Trial Outcomes & Findings for An Open-label Extension Study of an Investigational Drug, Fitusiran, in Patients With Moderate or Severe Hemophilia A or B (NCT NCT02554773)

Last Updated: 2024-06-05

Results Overview

An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An SAE is any untoward medical occurrence that results: death or life-threatening or inpatient hospitalization or prolongation of existing hospitalization or persistent or significant disability or congenital anomaly or medically important event. All AEs collected in LTE14762 were considered TEAE because all participants received dose in the parent study. AEs of special interest (AESI) are alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations \>3× upper limit of normal (ULN) or suspected or confirmed thromboembolic events or severe or serious injection site reactions or systemic injection associated reactions or cholecystitis or cholelithiasis.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

34 participants

Primary outcome timeframe

From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Results posted on

2024-06-05

Participant Flow

The study was conducted at 13 centers in 5 countries between 18 September 2015 and 21 March 2023. A total of 34 participants were enrolled in this study.

Participants were rolled over from the parent study TDR14767 (NCT02035605).

Participant milestones

Participant milestones
Measure	Original Dose Regimen [Safety Analysis Set 1 (SAS 1)] Participants received fitusiran 50 milligram (mg) or 80 mg subcutaneous (SC) injection every month (QM) under the original dose and regimen.	Antithrombin (AT)-Based Dose Regimen [Safety Analysis Set 2 (SAS 2)] Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg every 2 months (Q2M) SC injection under recommended AT-based dose regimen.
Original Dose Regimen (SAS 1) STARTED	34	0
Original Dose Regimen (SAS 1) COMPLETED	18	0
Original Dose Regimen (SAS 1) NOT COMPLETED	16	0
AT-Based Dose Regimen (SAS 2) STARTED	0	18
AT-Based Dose Regimen (SAS 2) COMPLETED	0	12
AT-Based Dose Regimen (SAS 2) NOT COMPLETED	0	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Original Dose Regimen [Safety Analysis Set 1 (SAS 1)] Participants received fitusiran 50 milligram (mg) or 80 mg subcutaneous (SC) injection every month (QM) under the original dose and regimen.	Antithrombin (AT)-Based Dose Regimen [Safety Analysis Set 2 (SAS 2)] Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg every 2 months (Q2M) SC injection under recommended AT-based dose regimen.
Original Dose Regimen (SAS 1) Physician Decision	1	0
Original Dose Regimen (SAS 1) Withdrawal by Subject	7	0
Original Dose Regimen (SAS 1) Adverse Event	3	0
Original Dose Regimen (SAS 1) Death	1	0
Original Dose Regimen (SAS 1) Other	4	0
AT-Based Dose Regimen (SAS 2) Withdrawal by Subject	0	1
AT-Based Dose Regimen (SAS 2) More than 1 AT measurement <15%	0	1
AT-Based Dose Regimen (SAS 2) Adverse Event	0	1
AT-Based Dose Regimen (SAS 2) Other	0	3

Baseline Characteristics

An Open-label Extension Study of an Investigational Drug, Fitusiran, in Patients With Moderate or Severe Hemophilia A or B

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.
Age, Continuous	36.6 years STANDARD_DEVIATION 10.7 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian/White	33 Participants n=5 Participants
Race/Ethnicity, Customized Asian/Oriental	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: Safety analysis set (SAS) included all participants who received at least a partial dose of study drug.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) Any TEAE	33 Participants	14 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) Any Treatment-emergent SAE	13 Participants	1 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) Any Treatment-emergent AESI	11 Participants	1 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) Any TEAE leading to study drug discontinuation	5 Participants	1 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) Any TEAE leading to death	1 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The SAS included all participants who received at least a partial dose of study drug.

Blood samples were collected to determine the hematology laboratory significant abnormalities. Here, DFB = decrease from baseline, NB = non-black, and B = black.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Hemoglobin: <= 115 gram per liter (g/L)	5 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Hemoglobin: >= 185 g/L	3 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Hemoglobin: DFB >= 20 g/L	10 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Hematocrit: <= 0.37 fraction of 1	8 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Hematocrit: >= 0.55 fraction of 1	5 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Erythrocyte Count: >= 6 x 10^12/L	9 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Platelet Count: < 100 x 10^9/L	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Leukocyte Count: <3 x 10^9/L (NB); <2 x 10^9/L (B)	3 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Leukocyte Count: >= 16 x 10^9/L	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Neutrophils: <1.5 x 10^9/L (NB); <1 x 10^9/L (B)	8 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Lymphocytes: > 4 x 10^9/L	0 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Monocytes: > 0.7 x 10^9/L	15 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Basophils: > 0.1 x 10^9/L	4 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology Eosinophils:>0.5x10^9/L or >ULN (ULN >=0.5x10^9/L)	11 Participants	1 Participants

PRIMARY outcome

Timeframe: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The SAS included all participants who received at least a partial dose of study drug.

Blood samples were collected to determine the clinical chemistry laboratory abnormalities. Here, mmol/L = millimoles per liter, LLN = lower limit of normal, mg/L = milligram per liter, umol/L = micromoles per liter, mL/min = milliliter per minute, m\^2 = meter square, CB = conjugated bilirubin, and DB = direct bilirubin.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Glucose: <= 3.9 mmol/L and < LLN	13 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Glucose:>=11.1 mmol/L(unfasted);>=7 mmol/L(fasted)	10 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry C-Reactive Protein: > 2 ULN or > 10 mg/L	20 Participants	7 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Sodium: <= 129 mmol/L	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Potassium: < 3 mmol/L	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Potassium: >= 5.5 mmol/L	5 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Creatinine: >= 150 umol/L	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Creatinine: >= 30% change from baseline	13 Participants	7 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Creatinine: >= 100% change from baseline	2 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Creatinine Clearance: >= 60 - < 90 mL/min/1.73m^2	18 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Creatinine Clearance: >= 15 - < 30 mL/min/1.73m^2	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Uric Acid: < 120 umol/L	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Uric Acid: > 408 umol/L	20 Participants	8 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry ALT: > 1 ULN	30 Participants	6 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry ALT: > 3 ULN	14 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry ALT: > 5 ULN	6 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry ALT: > 10 ULN	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry ALT: > 20 ULN	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry AST: > 1 ULN	22 Participants	7 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry AST: > 3 ULN	8 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry AST: > 5 ULN	5 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry AST: > 10 ULN	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Alkaline Phosphatase: > 1.5 ULN	4 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry Total Bilirubin: > 1.5 ULN	4 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry CB: DB >35% Bilirubin and Bilirubin >1.5 ULN	3 Participants	1 Participants

PRIMARY outcome

Timeframe: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The SAS included all participants who received at least a partial dose of study drug.

Urine samples collected to determine the significant abnormalities in urine.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The SAS included all participants who received at least a partial dose of study drug.

Participants vital signs were examined to determine the abnormalities. Vital signs included weight, supine systolic blood pressure (SSBP) and supine diastolic blood pressure (SDBP). Here, mmHg = millimeter of mercury, and IFB = increase from baseline.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs SSBP: >= 160 mmHg; IFB >= 20 mmHg	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs SDBP: <= 45 mmHg; DFB >= 20 mmHg	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs Weight: >= 5% DFB	8 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs Weight: >= 5% IFB	15 Participants	9 Participants

PRIMARY outcome

Timeframe: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The SAS included all participants who received at least a partial dose of study drug.

Standard 12-lead ECGs were recorded after at least 15 minutes in the supine position using an electrocardiographic device. The following were assessed: heart rate, rhythm, interval between the peaks of successive QRS complexes (RR), interval from the beginning of the P wave until the beginning of the QRS complex (PR), interval from start of the Q wave to the end of the S wave (QRS), interval between the start of the Q wave and the end of the T wave (QT), QT interval corrected for heart rate (QTc) automatic correction evaluation, QRS axis, left ventricular hypertrophy criteria, right ventricular hypertrophy criteria, repolarization charges, and overall cardiac impression for each participant. Here, msec = milliseconds.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) Ventricular Rate: < 50 beats/min	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) Ventricular Rate: > 90 beats/min	8 Participants	5 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) Ventricular Rate: >90 beats/min;IFB >=20 beats/min	3 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) Ventricular Rate: > 100 beats/min	5 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) Ventricular Rate:>100 beats/min;IFB >=20 beats/min	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) PR Interval: > 200 msec	3 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) PR Interval: > 200 msec; IFB >= 25%	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) PR Interval: > 220 msec	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) PR Interval: > 220 msec; IFB >= 25%	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) PR Interval: > 240 msec	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) PR Interval: > 240 msec;IFB >= 25%	2 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QRS Interval: > 110 msec	8 Participants	3 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QRS Interval: > 110 msec; IFB >= 25%	3 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QRS Interval: > 120 msec	3 Participants	2 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QRS Interval: > 120 msec; IFB >= 25%	3 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QTc Bazett: > 450 msec	2 Participants	4 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QTc Bazett: > 480 msec	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QTc Bazett: IFB (30-60) msec	8 Participants	4 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QTc Fridericia: > 450 msec	1 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QTc Fridericia: > 480 msec	0 Participants	1 Participants
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG) QTc Fridericia: IFB (30-60) msec	4 Participants	4 Participants

PRIMARY outcome

Timeframe: From first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The SAS included all participants who received at least a partial dose of study drug.

Physical examination included, at a minimum, an assessment of the participant's general appearance; skin; head, eyes, ears, nose, and throat; examinations of lymph nodes, abdomen, extremities/joints, neurological and mental status; heart and respiratory auscultation; peripheral arterial pulse; and pupil, knee, achilles, and plantar reflexes.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination	17 Participants	2 Participants

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: Full analysis set (FAS) included all participants in SAS.

The ABR was annualized for each participant using the following formula: ABR = total number of bleeding events/total number of days in the respective period x 365.25. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2).

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Annualized Bleeding Rate (ABR) During the Efficacy Period	3.035 bleeding events per year Interval 1.845 to 4.992	3.929 bleeding events per year Interval 1.622 to 9.52

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The FAS included all participants in SAS.

A spontaneous bleeding episode was defined as a bleeding event that occurred for no apparent or known reason, particularly into the joints, muscles, and soft tissues. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2).

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Annualized Spontaneous Bleeding Rate During the Efficacy Period	2.60 bleeding events per year Standard Deviation 5.96	3.96 bleeding events per year Standard Deviation 11.64

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The FAS included all participants in SAS.

A joint bleeding episode was defined as an event that is characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin over the joint; 2) increasing pain; or 3) progressive loss of range of motion or difficulty in using the limb as compared with baseline. The efficacy period was defined as treatment Day 29 to earlier of end of study date before the dose pause or the last fitusiran administration date before the dose pause + 28 days, whichever comes first for original dose regimen (SAS 1) and the dose re-start Day 169 to the end of study visit for AT-based dose regimen (SAS 2).

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Annualized Joint Bleeding Rate During the Efficacy Period	3.51 bleeding events per year Standard Deviation 6.97	4.78 bleeding events per year Standard Deviation 11.76

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The FAS included all participants in SAS.

Bleed-free duration was defined as the time interval between 2 protocol-defined treated bleeding events, excluding events that occurred during the intercurrent periods.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=34 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Time Intervals Between Bleeding Events	368.50 days Interval 56.0 to 1576.0	249.00 days Interval 11.0 to 427.0

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The FAS included all participants in SAS. Only participants analyzed for specific factor are reported.

Number of coagulation factor injections per bleed was determined. IU= international units, and kg= kilogram.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=11 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=3 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX) FVIII	63.66 IU/kg per year Standard Deviation 81.29	52.13 IU/kg per year Standard Deviation 8.50
Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX) FIXs	110.26 IU/kg per year Standard Deviation 93.74	108.63 IU/kg per year Standard Deviation 138.42

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The FAS included all participants in SAS. Only participants analyzed for specific factor are reported.

Number of BPA injections per bleed was determined.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=5 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=4 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Recombinant Factor VIIa (rFVIIa)	1316.19 microgram/kg per year Standard Deviation 2631.87	1431.84 microgram/kg per year Standard Deviation 2369.29

SECONDARY outcome

Timeframe: From Day 29 up to end of the study, maximum of up to 76 months

Population: The FAS included all participants in SAS. Only participants analyzed for this outcome measure are reported.

Number of BPA injections per bleed was determined.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=5 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Activated Prothrombin Complex Concentrate (aPCC)	381.81 units/kg per year Standard Deviation 409.82	—

SECONDARY outcome

Timeframe: Baseline and Month 24

Population: The FAS included all participants in SAS. Only participants analyzed at baseline and Month 24 are reported.

The EQ-5D-5L is a standardized and disease-generic instrument for use as a measure of quality of life (QoL) outcome. The EQ-5D-5L consists of 2 parts: EQ-5D descriptive system and EQ VAS. The EQ-5D descriptive system included questions for each of following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The VAS recorded participant's self-rated health on a vertical 20-centimeter. VAS scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The EQ-5D-5L questionnaire scores range from 0-100, where 0= worst self-perceived health and 100= best self-perceived health. Positive change from baseline indicates an improvement in QoL. Baseline refers to the last non-missing value on or before the first significant treatment in TDR14767(ALN-AT3SC-001) or LTE14762 study.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=15 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=3 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24 Index score	0.01 units on a scale Standard Deviation 0.14	0.09 units on a scale Standard Deviation 0.06
Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24 VAS score	4.73 units on a scale Standard Deviation 18.37	16.67 units on a scale Standard Deviation 7.64

SECONDARY outcome

Timeframe: Baseline and Month 24

Population: The FAS included all participants in SAS. Only participants analyzed at baseline and Month 24 are reported.

The Haem-A-QoL questionnaire is psychometrically tested QoL assessment instrument for participants with hemophilia and includes 46 items contributing to 10 QoL domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item is based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5= all the time), and the physical health and total transformed scores range from 0 to 100. Higher scores indicated greater impairment. Baseline refers to the last non-missing value on or before the first significant treatment in TDR14767(ALN-AT3SC-001) or LTE14762 study.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=14 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=3 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24 Total score	-0.20 units on a scale Standard Deviation 0.47	0.02 units on a scale Standard Deviation 0.34
Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24 Physical health score	-0.14 units on a scale Standard Deviation 0.58	-0.53 units on a scale Standard Deviation 0.61

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: Pharmacodynamic (PD) analysis set included all participants who received at least 1 dose of study drug and had at least 1 blood sample collection post dose to determine plasma AT and thrombin generation (TG) levels.

The AT activity level was analyzed up to end of treatment regimen. The baseline under the original dose and regimen was the last non-missing assessment before the first significant dose.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=16 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Antithrombin Activity Level at the End of Treatment Regimen	16.28 percentage Standard Deviation 4.53	24.76 percentage Standard Deviation 7.36

SECONDARY outcome

Timeframe: From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)

Population: The PD analysis set included all participants who received at least 1 dose of study drug and had at least 1 blood sample collection post dose to determine plasma AT and TG levels.

The TG data was analyzed by CoagScope and assay performed using calibrated automated thrombogram method. The baseline under the original dose and regimen was the last non-missing assessment before the first significant dose.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=16 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Thrombin Generation at the End of Treatment Regimen	71.39 nanomoles/liter Standard Deviation 24.67	32.31 nanomoles/liter Standard Deviation 20.05

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24

Population: Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.

Cmax was defined as maximum plasma concentration observed. The non-compartmental Pharmacokinetic (PK) analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=14 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=17 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Maximum Observed Concentration (Cmax) of Fitusiran Day 1	86.8 nanogram per milliliter (ng/mL) Standard Deviation 44.1	168 nanogram per milliliter (ng/mL) Standard Deviation 74.6
Maximum Observed Concentration (Cmax) of Fitusiran Month 12	75.2 nanogram per milliliter (ng/mL) Standard Deviation 50.3	149 nanogram per milliliter (ng/mL) Standard Deviation 53.2
Maximum Observed Concentration (Cmax) of Fitusiran Month 24	62.5 nanogram per milliliter (ng/mL) Standard Deviation 35.3	155 nanogram per milliliter (ng/mL) Standard Deviation 87.9

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24

Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 blood sample collection post dose to determine plasma concentrations of study drug. Only participants analyzed at each specific time point are reported.

tmax was defined as time to reach Cmax. The non-compartmental PK analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=14 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=17 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Time to Reach the Maximum Concentration (Tmax) of Fitusiran Day 1	3.97 hour Interval 0.5 to 8.08	4.00 hour Interval 2.0 to 8.07
Time to Reach the Maximum Concentration (Tmax) of Fitusiran Month 12	4.02 hour Interval 2.0 to 8.0	6.00 hour Interval 2.02 to 8.03
Time to Reach the Maximum Concentration (Tmax) of Fitusiran Month 24	4.00 hour Interval 4.0 to 4.0	7.83 hour Interval 4.05 to 8.0

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24

AUClast was defined as area under the concentration versus time curve from time 0 to the last measurable concentration. The non-compartmental PK analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=14 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=17 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran Day 1	1110 ng*hour/mL Standard Deviation 486	2130 ng*hour/mL Standard Deviation 769
Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran Month 12	961 ng*hour/mL Standard Deviation 551	2020 ng*hour/mL Standard Deviation 708
Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran Month 24	935 ng*hour/mL Standard Deviation 550	2070 ng*hour/mL Standard Deviation 917

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12

AUCinf was defined as area under the concentration versus time curve extrapolated to infinity. The non-compartmental PK analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=4 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=3 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran Day 1	1470 ng*h/mL Standard Deviation 441	2230 ng*h/mL Standard Deviation 641
Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran Month 12	356 ng*h/mL Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.	2860 ng*h/mL Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12

t1/2z associated with the terminal slope (λz) determined according to the following equation: t1/2z = 0.693/λz; where, λz is the slope of the regression line of the terminal phase of the plasma concentration versus time curve, in semi-logarithmic scale. The non-compartmental PK analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=5 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=3 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Terminal Half-Life (t1/2z) of Fitusiran Day 1	5.19 hour Standard Deviation 1.61	5.90 hour Standard Deviation 3.83
Terminal Half-Life (t1/2z) of Fitusiran Month 12	3.91 hour Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.	4.94 hour Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12

CL/F was defined as apparent clearance of study drug from the body. The non-compartmental PK analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=4 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=3 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Apparent Total Body Clearance (CL/F) of Fitusiran Day 1	37.6 liter per hour Standard Deviation 13.6	38.8 liter per hour Standard Deviation 12.7
Apparent Total Body Clearance (CL/F) of Fitusiran Month 12	143 liter per hour Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.	28.3 liter per hour Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12

Vss/F was defined as apparent volume of distribution of study drug at steady state concentration. The non-compartmental PK analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=4 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=3 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran Day 1	283 liter Standard Deviation 155	390 liter Standard Deviation 348
Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran Month 12	834 liter Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.	204 liter Standard Deviation NA Standard deviation could not be determined when only 1 participant was analyzed.

SECONDARY outcome

Timeframe: Postdose, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours at Month 24

Population: The PK analysis set included all participants who received at least 1 dose of study drug and have at least 1 urine sample collection post dose to determine urine concentrations of study drug. Only those participants with data available at Month 24 are reported.

fe was defined as the amount of fitusiran excreted in urine in 0-24 hour. The non-compartmental PK analysis was performed.

Outcome measures

Outcome measures
Measure	Original Dose Regimen (SAS 1) n=2 Participants Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=7 Participants Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Recovery of Fraction of the Dose Excreted in Urine (fe) in 0-24 Hours After Fitusiran Administration	10.7 percentage of study drug Standard Deviation 4.08	12.6 percentage of study drug Standard Deviation 4.92

Adverse Events

Original Dose Regimen (SAS 1)

Serious events: 13 serious events

Other events: 33 other events

Deaths: 1 deaths

AT-Based Dose Regimen (SAS 2)

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Publication restrictions are in place

Restriction type: OTHER

Measure	Original Dose Regimen (SAS 1) n=34 participants at risk Participants received fitusiran 50 mg or 80 mg SC injection QM under the original dose and regimen.	AT-Based Dose Regimen (SAS 2) n=18 participants at risk Participants received fitusiran 50 mg QM, 80 mg QM or 50 mg Q2M SC injection under recommended AT-based dose regimen.
Cardiac disorders Atrial Thrombosis	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Gastrointestinal disorders Gastric Ulcer Haemorrhage	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Gastrointestinal disorders Gastritis	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Gastrointestinal disorders Gastroduodenal Ulcer	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Gastrointestinal disorders Gastrointestinal Haemorrhage	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Gastrointestinal disorders Haemorrhagic Erosive Gastritis	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Gastrointestinal disorders Peptic Ulcer Haemorrhage	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Hepatobiliary disorders Cholecystitis	5.9% 2/34 • Number of events 3 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Hepatobiliary disorders Cholestasis	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Infections and infestations Lower Respiratory Tract Infection	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Infections and infestations Pneumonia	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Injury, poisoning and procedural complications Anaemia Postoperative	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Injury, poisoning and procedural complications Femur Fracture	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Investigations Transaminases Increased	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Musculoskeletal and connective tissue disorders Haemarthrosis	2.9% 1/34 • Number of events 2 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Musculoskeletal and connective tissue disorders Haemophilic Arthropathy	2.9% 1/34 • Number of events 2 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatocellular Carcinoma	0.00% 0/34 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	5.6% 1/18 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Nervous system disorders Seizure	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Nervous system disorders Subarachnoid Haemorrhage	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.
Skin and subcutaneous tissue disorders Pruritus	2.9% 1/34 • Number of events 1 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.	0.00% 0/18 • TEAEs data was collected from first dose of study drug (Day 1) up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months). Analysis was performed on the safety analysis set.