EFC14769

Genzyme Corporation

50 Binney Street, Cambridge, MA, United States, 02142

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Yes

No

No

Final

09 Aug 2021

No

Yes

14 Jul 2021

No

To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by the frequency of bleeding episodes.

The study was conducted by investigators experienced in the treatment of adults and adolescents subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimise distress and discomfort. Adult subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

01 Mar 2018

Yes

Yes

South Africa: 5

Denmark: 1

Japan: 1

Korea, Republic of: 17

Taiwan: 11

United States: 7

United Kingdom: 1

India: 34

Italy: 2

Turkey: 9

Ukraine: 10

China: 1

Hungary: 3

Australia: 5

Germany: 2

Israel: 1

France: 4

Malaysia: 6

120

12

0

0

0

0

0

14

104

2

0

Overall Study (overall period)

Randomised - controlled

Yes

Factor On-demand

Solution for injection

Intravenous bolus use

Per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.

Fitusiran

SAR439774

Solution for injection

Subcutaneous use

Fitusiran as an SC injection once monthly, dosing started on Day 1 of the treatment period for a total of 9 months.

Factor On-demand

Fitusiran 80 mg Prophylaxis

Factor On-demand

Fitusiran 80 mg Prophylaxis

ABR for subject during efficacy period (EP): annualised number of bleeding episodes during EP annualised to a 1-year interval of time. Treated Bleeding episode: any occurrence of haemorrhage that required administration of by-passing agents (BPA) or factor. It started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to (<=)72 hours apart were considered same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up)(maximum duration of EP: from Day 29-Day 246). This endpoint presents estimated results (i.e., results received by applying negative binomial [NB] regression model on data collected during EP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Primary

From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Factor On-demand v Fitusiran 80 mg Prophylaxis

119

Pre-specified

0.101

2-sided

ABR for subject during EP: annualised number of bleeding episodes during EP annualised to 1-year interval of time. ABR=number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up)(maximum duration of EP: from Day 29-Day 246). This endpoint presents observed results (i.e., descriptive statistics values based on the data collected during EP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Primary

From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

ABR for subject during treatment period (TP) was defined as annualised number of bleeding episodes during TP annualised to 1-year interval of time. Bleeding episode: any occurrence of haemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of [Day 246 or last day of bleeding follow up])(maximum duration of TP: from Day1-Day 246). This endpoint presents estimated results (i.e., results received by applying NB regression model on data collected during TP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Factor On-demand v Fitusiran 80 mg Prophylaxis

119

Pre-specified

0.13

2-sided

ABR for subject during TP: annualised number of bleeding episodes during TP annualised to 1- year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25.Bleeding episode: any occurrence of haemorrhage that required administration of BPA or factor. It started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=72 hours apart were considered same bleeding episode. TP: sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of [Day 246 or last day ofbleeding follow-up])(maximum duration of TP: Day 1-Day 246). Endpoint presents observed results(i.e., descriptive statistics values based on data collected during TP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Annualised spontaneous bleeding rate for subject during EP: annualised number of spontaneous bleeding episodes during EP annualised to 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up)(maximum duration of EP: from Day 29-Day 246). This endpoint presents estimated results (i.e., results received by applying NB regression model on data collected during EP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Factor On-demand v Fitusiran 80 mg Prophylaxis

119

Pre-specified

0.083

2-sided

ABR for subject:annualised number of spontaneous bleeding episodes during EP annualised to 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=72 hours apart were considered same bleeding episode. EP: time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of (Day 246,or last day of bleeding follow up)(maximum duration of EP:Day 29-Day 246).Endpoint presents observed results(i.e.,descriptive statistics values based on data collected during EP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Annualised joint bleeding rate for subject during EP: annualised number of bleeding episodes during EP annualised to 1-year interval of time. Joint bleeding episode was characterised by an unusual sensation in the joint (“aura”) in combination with 1) increasing swelling or warmth over the skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29-Day 246). This endpoint presents estimated results (i.e., results received by applying NB regression model on data collected during EP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Factor On-demand v Fitusiran 80 mg Prophylaxis

119

Pre-specified

0.097

2-sided

Annualised joint bleeding rate during EP: annualised number of bleeding episodes during EP annualised to 1-year interval of time. ABR=number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. Joint bleeding episode: characterised by an unusual sensation in joint (“aura”) in combination with 1) increasing swelling or warmth over skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using limb. It started from first sign of bleed and ended no more than 72hours after last treatment for bleed. EP: time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of (Day 246 or last day of bleeding follow up)(maximum duration of EP: from Day 29-Day 246). Endpoint presents observed results (i.e., descriptive statistics values based on data collected during EP). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Haem-A-QoL: subject-reported questionnaire designed for adult subjects (>=17 years of age) with haemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with haemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item was based on a 5-point Likert scale (1= never, 2= rarely,3= sometimes, 4= often, and 5=all the time), and higher scores represented greater impairment. Change from baseline in physical health domain score was reported in this endpoint. Raw score for physical health domain were transformed to a scale ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health. Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

Baseline (Day 1), Month 9

Factor On-demand v Fitusiran 80 mg Prophylaxis

103

Pre-specified

-19.75

2-sided

Haem-A-QoL: subject-reported questionnaire designed for adult subjects (>=17 years of age) with haemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with haemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item was based on a 5-point Likert scale (1= never, 2= rarely,3= sometimes, 4= often, and 5=all the time), and higher scores represent greater impairment. Raw score for each domain were transformed to a scale ranged between 0 and 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health. Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

Baseline (Day 1), Month 9

Factor On-demand v Fitusiran 80 mg Prophylaxis

103

Pre-specified

-7.07

2-sided

ABR was annualised number of bleeding episodes during onset period per subject annualised to 1-yearinterval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This endpoint presents estimated results (i.e., results received by applying NB regression model on data collected during onset period). Analysis performed on ITT population. Here, subjects analysed=subjects with available data.

Secondary

From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest

An adverse event (AE) was defined as any untoward medical occurrence in a subject who received study drug which did not necessarily have a causal relationship with the treatment. Treatment-emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1visit in the factor on-demand arm. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. Analysis was performed on safety analysis set that included all subjects who received at least 1 dose of study drug or were randomised to on-demand arm, analysed according to the actual treatment received.

Secondary

From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up)

From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up).

Treatment-emergent AE were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the factor on-demand arm. Analysis was performed on safety analysis set.

24.0

Factor On-demand

Fitusiran 80 mg Prophylaxis