Clinical Trial Results:
A Phase 3b, Prospective, Open-Label, Uncontrolled, Multicenter Study on Long-Term Safety and Efficacy of rVWF in Pediatric and Adult Subjects With Severe Von Willebrand Disease (VWD)

Clinical trials

Clinical Trial Results: A Phase 3b, Prospective, Open-Label, Uncontrolled, Multicenter Study on Long-Term Safety and Efficacy of rVWF in Pediatric and Adult Subjects With Severe Von Willebrand Disease (VWD)

Clinical Trial Results:
A Phase 3b, Prospective, Open-Label, Uncontrolled, Multicenter Study on Long-Term Safety and Efficacy of rVWF in Pediatric and Adult Subjects With Severe Von Willebrand Disease (VWD)

Trial information

Subject disposition

Baseline characteristics

End points

Adverse events

More information

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Adverse events

Adverse events

More information

More information

Primary: Spontaneous Annualized Bleeding Rate (sABR)

Secondary: Number of participants with Treatment emergent Adverse Events (TEAEs) and Serious TEAEs

Secondary: Number of Participants Based on Severity of TEAEs

Secondary: Number of Participants Based on Causality of TEAEs

Secondary: Number of Participants With Thromboembolic Events

Secondary: Number of Participants who Developed Neutralizing Antibodies to von Willebrand factor (VWF)

Secondary: Number of Participants With Hypersensitivity Reactions

Secondary: Number of Participants who Developed Total Binding Antibodies to von Willebrand factor (VWF)

Secondary: Number of Participants who Developed Neutralizing Antibodies to Factor VIII (FVIII)

Secondary: Number of Participants who Developed Binding Antibodies to Chinese hamster ovary (CHO) proteins

Secondary: Number of Participants who Developed Total Binding Antibodies to Factor VIII (FVIII)

Secondary: Number of Participants who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG)

Secondary: Number of Participants who Develop Binding Antibodies to recombinant Furin (rFurin)

Secondary: Number of Participants With Clinically Significant Changes in Vital Signs

Secondary: Number of Participants With Clinically Significant Changes in Laboratory Parameters

Secondary: Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment

Secondary: Number of Participants Categorized Based on Weekly Number of Infusions

Secondary: Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR)

Secondary: Time to First Bleeding Event on Prophylaxis Treatment

Secondary: Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding

Secondary: Total Number of Infusions During Prophylactic Treatment

Secondary: Average Number of Infusions Per Week During Prophylactic Treatment

Secondary: Number of Participants who Achieved Transfusion-free Maintenance of Hemoglobin Levels

Secondary: Change From Baseline in Ferritin Levels Over Time

Secondary: Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment

Secondary: Overall Hemostatic Efficacy Rating

Secondary: Number of Infusions of ADVATE

Secondary: Number of Infusions of Vonicog Alfa

Secondary: Weight-adjusted Consumption of Vonicog alfa per Bleeding Episode

Secondary: Weight-adjusted Consumption of ADVATE per Bleeding Episode

Primary: Spontaneous Annualized Bleeding Rate (sABR)

Primary: Spontaneous Annualized Bleeding Rate (sABR)

Secondary: Number of participants with Treatment emergent Adverse Events (TEAEs) and Serious TEAEs

Secondary: Number of participants with Treatment emergent Adverse Events (TEAEs) and Serious TEAEs

Secondary: Number of Participants Based on Severity of TEAEs

Secondary: Number of Participants Based on Severity of TEAEs

Secondary: Number of Participants Based on Causality of TEAEs

Secondary: Number of Participants Based on Causality of TEAEs

Secondary: Number of Participants With Thromboembolic Events

Secondary: Number of Participants With Thromboembolic Events

Secondary: Number of Participants who Developed Neutralizing Antibodies to von Willebrand factor (VWF)

Secondary: Number of Participants who Developed Neutralizing Antibodies to von Willebrand factor (VWF)

Secondary: Number of Participants With Hypersensitivity Reactions

Secondary: Number of Participants With Hypersensitivity Reactions

Secondary: Number of Participants who Developed Total Binding Antibodies to von Willebrand factor (VWF)

Secondary: Number of Participants who Developed Total Binding Antibodies to von Willebrand factor (VWF)

Secondary: Number of Participants who Developed Neutralizing Antibodies to Factor VIII (FVIII)

Secondary: Number of Participants who Developed Neutralizing Antibodies to Factor VIII (FVIII)

Secondary: Number of Participants who Developed Binding Antibodies to Chinese hamster ovary (CHO) proteins

Secondary: Number of Participants who Developed Binding Antibodies to Chinese hamster ovary (CHO) proteins

Secondary: Number of Participants who Developed Total Binding Antibodies to Factor VIII (FVIII)

Secondary: Number of Participants who Developed Total Binding Antibodies to Factor VIII (FVIII)

Secondary: Number of Participants who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG)

Secondary: Number of Participants who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG)

Secondary: Number of Participants who Develop Binding Antibodies to recombinant Furin (rFurin)

Secondary: Number of Participants who Develop Binding Antibodies to recombinant Furin (rFurin)

Secondary: Number of Participants With Clinically Significant Changes in Vital Signs

Secondary: Number of Participants With Clinically Significant Changes in Vital Signs

Secondary: Number of Participants With Clinically Significant Changes in Laboratory Parameters

Secondary: Number of Participants With Clinically Significant Changes in Laboratory Parameters

Secondary: Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment

Secondary: Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment

Secondary: Number of Participants Categorized Based on Weekly Number of Infusions

Secondary: Number of Participants Categorized Based on Weekly Number of Infusions

Secondary: Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR)

Secondary: Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR)

Secondary: Time to First Bleeding Event on Prophylaxis Treatment

Secondary: Time to First Bleeding Event on Prophylaxis Treatment

Secondary: Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding

Secondary: Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding

Secondary: Total Number of Infusions During Prophylactic Treatment

Secondary: Total Number of Infusions During Prophylactic Treatment

Secondary: Average Number of Infusions Per Week During Prophylactic Treatment

Secondary: Average Number of Infusions Per Week During Prophylactic Treatment

Secondary: Number of Participants who Achieved Transfusion-free Maintenance of Hemoglobin Levels

Secondary: Number of Participants who Achieved Transfusion-free Maintenance of Hemoglobin Levels

Secondary: Change From Baseline in Ferritin Levels Over Time

Secondary: Change From Baseline in Ferritin Levels Over Time

Secondary: Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment

Secondary: Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment

Secondary: Overall Hemostatic Efficacy Rating

Secondary: Overall Hemostatic Efficacy Rating

Secondary: Number of Infusions of ADVATE

Secondary: Number of Infusions of ADVATE

Secondary: Number of Infusions of Vonicog Alfa

Secondary: Number of Infusions of Vonicog Alfa

Secondary: Weight-adjusted Consumption of Vonicog alfa per Bleeding Episode

Secondary: Weight-adjusted Consumption of Vonicog alfa per Bleeding Episode

Secondary: Weight-adjusted Consumption of ADVATE per Bleeding Episode

Secondary: Weight-adjusted Consumption of ADVATE per Bleeding Episode

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Summary
EudraCT number	2018-003453-16
Trial protocol	FR NL DE ES AT IT BE
Global end of trial date	30 Jan 2025

Results information
Results version number	v1(current)
This version publication date	20 Jul 2025
First version publication date	20 Jul 2025
Other versions

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

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Sponsor protocol code

SHP677-304

ISRCTN number

US NCT number

NCT03879135

WHO universal trial number (UTN)

Sponsor organisation name

Takeda

Sponsor organisation address

95 Hayden Ave, Lexington, MA, United States, 02421

Public contact

Study Director, Takeda, TrialDisclosures@takeda.com

Scientific contact

Study Director, Takeda, TrialDisclosures@takeda.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?

Yes

Analysis stage

Final

Date of interim/final analysis

30 Jan 2025

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2025

Was the trial ended prematurely?

Main objective of the trial

The main aim of this study is to check effectiveness of rVWF (vonicog alfa) prophylaxis based on the annualized bleeding rate (ABR) of spontaneous (not related to trauma) bleeding episodes in pediatric and adult participants during the first 12 months on study treatment.

Protection of trial subjects

Each participant or their parents/guardians/legally authorized representatives signed an informed consent form (ICF) before participating in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Apr 2019

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Italy: 3

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

Türkiye: 11

Country: Number of subjects enrolled

United States: 11

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

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Recruitment details

Participants took part in the study at 23 investigative sites globally from 1 April 2019 to 30 January 2025.

Screening details

38 subjects with diagnosis of Von Willebrand disease were enrolled. Only subjects who received treatment(N=35) were included in analysis.These subjects received rVWF(vonicog alfa), 50±10 IU/kg,IV infusion in either prophylaxis/OD cohorts. Some subjects received supportive treatment with ADVATE for treating BEs if deemed necessary by investigator.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Prophylaxis

Arm description

Adult participants who transitioned from the phase 3 prophylaxis parent study 071301 (NCT02973087) received the same prophylactic dose, 50±10 IU/kg, IV infusion of vonicog alfa twice weekly as in parent study 071301.

Arm type

Experimental

Investigational medicinal product name

Vonicog alfa

Investigational medicinal product code

Other name

BAX-111, SHP-677, TAK-577

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vonicog alfa, prophylactic dose 50±10 IU/kg, IV, infusion, twice weekly.

Cohort 2: Prophylaxis

Arm description

Adult participants who transitioned from parent study 071301 (NCT02973087) with no clinically significant BE for the past 6 months started this continuation study at a lower dose/frequency of vonicog alfa once weekly or twice weekly prophylactic dose, 50±10 IU/kg, IV infusion compared to the dose received (50±10 IU/kg, IV infusion, thrice weekly) in parent study 071301.

Arm type

Experimental

Investigational medicinal product name

Vonicog alfa

Investigational medicinal product code

Other name

BAX-111, SHP-677, TAK-577

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vonicog alfa, prophylactic dose 50±10 IU/kg, IV infusion, once weekly or twice weekly.

Cohort 3: Prophylaxis

Arm description

Adolescent participants (aged 12 to <18 years) who transitioned from the phase 3 OD and surgery parent study 071102 (NCT02932618) switched from receiving vonicog alfa OD treatment to receiving prophylactic dose of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Arm type

Experimental

Investigational medicinal product name

Vonicog alfa

Investigational medicinal product code

Other name

BAX-111, SHP-677, TAK-577

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vonicog alfa, prophylactic dose, 50±10 IU/kg, IV infusion once weekly or twice weekly .

Cohort 4: Prophylaxis

Arm description

Newly enrolled adult and adolescent (aged 12 to <18 years) participants who switched from OD treatment with Von Willebrand Factor (VWF) products started 50±10 IU/kg, IV infusion once weekly prophylaxis with vonicog alfa in this continuation study.

Arm type

Experimental

Investigational medicinal product name

Vonicog alfa

Investigational medicinal product code

Other name

BAX-111, SHP-677, TAK-577

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vonicog alfa prophylactic dose, 50±10 IU/kg, IV infusion, once weekly.

Cohort 5: On Demand

Arm description

Pediatric participants of all ages from parent study 071102 (NCT02932618) continued receiving OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Arm type

Experimental

Investigational medicinal product name

Vonicog alfa

Investigational medicinal product code

Other name

BAX-111, SHP-677, TAK-577

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vonicog alfa, 50±10 IU/kg, IV infusion, once weekly or twice weekly.

Cohort 6: On Demand

Arm description

Adult participants from parent study 071301 (NCT02973087) switched back from prophylactic treatment in study 071301 to OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Arm type

Experimental

Investigational medicinal product name

Vonicog alfa

Investigational medicinal product code

Other name

BAX-111, SHP-677, TAK-577

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vonicog alfa, 50±10 IU/kg, IV infusion once weekly or twice weekly.

Number of subjects in period 1	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Started	10	1	1	5	16	2
Completed	10	1	1	3	15	1
Not completed	0	0	0	2	1	1
Physician decision	-	-	-	1	-	-
Consent withdrawn by subject	-	-	-	-	-	1
Site Closed by Sponsor	-	-	-	1	1	-

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Reporting group title

Cohort 1: Prophylaxis

Reporting group description

Reporting group title

Cohort 2: Prophylaxis

Reporting group description

Reporting group title

Cohort 3: Prophylaxis

Reporting group description

Reporting group title

Cohort 4: Prophylaxis

Reporting group description

Reporting group title

Cohort 5: On Demand

Reporting group description

Reporting group title

Cohort 6: On Demand

Reporting group description

Reporting group values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand	Total
Number of subjects	10	1	1	5	16	2	35
Age categorical
Units: participants
<6 years	0	0	0	0	3	0	3
>=6 to <12 years	0	0	0	0	5	0	5
>=12 to <18 years	0	0	1	2	6	0	9
>=18 years	10	1	0	3	2	2	18
Gender categorical
Units: Subjects
Female	4	1	0	2	9	1	17
Male	6	0	1	3	7	1	18
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0
White	9	0	1	4	14	2	30
More than one race	0	0	0	0	1	0	1
Unknown or Not Reported	1	1	0	1	1	0	4
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	0	0	1	0	2
Not Hispanic or Latino	8	0	1	5	14	2	30
Unknown or Not Reported	1	1	0	0	1	0	3

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Reporting group title

Cohort 1: Prophylaxis

Reporting group description

Reporting group title

Cohort 2: Prophylaxis

Reporting group description

Reporting group title

Cohort 3: Prophylaxis

Reporting group description

Reporting group title

Cohort 4: Prophylaxis

Reporting group description

Reporting group title

Cohort 5: On Demand

Reporting group description

Reporting group title

Cohort 6: On Demand

Reporting group description

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End point title

Spontaneous Annualized Bleeding Rate (sABR) ^[1] ^[2]

End point description

sABR was derived as [number of treated bleeds] / [duration in years]. Bleeds with unknown causality were considered as spontaneous. Bleeds were categorized based on the investigator assessment of cause. sABR during the first 12 months of prophylactic treatment with rVWF (vonicog alfa) was reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. '99999' denotes that standard deviation was not estimable for a single participant.

End point type

Primary

End point timeframe

Up to 12 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis was planned for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: spontaneous bleeds per year
arithmetic mean (standard deviation)	1.430 ( 2.3894 )	1.040 ( 99999 )	0.000 ( 99999 )	3.022 ( 2.4746 )

No statistical analyses for this end point

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End point title

Number of participants with Treatment emergent Adverse Events (TEAEs) and Serious TEAEs

End point description

AE:any untoward medical occurrence in participant administered a pharmaceutical product;untoward medical occurrence does not necessarily have a causal relationship with this treatment.AE can therefore be any unfavorable&unintended sign(including an abnormal laboratory finding),symptom/disease temporally associated with use of medicinal(investigational) product whether or not it is related to medicinal product.TEAE :any AE that started after first administration of study drug in this continuation study.Serious TEAEs:any untoward medical occurrence that:results in death,is life-threatening,requires inpatient hospitalization/prolongation of existing hospitalization,results in persistent/significant disability/incapacity,leads to a congenital anomaly/birth defect in offspring of participant/ is medically important.SAS:all participants who received any amount of vonicog alfa as obtained from study drug administration eDiary,study drug administration details eCRF,or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants
TEAEs	8	1	1	4	15	2
Serious TEAEs	3	0	0	1	3	1

No statistical analyses for this end point

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End point title

Number of Participants Based on Severity of TEAEs

End point description

An AE is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. Severity of TEAEs was determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities and may required therapeutic intervention; Severe: Inability to carry out usual activities with sequelae, which required therapeutic intervention. Number of participants with TEAEs based on severity of TEAEs were reported. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

No statistical analyses for this end point

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End point title

Number of Participants Based on Causality of TEAEs

End point description

An AE is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAE was defined as any AE that started after the first administration of study drug in this continuation study. A physician/investigator made the assessment of relationship to investigational product for each AE. Number of participants with TEAEs based on causality were reported. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants With Thromboembolic Events

End point description

Thromboembolism defined as formation of a clot (thrombus) in a blood vessel that breaks loose, is carried by the blood stream and could plug another vessel. Number of participants with thromboembolic events as TEAEs of special interest were reported. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants who Developed Neutralizing Antibodies to von Willebrand factor (VWF)

End point description

Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities were measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of participants who developed neutralizing antibodies to rVWF were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants With Hypersensitivity Reactions

End point description

Hypersensitivity (also called hypersensitivity reaction or intolerance) defined as undesirable reactions produced by the normal immune system, including allergies and autoimmunity. Potential hypersensitivity events were identified by broad search criteria and then medically assessed. Number of participants with hypersensitivity reactions as TEAEs of special interest was calculated. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants who Developed Total Binding Antibodies to von Willebrand factor (VWF)

End point description

The presence of total binding anti-VWF antibodies was determined by an enzyme-linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin (Ig) antibodies (IgG, IgM and IgA). Number of participants who developed of total binding antibodies to rVWF were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants who Developed Neutralizing Antibodies to Factor VIII (FVIII)

End point description

Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities was measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of participants who developed neutralizing antibodies to FVIII were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants who Developed Binding Antibodies to Chinese hamster ovary (CHO) proteins

End point description

Total Ig antibodies (IgG, IgA, IgM) against CHO protein were analyzed using ELISA. Number of participants who developed binding antibodies to CHO proteins were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants who Developed Total Binding Antibodies to Factor VIII (FVIII)

End point description

Binding antibodies against FVIII were analyzed using a proprietary enzyme immunoassay. Number of participants who developed of total binding antibodies to FVIII were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	1	0

No statistical analyses for this end point

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End point title

Number of Participants who Developed Binding Antibodies to Mouse Immunoglobulin G (IgG)

End point description

Detection and quantification of IgG antibodies originating from human plasma that were directed against mouse-IgG (HAMA: human anti- mouse antibodies) were assessed using ELISA (Medac, Hamburg, Germany). Number of participants who developed binding antibodies to Mouse IgG were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants who Develop Binding Antibodies to recombinant Furin (rFurin)

End point description

Total Ig antibodies (IgG, IgA, IgM) against human furin were analyzed using ELISA. Number of participants who developed binding antibodies to rFurin were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants With Clinically Significant Changes in Vital Signs

End point description

Vital signs included blood pressure (systolic and diastolic), pulse rate, respiratory rate and body temperature. Number of participants with clinically significant change from baseline in vital signs were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants With Clinically Significant Changes in Laboratory Parameters

End point description

Clinical laboratory parameters included serum chemistry, hematology and urinalysis assessments. Number of participants with clinically significant change from baseline in clinical laboratory parameters were assessed. The SAS consisted of all participants who received any amount of vonicog alfa as obtained from the study drug administration eDiary, study drug administration details eCRF, or PK infusion eCRF. '9999' denotes that no postbaseline results were collected for any urinalysis parameters in the OD cohorts.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	10	1	1	5	16	2
Units: participants
Serum Chemistry	0	0	0	0	0	0
Hematology	0	0	0	0	0	0
Urinalysis	0	0	0	0	9999	9999

No statistical analyses for this end point

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End point title

Spontaneous Annualized Bleeding Rate (sABR) Under Prophylactic Treatment ^[3]

End point description

sABR was derived as [number of treated bleeds] / [duration in years]. Bleeds with unknown causality were considered as spontaneous. Bleeds were categorized based on the investigator assessment of cause. sABR during prophylaxis treatment with rVWF (vonicog alfa) while enrolled in the study were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. '99999' denotes that standard deviation was not estimable for a single participant.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: spontaneous bleeds per year
arithmetic mean (standard deviation)	1.122 ( 2.1084 )	0.330 ( 99999 )	0.000 ( 99999 )	2.110 ( 1.9954 )

No statistical analyses for this end point

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End point title

Number of Participants Categorized Based on Weekly Number of Infusions ^[4]

End point description

Categorized as ≥ 0 to < 1 infusion per week, ≥ 1 to < 2 infusions per week, ≥ 2 to < 3 infusions per week, ≥ 3 infusions per week. The number of participants categorized based on number of infusions per week during prophylactic treatment with rVWF (vonicog alfa) were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: participants
≥0 to <1	1	0	0	0
≥ 1to <2	6	1	1	5
≥2 to <3	3	0	0	0
≥3	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Participants Categorized Based on Spontaneous Annualized Bleeding Rate (sABR) ^[5]

End point description

The sABR was the number of spontaneous bleeds divided by the observation period in years, where an observation period = (date of completion/termination-date of first dose+1)/365.2425. sABR was categorized based on number of BEs as 0, greater than (>) 0 through 2, >2 through 5, >5 during the prophylactic treatment with rVWF (vonicog alfa). Bleeding at multiple locations related to the same injury was counted as single BE. BEs of unknown cause were counted as spontaneous bleeds. Number of participants categorized based on sABR during prophylactic treatment with rVWF (vonicog alfa) were reported. The FAS consisted of all participants who satisfied all entry criteria and received any amount of study drug.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: participants
0 bleeds/year	5	0	1	0
>0 to ≤2 bleeds/year	3	1	0	3
>2 to ≤5 bleeds/year	1	0	0	1
>5 bleeds/year	1	0	0	1

No statistical analyses for this end point

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End point title

Time to First Bleeding Event on Prophylaxis Treatment ^[6]

End point description

Time to event estimates and confidence intervals obtained from Kaplan-Meier analysis. Participants with 0 bleeds during each study period were censored at the date of the last day in that study period. The FAS consisted of all participants who satisfied all entry criteria and received any amount of study drug. Subjects analysed is the number of participants with event. '9' and '99999' indicates that the lower and upper limit of 95% Confidence interval (CI) was not estimable due to censoring.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	7	1	0 ^[7]	5
Units: days
median (confidence interval 95%)	172 (5 to 99999)	141 (9 to 99999)	( to )	88 (9 to 99999)

Notes
[7] - No participants with data were available for analyses.

No statistical analyses for this end point

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End point title

Spontaneous Annualized Bleeding Rate (sABR) by Location of Bleeding ^[8]

End point description

sABR was derived as [number of treated bleeds] / [duration in years]. sABR for BEs based on location of bleeding: Skin, Muscle, Mucosal Nasal, Mucosal Oral, Joint, Gastrointestinal (GI), Menstrual/Heavy Menstrual, Venipuncture Site, Soft Tissue, Body Cavity, Hematuria, Central Nervous System (CNS) and Other, while on prophylactic treatment with rVWF (vonicog alfa) were reported. The FAS consisted of all participants who satisfied all entry criteria and received any amount of study drug. 'n' is the number of participants with data available for analyses for the specified category. 'n' denotes the number of participants with data available for analyses for the specified category. '999' denotes mean was not estimable as number of participants analysed was zero. '99999' indicates that standard deviation was not estimable for a single participant.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: bleeds per year
arithmetic mean (standard deviation)
Skin (n=10,1,1,5)	0.033 ( 0.1044 )	0.000 ( 99999 )	0.000 ( 99999 )	0.000 ( 0.0000 )
Muscle (n=10,1,1,5)	0.000 ( 0.0000 )	0.000 ( 99999 )	0.000 ( 99999 )	0.068 ( 0.1521 )
Mucosal, Nasal (n=10,1,1,5)	0.199 ( 0.3542 )	0.000 ( 99999 )	0.000 ( 99999 )	0.068 ( 0.1521 )
Mucosal, Oral (n=10,1,1,5)	0.268 ( 0.7358 )	0.330 ( 99999 )	0.000 ( 99999 )	0.268 ( 0.5993 )
Joint (n=10,1,1,5)	0.067 ( 0.2119 )	0.000 ( 99999 )	0.000 ( 99999 )	1.370 ( 2.3644 )
GI (n=10,1,1,5)	0.000 ( 0.0000 )	0.000 ( 99999 )	0.000 ( 99999 )	0.136 ( 0.3041 )
Menstrual/Heavy Menstrual (n=2,1,0,2)	2.770 ( 3.9174 )	0.000 ( 99999 )	999 ( 99999 )	0.500 ( 0.7071 )
Venipuncture Site (n=10,1,1,5)	0.000 ( 0.0000 )	0.000 ( 99999 )	0.000 ( 99999 )	0.000 ( 0.0000 )
Soft Tissue (n=10,1,1,5)	0.000 ( 0.0000 )	0.000 ( 99999 )	0.000 ( 99999 )	0.000 ( 0.0000 )
Body Cavity (n=10,1,1,5)	0.000 ( 0.0000 )	0.000 ( 99999 )	0.000 ( 99999 )	0.000 ( 0.0000 )
Hematuria (n=10,1,1,5)	0.000 ( 0.0000 )	0.000 ( 99999 )	0.000 ( 99999 )	0.000 ( 0.0000 )
CNS (n=10,1,1,5)	0.000 ( 0.0000 )	0.000 ( 99999 )	0.000 ( 99999 )	0.000 ( 0.0000 )
Other (n=10,1,1,5)	0.067 ( 0.1413 )	0.000 ( 99999 )	0.000 ( 99999 )	0.068 ( 0.1521 )

No statistical analyses for this end point

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End point title

Total Number of Infusions During Prophylactic Treatment ^[9]

End point description

Total number of infusions during prophylactic treatment with rVWF (vonicog alfa) were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. '99999' denotes that standard deviation was not estimable for a single participant.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: infusions
arithmetic mean (standard deviation)	287.8 ( 53.42 )	157.0 ( 99999 )	177.0 ( 99999 )	159.2 ( 41.55 )

No statistical analyses for this end point

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End point title

Average Number of Infusions Per Week During Prophylactic Treatment ^[10]

End point description

Average number of infusions per week during prophylactic treatment with rVWF (vonicog alfa) were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. '99999' denotes that standard deviation was not estimable for a single participant.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: infusions per week
arithmetic mean (standard deviation)	1.87 ( 0.351 )	1.01 ( 99999 )	1.14 ( 99999 )	1.38 ( 0.372 )

No statistical analyses for this end point

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End point title

Number of Participants who Achieved Transfusion-free Maintenance of Hemoglobin Levels ^[11]

End point description

Transfusion free maintenance of hemoglobin levels during prophylactic treatment with rVWF (vonicog alfa) were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: participants	8	1	1	5

No statistical analyses for this end point

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End point title

Change From Baseline in Ferritin Levels Over Time ^[12]

End point description

Change from baseline in ferritin levels over time during prophylactic treatment with rVWF (vonicog alfa) were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Subjects analysed are the number of participants with data available for analysis at Baseline. 'n' denotes the number of participants with data available for analyses at the specified timepoint.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	2	0 ^[13]	0 ^[14]	5
Units: picomole per liter (pmol/L)
arithmetic mean (standard deviation)
Baseline (n=2,0,0,5)	148.5 ( 171.83 )	( )	( )	90.8 ( 110.82 )
Month 1 (n=2,0,0,5)	11.0 ( 18.38 )	( )	( )	-31.0 ( 44.89 )
Month 2 (n=2,0,0,5)	0.0 ( 1.41 )	( )	( )	-43.8 ( 59.60 )
Month 3 (n=2,0,0,4)	-18.5 ( 21.92 )	( )	( )	-33.3 ( 64.57 )
Month 6 (n=2,0,0,5)	2.0 ( 2.83 )	( )	( )	-16.6 ( 19.88 )
Month 9 (n=2,0,0,5)	58.5 ( 91.22 )	( )	( )	-12.8 ( 53.05 )
Month 12 (n=2,0,0,4)	19.0 ( 26.87 )	( )	( )	-27.0 ( 27.51 )
Month 15 (n=2,0,0,3)	5.5 ( 13.44 )	( )	( )	-25.7 ( 80.16 )
Month 18 (n=2,0,0,3)	18.0 ( 46.67 )	( )	( )	-49.7 ( 52.56 )
Month 21 (n=2,0,0,5)	37.5 ( 64.35 )	( )	( )	-59.3 ( 50.16 )
Month 24 (n=2,0,0,5)	12.0 ( 26.87 )	( )	( )	-53.3 ( 91.22 )
Month 27 (n=2,0,0,5)	34.0 ( 60.81 )	( )	( )	-54.0 ( 55.56 )
Month 30(n=2,0,0,3)	46.5 ( 77.07 )	( )	( )	-70.7 ( 70.12 )
Month 33 (n=2,0,0,3)	71.5 ( 106.77 )	( )	( )	-21.3 ( 114.00 )
End of Study (n=2,0,0,5)	38.5 ( 48.79 )	( )	( )	-27.6 ( 52.46 )

Notes
[13] - No participants were analysed.
[14] - No participants were analysed.

No statistical analyses for this end point

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End point title

Total Weight Adjusted Consumption of Recombinant Von Willebrand Factor (rVWF) (Vonicog Alfa) Per Participant During Prophylactic Treatment ^[15]

End point description

For each participant, the body weight-adjusted dose (IU/kg) was derived as the number of units of rVWF infused (IU) divided by the last available body weight (kilogram [kg]) prior to the infusion. Total weight adjusted consumption of rVWF (vonicog alfa) per participant during prophylactic treatment with rVWF (vonicog alfa) was reported as International Units per kilogram (IU/kg). The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. '99999' denotes that standard deviation was not estimable for a single participant.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the prophylaxis cohort.

End point values	Cohort 1: Prophylaxis	Cohort 2: Prophylaxis	Cohort 3: Prophylaxis	Cohort 4: Prophylaxis
Number of subjects analysed	10	1	1	5
Units: IU/kg
arithmetic mean (standard deviation)	14953.497 ( 3349.4461 )	9992.460 ( 99999 )	9270.620 ( 99999 )	9171.746 ( 1505.5667 )

No statistical analyses for this end point

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End point title

Overall Hemostatic Efficacy Rating ^[16]

End point description

.Hemostatic efficacy for treatment of BEs was rated on 4-point Likert scale as:excellent=full relief of pain&cessation of objective signs of bleeding after single infusion,no additional infusion is required for control of bleeding&administration of further infusion to maintain hemostasis would not affect scoring;good=definite pain relief&/or improvement in signs of bleeding after single infusion,possibly requires >2 infusions for complete resolution&administration of further infusion to maintain hemostasis would not affect scoring;fair=probable&/or slight relief of pain&slight improvement in signs of bleeding after single infusion,required multiple infusions for complete resolution;none=no improvement of signs/symptoms or conditions worsen.Missing=number of unique BEs without any overall hemostatic efficacy rating at resolution of breakthrough BE. Analysis Population: FAS. Subjects analysed is the number of participants with treated bleeding episodes.

End point type

Secondary

End point timeframe

Initial 12 months of study

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the On Demand cohort.

End point values	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	15	2
Units: bleeding episodes
number (not applicable)
Excellent	74	21
Good	1	0
Fair	0	0
None	0	0
Missing	1	3

No statistical analyses for this end point

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End point title

Number of Infusions of ADVATE ^[17]

End point description

Number of infusions of ADVATE (rFVIII, octocog alfa) utilized to treat BEs during OD treatment while enrolled in the study were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Subjects analysed is the number of participants with ADVATE-treated bleeding episodes.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the On Demand cohort.

End point values	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	7	1
Units: infusions
arithmetic mean (standard deviation)	1.1 ( 0.25 )	1.0 ( 0.00 )

No statistical analyses for this end point

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End point title

Number of Infusions of Vonicog Alfa ^[18]

End point description

Number of infusions of rVWF (vonicog alfa) utilized to treat BEs during OD treatment while enrolled in the study were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the On Demand cohort.

End point values	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	16	2
Units: infusions
arithmetic mean (standard deviation)	1.1 ( 0.65 )	1.2 ( 0.45 )

No statistical analyses for this end point

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End point title

Weight-adjusted Consumption of Vonicog alfa per Bleeding Episode ^[19]

End point description

Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion. Weight-adjusted consumption of rVWF (vonicog alfa) per bleeding episode during OD treatment while enrolled in the study were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the On Demand cohort.

End point values	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	16	2
Units: IU/kg per bleeding episode
arithmetic mean (standard deviation)	56.109 ( 33.1312 )	61.713 ( 26.6936 )

No statistical analyses for this end point

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End point title

Weight-adjusted Consumption of ADVATE per Bleeding Episode ^[20]

End point description

Weight-adjusted consumption (IU/kg) was derived as the total units infused (IU) divided by the last available body weight (kg) prior to the infusion. Weight-adjusted consumption of ADVATE (rFVIII, octocog alfa) per bleeding episode during OD treatment while enrolled in the study were reported. The FAS consisted of all participants who satisfied all the entry criteria and received any amount of study drug. Subjects analysed is the number of participants with ADVATE-treated bleeding episodes.

End point type

Secondary

End point timeframe

Up to 5.8 years

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable for the arms in the On Demand cohort.

End point values	Cohort 5: On Demand	Cohort 6: On Demand
Number of subjects analysed	7	1
Units: IU/kg per bleeding episode
arithmetic mean (standard deviation)	39.217 ( 11.0752 )	35.175 ( 2.2274 )

No statistical analyses for this end point

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Timeframe for reporting adverse events

Up to 5.8 years

Adverse event reporting additional description

The SAS consisted of all participants who received any amount of rVWF as obtained from the IP administration eDiary, Study Drug Administration Details eCRF or Pharmacokinetic Infusion eCRF.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.1

Reporting group title

Cohort 2: Prophylaxis: Adult ≥18 years

Reporting group description

Reporting group title

Cohort 1: Prophylaxis: Adult ≥18 years

Reporting group description

Reporting group title

Cohort 4: Prophylaxis: Pediatric 12 to <18 years

Reporting group description

Newly enrolled adolescent (aged 12 to <18 years) participants who switched from OD treatment with VWF products started 50±10 IU/kg, IV infusion once weekly prophylaxis with vonicog alfa in this continuation study.

Reporting group title

Cohort 3: Prophylaxis: Pediatric 12 to <18 years

Reporting group description

Reporting group title

Cohort 4: Prophylaxis: Adult ≥18 years

Reporting group description

Newly enrolled adult participants who switched from OD treatment with VWF products started 50±10 IU/kg, IV infusion once weekly prophylaxis with vonicog alfa in this continuation study.

Reporting group title

Cohort 5: On Demand: Pediatric <6 years

Reporting group description

Pediatric participants of <6 years of age from Parent Study 071102/NCT02932618 continued receiving OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Reporting group title

Cohort 5: On Demand: Pediatric 6 to <12 years

Reporting group description

Pediatric participants of 6 to <12 years age from parent study 071102 (NCT02932618) continued receiving OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Reporting group title

Cohort 5: On Demand: Pediatric 12 to <18 years

Reporting group description

Pediatric participants of 12 to <18 years of age from parent study 071102 (NCT02932618) continued receiving OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Reporting group title

Cohort 5: On Demand: Adult ≥18 years

Reporting group description

Adult Participants from Parent Study 071102/NCT02932618 continued receiving OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Reporting group title

Cohort 6: On Demand: Adult ≥18 years

Reporting group description

Adult participants from parent study 071301 (NCT02973087) switched back from prophylactic treatment in Study 071301 to OD treatment of vonicog alfa 50±10 IU/kg, IV infusion, once weekly or twice weekly in this continuation study.

Serious adverse events	Cohort 2: Prophylaxis: Adult ≥18 years	Cohort 1: Prophylaxis: Adult ≥18 years	Cohort 4: Prophylaxis: Pediatric 12 to <18 years	Cohort 3: Prophylaxis: Pediatric 12 to <18 years	Cohort 4: Prophylaxis: Adult ≥18 years	Cohort 5: On Demand: Pediatric <6 years	Cohort 5: On Demand: Pediatric 6 to <12 years	Cohort 5: On Demand: Pediatric 12 to <18 years	Cohort 5: On Demand: Adult ≥18 years	Cohort 6: On Demand: Adult ≥18 years
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 1 (0.00%)	3 / 10 (30.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0	0
Investigations
Haemoglobin decreased
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Medical device site extravasation
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst ruptured
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronavirus infection
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 2: Prophylaxis: Adult ≥18 years	Cohort 1: Prophylaxis: Adult ≥18 years	Cohort 4: Prophylaxis: Pediatric 12 to <18 years	Cohort 3: Prophylaxis: Pediatric 12 to <18 years	Cohort 4: Prophylaxis: Adult ≥18 years	Cohort 5: On Demand: Pediatric <6 years	Cohort 5: On Demand: Pediatric 6 to <12 years	Cohort 5: On Demand: Pediatric 12 to <18 years	Cohort 5: On Demand: Adult ≥18 years	Cohort 6: On Demand: Adult ≥18 years
Total subjects affected by non serious adverse events
subjects affected / exposed	1 / 1 (100.00%)	8 / 10 (80.00%)	2 / 2 (100.00%)	1 / 1 (100.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	5 / 5 (100.00%)	6 / 6 (100.00%)	1 / 2 (50.00%)	2 / 2 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Varicose vein
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Chills
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Chest discomfort
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Infusion site rash
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Pyrexia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	2	0	1	2	0	0	0	0
Reproductive system and breast disorders
Intermenstrual bleeding
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Dysmenorrhoea
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	4	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Asthma
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Cough
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	5	1	1	0	0
Catarrh
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 1 (100.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	1	0	0	0	0	1	0	2	0	0
Pleural effusion
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Respiratory tract congestion
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Product issues
Device malfunction
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Investigations
Anti factor VIII antibody positive
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	1	1	0	0
Blood triglycerides increased
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Serum ferritin decreased
subjects affected / exposed	1 / 1 (100.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	2	0	0	2	0	0	0	0	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Arthropod sting
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0
Bone contusion
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Chest injury
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Fall
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Epicondylitis
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Fracture displacement
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Head injury
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Joint injury
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Ligament sprain
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Procedural pain
subjects affected / exposed	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Meniscus injury
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0
Limb injury
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	1	1	0	0
Road traffic accident
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Skin laceration
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0
Spinal compression fracture
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Stress fracture
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Traumatic haematoma
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0
Wound
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Sunburn
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0
Congenital, familial and genetic disorders
Lymphatic malformation
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Cardiac disorders
Bundle branch block right
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Palpitations
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Headache
subjects affected / exposed	1 / 1 (100.00%)	3 / 10 (30.00%)	2 / 2 (100.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)
occurrences all number	1	5	12	0	0	0	1	0	3	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	2	0	0	1	0	0	0	0	1
Eosinophilia
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Iron deficiency anaemia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	1	0	1	0	1	0
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Ear pain
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Astigmatism
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1
Conjunctivitis allergic
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0	1	0
Abdominal distension
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Abdominal pain
subjects affected / exposed	1 / 1 (100.00%)	1 / 10 (10.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	1	1	1	0	0	1	0	0	0	0
Angular cheilitis
subjects affected / exposed	1 / 1 (100.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Dental caries
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Dyspepsia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	1	0	0	0
Diarrhoea
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	1	0	0	1	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Flatulence
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Faeces discoloured
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Enteritis
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Dysphagia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Irritable bowel syndrome
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0
Salivary hypersecretion
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Toothache
subjects affected / exposed	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	3 / 3 (100.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	1	5	0	1	0	0
Tooth deposit
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Bile duct stone
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Haemobilia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Cholelithiasis
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Hepatomegaly
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Perioral dermatitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Skin disorder
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Ecchymosis
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Petechiae
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Nephrolithiasis
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	1	0	0
Haemophilic arthropathy
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	1 / 1 (100.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	2	0	2	0	1	0	0	0	0	0
Joint effusion
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Pain in extremity
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)
occurrences all number	0	2	1	0	0	0	1	0	1	0
Tendonitis
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Juvenile idiopathic arthritis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
COVID-19
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	1	2	3	1	3	1	0
Conjunctivitis bacterial
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Croup infectious
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0
Coronavirus infection
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0
Gastroenteritis
subjects affected / exposed	1 / 1 (100.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0
Gingivitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Gastroenteritis viral
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Influenza
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Laryngitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	1 / 1 (100.00%)	0 / 10 (0.00%)	1 / 2 (50.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	2	0	2	0	0	0	0	0	0	0
Otitis media
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Onychomycosis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Periodontitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Otitis media acute
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Pharyngitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Rhinitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Pneumonia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	1 / 1 (100.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0
Tracheobronchitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Viral infection
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 5 (60.00%)	1 / 6 (16.67%)	1 / 2 (50.00%)	1 / 2 (50.00%)
occurrences all number	0	1	0	0	0	1	3	2	3	1
Viral rhinitis
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Vitamin B12 deficiency
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Iron deficiency
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 2 (50.00%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	2	0	0	1	1	4
Obesity
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0
Zinc deficiency
subjects affected / exposed	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 2 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

29 May 2019

The following change was made as per protocol amendment 01: 1. Requirement of human leukocyte antigen genotyping was removed from screening. 2. Pregnant Partner reporting was added.

19 May 2020

The following change was made as per protocol amendment 03: Wording was included to provide for additional interim analyses to be performed as needed to support submissions to health authorities.

20 Dec 2021

The following changes were made as per protocol amendment 4: 1. Updated Sponsor name to Takeda. 2. The time for completion of the study was extended to December 2025. 3. The total sample size was updated to include up to 71 pediatric and adult subjects.

Were there any global interruptions to the trial? No

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

None reported

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End point values

Cohort 1: Prophylaxis

Cohort 2: Prophylaxis

Cohort 3: Prophylaxis

Cohort 4: Prophylaxis

Cohort 5: On Demand

Cohort 6: On Demand

Number of subjects analysed

Units: participants