( 0.306 )
Week 61 (n=17,18)	0.153 ( 0.286 )	0.184 ( 0.350 )
Week 63 (n=17,17)	0.202 ( 0.265 )	0.177 ( 0.357 )
Week 65 (n=16,16)	0.101 ( 0.232 )	0.198 ( 0.384 )
Week 67 (n=17,16)	0.178 ( 0.241 )	0.162 ( 0.363 )
Week 69 (n=16,17)	0.168 ( 0.255 )	0.169 ( 0.348 )
Week 71 (n=14,15)	0.220 ( 0.288 )	0.236 ( 0.388 )
Week 73 (n=14,16)	0.261 ( 0.335 )	0.174 ( 0.348 )
Week 75 (n=15,16)	0.275 ( 0.321 )	0.197 ( 0.362 )
Week 77 (n=14,16)	0.249 ( 0.374 )	0.232 ( 0.398 )
Week 79 (n=14,16)	0.299 ( 0.419 )	0.290 ( 0.464 )
Week 81 (n=13,16)	0.438 ( 0.463 )	0.207 ( 0.421 )
Week 83 (n=14,13)	0.297 ( 0.379 )	0.233 ( 0.394 )
Week 85 (n=13,15)	0.374 ( 0.374 )	0.266 ( 0.426 )
Week 87 (n=12,13)	0.334 ( 0.409 )	0.344 ( 0.471 )
Week 89 (n=12,13)	0.348 ( 0.482 )	0.198 ( 0.351 )
Week 91 (n=11,12)	0.313 ( 0.449 )	0.279 ( 0.449 )
Week 93 (n=11,12)	0.262 ( 0.383 )	0.178 ( 0.373 )
Week 95 (n=11,13)	0.263 ( 0.495 )	0.198 ( 0.414 )
Week 97 (n=11,12)	0.245 ( 0.306 )	0.210 ( 0.407 )
Week 99 (n=11,13)	0.266 ( 0.351 )	0.213 ( 0.370 )
Week 101 (n=11,12)	0.289 ( 0.289 )	0.207 ( 0.417 )
Week 103 (n=11,13)	0.219 ( 0.291 )	0.212 ( 0.389 )
Week 105 (n=11,12)	0.216 ( 0.291 )	0.174 ( 0.399 )
Week 107 (n=11,13)	0.182 ( 0.273 )	0.245 ( 0.459 )
Week 109 (n=10,11)	0.207 ( 0.311 )	0.254 ( 0.507 )
Week 111 (n=11,12)	0.282 ( 0.556 )	0.263 ( 0.459 )
Week 113 (n=11,12)	0.248 ( 0.366 )	0.335 ( 0.614 )
Week 115 (n=10,11)	0.324 ( 0.413 )	0.165 ( 0.432 )
Week 117 (n=9,10)	0.450 ( 0.492 )	0.181 ( 0.489 )
Week 119 (n=9,10)	0.348 ( 0.400 )	0.187 ( 0.404 )
Week 121 (n=9,8)	0.459 ( 0.414 )	0.174 ( 0.479 )
Week 123 (n=9,9)	0.350 ( 0.375 )	0.192 ( 0.512 )
Week 125 (n=8,7)	0.303 ( 0.425 )	0.114 ( 0.298 )
Week 127 (n=7,8)	0.309 ( 0.401 )	0.220 ( 0.420 )
Week 129 (n=7,7)	0.393 ( 0.506 )	0.191 ( 0.506 )
Week 131 (n=6,5)	0.480 ( 0.529 )	0.222 ( 0.430 )
Week 133 (n=5,4)	0.342 ( 0.469 )	0.125 ( 0.155 )
Week 135 (n=5,5)	0.454 ( 0.643 )	0.280 ( 0.425 )
Week 137 (n=4,3)	0.545 ( 0.631 )	0.070 ( 0.121 )
Week 139 (n=5,3)	0.494 ( 0.676 )	0.293 ( 0.508 )
Week 141 (n=3,2)	0.667 ( 0.583 )	0.025 ( 0.035 )
Week 143 (n=4,3)	0.513 ( 0.604 )	0.270 ( 0.292 )
Week 145 (n=2,3)	0.580 ( 0.820 )	0.130 ( 0.141 )
Week 147 (n=3,2)	0.400 ( 0.592 )	0.195 ( 0.276 )
Week 149 (n=1,2)	0.000 ( 99999 )	0.000 ( 0.000 )
Week 151 (n=2,1)	0.000 ( 0.000 )	0.000 ( 99999 )
Week 153 (n=1,1)	0.000 ( 99999 )	0.000 ( 99999 )
Week 155 (n=1,1)	0.000 ( 99999 )	0.000 ( 99999 )
Week 157 (n=1,1)	0.000 ( 99999 )	0.000 ( 99999 )
Week 159 (n=1,1)	0.000 ( 99999 )	0.000 ( 99999 )
Week 161 (n=1,1)	0.180 ( 99999 )	0.000 ( 99999 )
Week 163 (n=1,1)	0.000 ( 99999 )	0.000 ( 99999 )
Week 165 (n=1,0)	0.000 ( 99999 )	9999 ( 99999 )
Week 167 (n=1,0)	0.000 ( 99999 )	9999 ( 99999 )
Week 169 (n=1,0)	0.000 ( 99999 )	99999 ( 99999 )
Week 171 (n=1,0)	0.000 ( 99999 )	9999 ( 99999 )
Week 173 (n=1,0)	0.000 ( 99999 )	9999 ( 99999 )
Week 175 (n=1,0)	0.000 ( 99999 )	9999 ( 99999 )
ET/SFU Visit (n=19,18)	0.055 ( 0.200 )	0.181 ( 0.426 )

No statistical analyses for this end point

Secondary: Part B: Number of Healthcare Visits by Type

Top of page

End point title

Part B: Number of Healthcare Visits by Type

End point description

In this endpoint, number of healthcare visits which included non-study healthcare resource utilisation visit (consisted mainly of extra visits to the office of the study doctor, visit to a generalist doctor or visit to a specialist doctor), hospitalisation visit and visit to hospital emergency is reported. Analysis was performed on Part B-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]).

End point type

Secondary

End point timeframe

From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)

End point values	BIVV009/BIVV009	Placebo/BIVV009
Number of subjects analysed	19	20
Units: visits
number (not applicable)
Non-study healthcare resource utilisation visits	13	12
Hospitalisation	3	1
Visit to a hospital emergency room	1	3

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Part A:first dose (Day 0) up to Week 25; Part B 6.5 g cohort:first dose (Week 26) up to 149 weeks of treatment+9 weeks of follow-up (up to Week 184); Part B, 7.5 g cohort:first dose (Week 26) up to 137 weeks of treatment+9 weeks follow up (up to Week 172)

Adverse event reporting additional description

Reported AEs and SAEs including fatal AEs were TEAEs that developed/worsened or became serious during on-treatment period. Analysis was performed on SAS.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Part A: BIVV009 6.5 g

Reporting group description

Subjects with primary CAD and body weight <75 kg and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of BIVV009 6.5 g on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

Reporting group title

Part A: BIVV009 7.5 g

Reporting group description

Subjects with primary CAD and body weight >=75 kg and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of BIVV009 7.5 g on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

Reporting group title

Part A: Placebo

Reporting group description

Reporting group title

Part B: BIVV009 6.5 g

Reporting group description

Reporting group title

Part B: BIVV009 7.5 g

Reporting group description

Serious adverse events	Part A: BIVV009 6.5 g	Part A: BIVV009 7.5 g	Part A: Placebo	Part B: BIVV009 6.5 g	Part B: BIVV009 7.5 g
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 17 (11.76%)	1 / 5 (20.00%)	0 / 20 (0.00%)	6 / 32 (18.75%)	1 / 7 (14.29%)
number of deaths (all causes)	0	0	0	1	0
number of deaths resulting from adverse events
Investigations
Blood Immunoglobulin M Increased
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (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
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous Cell Carcinoma Of Lung
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (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 / 1	0 / 0
Injury, poisoning and procedural complications
Hip Fracture
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (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
Muscle Strain
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (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
Congenital, familial and genetic disorders
Polycystic Liver Disease
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (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
Vascular disorders
Hypertension
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (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
Raynaud's Phenomenon
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (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
Nervous system disorders
Cerebral Venous Sinus Thrombosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (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
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (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
Musculoskeletal and connective tissue disorders
Lumbar Spinal Stenosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
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
Osteoarthritis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	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
Infections and infestations
Febrile Infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (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
Urinary Tract Infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
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

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

Non-serious adverse events	Part A: BIVV009 6.5 g	Part A: BIVV009 7.5 g	Part A: Placebo	Part B: BIVV009 6.5 g	Part B: BIVV009 7.5 g
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 17 (94.12%)	5 / 5 (100.00%)	3 / 20 (15.00%)	28 / 32 (87.50%)	7 / 7 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0
Melanocytic Naevus
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Vascular disorders
Cyanosis
subjects affected / exposed	4 / 17 (23.53%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	2 / 7 (28.57%)
occurrences all number	10	0	0	2	3
Extremity Necrosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Flushing
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	3
Haematoma
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Hypertension
subjects affected / exposed	4 / 17 (23.53%)	1 / 5 (20.00%)	0 / 20 (0.00%)	5 / 32 (15.63%)	2 / 7 (28.57%)
occurrences all number	7	1	0	7	3
Hypotension
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	1	0	0	1	1
Orthostatic Hypotension
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Poor Venous Access
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0
Raynaud's Phenomenon
subjects affected / exposed	3 / 17 (17.65%)	1 / 5 (20.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	0 / 7 (0.00%)
occurrences all number	4	2	0	3	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	4 / 32 (12.50%)	2 / 7 (28.57%)
occurrences all number	0	1	0	6	2
Catheter Site Dryness
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Chest Discomfort
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Chest Pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Chills
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Fatigue
subjects affected / exposed	1 / 17 (5.88%)	1 / 5 (20.00%)	0 / 20 (0.00%)	7 / 32 (21.88%)	5 / 7 (71.43%)
occurrences all number	1	2	0	7	10
General Physical Health Deterioration
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1
Influenza Like Illness
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	1	0	0	0	1
Injection Site Erythema
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	3	0
Injection Site Pruritus
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Malaise
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1
Oedema Peripheral
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	1 / 7 (14.29%)
occurrences all number	1	0	0	2	1
Pyrexia
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	5 / 32 (15.63%)	1 / 7 (14.29%)
occurrences all number	0	1	0	6	1
Vaccination Site Erythema
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Vaccination Site Pain
subjects affected / exposed	1 / 17 (5.88%)	1 / 5 (20.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	1 / 7 (14.29%)
occurrences all number	1	1	0	2	1
Vaccination Site Rash
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Immune system disorders
Seasonal Allergy
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	1	0	1	1
Reproductive system and breast disorders
Benign Prostatic Hyperplasia
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Breast Calcifications
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0
Breast Cyst
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Cervical Dysplasia
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	1 / 20 (5.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	1	2	0
Dyspnoea
subjects affected / exposed	0 / 17 (0.00%)	2 / 5 (40.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	3 / 7 (42.86%)
occurrences all number	0	2	0	2	4
Epistaxis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	1	0	0	2	0
Oropharyngeal Pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 17 (5.88%)	1 / 5 (20.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	2	1	0	1	0
Depressed Mood
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0
Insomnia
subjects affected / exposed	1 / 17 (5.88%)	1 / 5 (20.00%)	0 / 20 (0.00%)	4 / 32 (12.50%)	0 / 7 (0.00%)
occurrences all number	2	1	0	8	0
Product issues
Device Kink
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Aspartate Aminotransferase Increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	2
Blood Immunoglobulin M Increased
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0
Blood Pressure Increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	3	0
Blood Urine Present
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Transaminases Increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
White Blood Cell Count Decreased
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0
Injury, poisoning and procedural complications
Face Injury
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Fall
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	4 / 32 (12.50%)	1 / 7 (14.29%)
occurrences all number	1	0	0	5	3
Fibula Fracture
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Infusion Related Reaction
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	2	0	0	1	0
Skin Laceration
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0
Sunburn
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Tooth Fracture
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	1	0	0	1	1
Vaccination Complication
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Wound
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	2 / 7 (28.57%)
occurrences all number	0	0	0	1	2
Tachycardia
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 17 (11.76%)	0 / 5 (0.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	2 / 7 (28.57%)
occurrences all number	2	0	0	3	2
Headache
subjects affected / exposed	4 / 17 (23.53%)	1 / 5 (20.00%)	0 / 20 (0.00%)	4 / 32 (12.50%)	2 / 7 (28.57%)
occurrences all number	7	1	0	9	5
Memory Impairment
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0
Paraesthesia
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Parkinsonism
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Phantom Limb Syndrome
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 17 (0.00%)	2 / 5 (40.00%)	0 / 20 (0.00%)	9 / 32 (28.13%)	2 / 7 (28.57%)
occurrences all number	0	2	0	11	3
Blood Loss Anaemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Haemolysis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0
Iron Deficiency Anaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	1 / 7 (14.29%)
occurrences all number	0	0	0	4	1
Leukocytosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	1	0	0	2	0
Eye disorders
Visual Acuity Reduced
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	0 / 7 (0.00%)
occurrences all number	0	0	0	3	0
Abdominal Pain Upper
subjects affected / exposed	1 / 17 (5.88%)	1 / 5 (20.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	1	1	0	2	0
Angular Cheilitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Colitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Constipation
subjects affected / exposed	2 / 17 (11.76%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	4	0	0	3	0
Dental Caries
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Diarrhoea
subjects affected / exposed	1 / 17 (5.88%)	1 / 5 (20.00%)	0 / 20 (0.00%)	6 / 32 (18.75%)	1 / 7 (14.29%)
occurrences all number	1	4	0	13	1
Dyspepsia
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	0 / 7 (0.00%)
occurrences all number	0	0	0	4	0
Faeces Discoloured
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Glossodynia
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Nausea
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	2 / 7 (28.57%)
occurrences all number	2	0	0	3	2
Odynophagia
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Paraesthesia Oral
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Tongue Ulceration
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Toothache
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Vomiting
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0
Hepatobiliary disorders
Biliary Colic
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Cholelithiasis
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Dermatitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Dry Skin
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0
Eczema
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	3	0
Erythema
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1
Night Sweats
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1
Pruritus
subjects affected / exposed	2 / 17 (11.76%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	2 / 7 (28.57%)
occurrences all number	3	0	0	1	2
Rash
subjects affected / exposed	2 / 17 (11.76%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	2	0	0	1	0
Skin Discolouration
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	0
Skin Lesion
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Toxic Skin Eruption
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Haemoglobinuria
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	2 / 7 (28.57%)
occurrences all number	1	0	0	3	2
Renal Cyst
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 17 (11.76%)	1 / 5 (20.00%)	1 / 20 (5.00%)	6 / 32 (18.75%)	2 / 7 (28.57%)
occurrences all number	2	1	1	7	2
Back Pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	1 / 20 (5.00%)	2 / 32 (6.25%)	1 / 7 (14.29%)
occurrences all number	0	0	1	2	1
Bone Swelling
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Lumbar Spinal Stenosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Muscle Spasms
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Musculoskeletal Pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Myalgia
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1
Neck Pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0
Pain In Extremity
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	1 / 7 (14.29%)
occurrences all number	0	0	0	2	1
Pain In Jaw
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Infections and infestations
Anal Abscess
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Cystitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	2 / 7 (28.57%)
occurrences all number	0	0	0	2	2
Diverticulitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0
Gastroenteritis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	3 / 32 (9.38%)	1 / 7 (14.29%)
occurrences all number	0	0	0	3	1
Herpes Zoster
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0
Influenza
subjects affected / exposed	2 / 17 (11.76%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0
Mastoiditis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 17 (0.00%)	2 / 5 (40.00%)	0 / 20 (0.00%)	5 / 32 (15.63%)	2 / 7 (28.57%)
occurrences all number	0	2	0	9	3
Oral Candidiasis
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Oral Herpes
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0
Pneumonia
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory Tract Infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	1 / 20 (5.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	1	1	1
Rhinitis
subjects affected / exposed	3 / 17 (17.65%)	1 / 5 (20.00%)	0 / 20 (0.00%)	2 / 32 (6.25%)	1 / 7 (14.29%)
occurrences all number	3	1	0	4	1
Sinusitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0
Skin Candida
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0
Staphylococcal Skin Infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0
Tooth Infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	4 / 32 (12.50%)	1 / 7 (14.29%)
occurrences all number	0	1	0	5	2
Urinary Tract Infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	1
Vulval Abscess
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	2	0	0	1	0
Diabetes Mellitus
subjects affected / exposed	0 / 17 (0.00%)	0 / 5 (0.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1
Hyperkalaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 5 (20.00%)	0 / 20 (0.00%)	0 / 32 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	1
Iron Deficiency
subjects affected / exposed	1 / 17 (5.88%)	0 / 5 (0.00%)	0 / 20 (0.00%)	1 / 32 (3.13%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

09 Sep 2017

Following changes were done: Incorporated a change in responsibility and obligations of the study sponsor; deleted exploratory efficacy end-point PGIS; changed timing of 12 lead electrocardiogram assessments.

21 Mar 2018

Following Changes were made: Consolidated all of changes in Amendments 1.1 to 1.6; added Phase 3 to title; updated background and study rationale; specified Part B length of study was 1 year and not approximately 1 year; End of Study/EOT visits were changed from 6 weeks to 9 weeks post last dose; number of subjects was changed from 40 subjects to approximately 40 subjects; added that subjects who received transfusion during Part A would be eligible for Part B; Inclusion criterion 5: Updated to include subjects with Gilbert’s Syndrome with bilirubin > upper limit of normal; inclusion criterion 6: added that subjects with ferritin values <lowe were not to be included and allowed concurrent treatment with iron supplementation if subject on a stable dose; Inclusion criterion 9: serogroup B meningococcus was added as a requirement; added inclusion criterion 10: subjects had to be willing to receive transfusion during study if they met study criteria for infusion; Inclusion criteria 12 and 13: post treatment birth control requirement increased from 6 to 9 weeks; Exclusion criterion 2: changed to exclude subjects with a blood transfusion within 6 months of screening or >1 transfusion within 12 months of screening; Exclusion criterion 4: Added that subjects with existing ANA could be adjudicated; Exclusion criterion 14 added: excluded subjects with hypersensitivity to sutimlimab or its components; original Appendix B (Vaccination Schedule) was removed and vaccination instructions were included within body of protocol; original Appendix C (Guidelines for Diagnosis and Treatment of Hypersensitivity Reactions and Anaphylaxis) was removed; healthcare resource utilisation survey was added to the assessments and description of the survey was added as an appendix; appendices were renumbered; For consistency across protocols, hemolytic “flare” was changed to hemolytic breakthrough; beginning on Day 0, urine pregnancy testing was changed to serum or urine pregnancy testing.

19 Jul 2018

Following changes were done: The study number was revised; PGIS was added per United States Food and Drug Administration request; a 25 milliliter (mL) vial (50 mg/mL) vial was added; inclusion criterion 9: added that previous vaccinations had to be documented records and serogroup B meningococcus vaccine requirement only applied where available (this was already included elsewhere in the protocol); corrected start date for the collection of pharmacokinetics and pharmacodynamics samples during Part B; sutimlimab background information of the study was revised for clarity and updated to mention Part E; added that subjects who received transfusion(s) during screening/observation period had to have their baseline visit at least 7 days after the transfusion; for subjects who had a transfusion, screening period could have been extended from 6 to 7 weeks; updated clinical experience section; the vaccination schedule from the country-specific protocol for Japan (Version 3.1) was added to the vaccination schedule for the other participating countries; windows were added for post-dose vital signs, ECGs, and PK/PD sampling time points; modified text to indicate sutimlimab would be supplied in larger volume and concentration.

15 Oct 2019

Following changes were done: Added home infusion in prespecified countries (US, Netherlands, Norway, France, Italy, Austria, Germany, Spain) in Part B, which was to be supported by a healthcare professional caregiver; added exploratory objective to describe the safety and subjects satisfaction with the convenience of home infusions with sutimlimab in a subset of subjects in Part B; added secondary objective to Part B to exploratory objective to evaluate immunogenicity of sutimlimab; added more time points for ADA sample collection and same objective added as an exploratory objective to Parts A and B; efficacy endpoint added to assess satisfaction with home infusion; safety endpoint added to assess AEs with home infusion; specified that predose PD back-up samples could be used to assess immunogenicity in subjects who consented to future use of sample; added time points for systemic lupus erythematosus panel sample collection during Part B. • Clarified PK/PD sampling schedules for Part B to match text description to assessment table • Corrected Appendix A to delete iron from chemistry panel • Added Appendix K which described country-specific requirements for home infusion substudy

07 Jul 2020

Following changes were done: Hypersensitivity or allergic reactions including anaphylaxis to IMP were added to reasons for study discontinuation; to match the statistical analysis plan, the intent-to-treat population was to be referred to as the Full Analysis Set; for home infusion substudy, removed requirements for cardiac resuscitation equipment during home infusion as the risk of emergency situations occurring during home infusions was minimized by enrolling subjects without a history of hypersensitivity reactions to IMP and assistance by personnel trained in basic life support was implemented; added that substudy is only open to subjects who have not or do not plan to receive undiluted infusions; introduced the option of infusion with undiluted solution of sutimlimab in a subset of subjects in Part B; added exploratory endpoint to describe safety of undiluted infusions in Part B; reworded primary endpoint (“responder”) definition for clarity, but definition was unchanged; clarified the order of post dose assessments so that assessments that may impact vital signs (eg, blood draws) occur after vital signs are measured.

04 Nov 2020

Following changes were done: “Post-infusion vital signs and” were added to the list of endpoints for the subjects receiving undiluted infusions; for the primary endpoint (responder status) analysis for Part A, Fisher’s Exact test was replaced by “Cochran-Mantel-Haenszel (CMH) test”; post infusion vital signs and” were added to the list of endpoints for the subjects receiving undiluted infusions; In Table 3, footnote “l” “added the follow text, “or for post-infusion vital signs in case of undiluted administration, after each undiluted infusion”; references to the study procedural manual were either removed or replaced by references to the applicable study manuals; references to the central laboratory were removed from the laboratory evaluation section; primary efficacy analysis method was changed from Fisher’s exact test to a stratified CMH test.

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WITHOUT A RECENT HISTORY OF BLOOD TRANSFUSION

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A: Percentage of Subjects With Response to Treatment

Primary: Part A: Percentage of Subjects With Response to Treatment

Primary: Part B: Number of Subjects With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs)

Primary: Part B: Number of Subjects With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs)

Secondary: Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint

Secondary: Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint

Secondary: Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint

Secondary: Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint

Secondary: Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint

Secondary: Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint

Secondary: Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint

Secondary: Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint

Secondary: Part A: Percentage of Subjects With Solicited Symptomatic Anemia at Week 26

Secondary: Part A: Percentage of Subjects With Solicited Symptomatic Anemia at Week 26

Secondary: Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points

Secondary: Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points

Secondary: Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points

Secondary: Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points

Secondary: Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points

Secondary: Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points

Secondary: Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points

Secondary: Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points

Secondary: Part B: Change From Baseline in 5-level European Quality of Life 5- Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Each Specified Time Points

Secondary: Part B: Change From Baseline in 5-level European Quality of Life 5- Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Each Specified Time Points

Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points

Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points

Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points

Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points

Secondary: Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points

Secondary: Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points

Secondary: Part B: Number of Blood Transfusions Per Subject

Secondary: Part B: Number of Blood Transfusions Per Subject

Secondary: Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points

Secondary: Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points

Secondary: Part B: Number of Healthcare Visits by Type

Secondary: Part B: Number of Healthcare Visits by Type

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WITHOUT A RECENT HISTORY OF BLOOD TRANSFUSION