EFC14768

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

19 Jul 2021

No

Yes

23 Jun 2021

No

To evaluate the efficacy of fitusiran compared to on-demand treatment with bypassing agents (BPAs), 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.

14 Feb 2018

Yes

Yes

Korea, Republic of: 7

Ukraine: 4

Taiwan: 1

India: 20

Japan: 1

Australia: 2

Germany: 1

United States: 5

Canada: 1

Malaysia: 9

Turkey: 6

57

1

0

0

0

0

0

10

47

0

0

Overall Study (overall period)

Randomised - controlled

Yes

Bypassing agents (BPA) 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 80 mg SC injection once monthly, on Day 1 of the treatment period for a total of 9 months.

Bypassing agents (BPA) on-demand

Fitusiran 80 mg Prophylaxis

Bypassing agents (BPA) on-demand

Fitusiran 80 mg Prophylaxis

BPA on-demand

Subjects received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.

Fitusiran Prophylaxis

Subjects received fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.

ABR for subject during efficacy period (EP) was defined as annualised number of bleeding episodes during EP annualised to a 1-year interval of time. Treated Bleeding episode: 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 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 the 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 to Day 246). This endpoint represents estimated results (i.e., results received by applying negative binomial [NB] regression model on data collected during EP). Analysis was performed on ITT population which included all randomised subjects.

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

Bypassing agents (BPA) on-demand v Fitusiran 80 mg Prophylaxis

57

Pre-specified

0.092

2-sided

ABR for subject during EP was defined as annualised number of bleeding episodes during EP annualised to a 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 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. EP was defined as time duration starting from Day 29 when the 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 represents observed results (i.e., descriptive statistics values based on the data which was collected during EP). Analysis was performed on ITT population.

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 a 1-year interval of time. Bleeding episode: 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 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 Day 1 to Day 246). This endpoint represents estimated results (i.e., results received by applying NB regression model on data collected during TP). Analysis was performed on intent-to-treat (ITT) population.

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

Bypassing agents (BPA) on-demand v Fitusiran 80 mg Prophylaxis

57

Pre-specified

0.108

2-sided

ABR for subject during TP was defined as 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 hemorrhage 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 was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on 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 TP: from Day 1-Day 246). This endpoint represents observed results (i.e., descriptive statistics values based on data collected during TP). Analysis was performed on ITT population.

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 was defined as annualised number of spontaneous bleeding episodes during EP annualised to a 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 a bleed and ended no more than 72 hours after 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. 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 represents estimated results (i.e., results received by applying NB regression model on data collected during EP). Analysis was performed on ITT population.

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

Bypassing agents (BPA) on-demand v Fitusiran 80 mg Prophylaxis

57

Pre-specified

0.056

2-sided

ABR for subject during EP: 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 the 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 the 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 the last day of bleeding follow up)(maximum duration of EP: from Day 29-Day 246).This endpoint represents observed results (i.e., descriptive statistics values based on data collected during EP). Analysis was performed on ITT population.

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 was defined as annualised number of bleeding episodes during EP annualised to a 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) increased 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 the bleed. EP was defined as time duration starting from Day 29 when the 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 to Day 246). This endpoint presents estimated results (i.e., results received by applying NB regression model on data collected during EP). Analysis was performed on ITT population.

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

Bypassing agents (BPA) on-demand v Fitusiran 80 mg Prophylaxis

57

Pre-specified

0.098

2-sided

Annualised joint bleeding rate for subject during EP: annualised number of joint 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 was characterised by an unusual sensation in joint (“aura”) in combination with 1) increasing swelling or warmth over skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of bleed and ended no more than 72 hours 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 was performed on ITT population.

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 hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. 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 to 100, where lower scores denoted better physical health. Analysis was performed on ITT population. Here, "number of subjects analysed" = subjects evaluable for this endpoint.

Secondary

Baseline (Day 1), Month 9

Bypassing agents (BPA) on-demand v Fitusiran 80 mg Prophylaxis

49

Pre-specified

-28.72

2-sided

Haem-A-QoL: subject-reported questionnaire designed for adult subjects (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for each domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores denoted better quality of life. Analysis was performed on ITT population. Here, "number of subjects analysed" = subjects evaluable for this endpoint.

Secondary

Baseline (Day 1), Month 9

Bypassing agents (BPA) on-demand v Fitusiran 80 mg Prophylaxis

48

Pre-specified

-14.85

2-sided

ABR was annualised number of bleeding episodes during onset period per subject annualised to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that may 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 represents estimated results (i.e., results received by applying NB regression model on data collected during onset period). Analysis was performed on ITT population.

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 1 visit in the BPA 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-months follow-up)

AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up).

TEAEs: any AE with onset date after first dose of fitusiran in fitusiran prophylaxis arm or after Day 1 visit in the BPA on-demand arm. Analysis done on safety analysis set. Three subjects who were treated with fitusiran but not randomised as per protocol addendum for China, were included in safety analysis for the fitusiran prophylaxis arm.

24.0

Bypassing agents (BPA) on-demand

Fitusiran 80 mg Prophylaxis