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

An Open-label Extension Study of Subcutaneously Administered Fitusiran in Patients With Moderate or Severe Hemophilia A or B Who Have Participated in a Previous Clinical Study With Fitusiran

Primary Objective:

To evaluate the long-term safety and tolerability of fitusiran in male patients with moderate or severe hemophilia A or B

Secondary Objectives:

• To investigate the long-term efficacy of fitusiran
• To characterize the safety and efficacy of concomitantly administered Factor VIII (FVIII), Factor IX (FIX) or bypassing agents (BPA) and fitusiran for treatment of bleeding episodes
• To assess changes in health-related quality of life (QOL) over time
• To characterize antithrombin (AT) reduction and thrombin generation (TG) increase
• To characterize the pharmacokinetics (PK) of fitusiran

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Hemophilia B
• Intervention / Treatment: Drug: Fitusiran (SAR439774)

Detailed Description

It is anticipated that patients in this study will receive treatment with open label fitusiran for approximately 7 years or until fitusiran becomes commercially available, whichever occurs first.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria
    • Clinical Trial Site
  • Sofia, Bulgaria
    • Clinical Trial Site
• Russian Federation
  • Kirov, Russian Federation
    • Clinical Trial Site
  • Moscow, Russian Federation
    • Clinical Trial Site
• Switzerland
  • Zurich, Switzerland
    • Clinical Trial Site
• United Kingdom
  • Basingstoke, United Kingdom
    • Clinical Trial Site
  • Glasgow, United Kingdom
    • Clinical Trial Site
  • London, United Kingdom, NW3 2QG
    • Clinical Trial Site
  • London, United Kingdom, SW17 0QT
    • Clinical Trial Site
  • Truro, United Kingdom
    • Clinical Trial Site
• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Clinical Trial Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Completed and tolerated study drug dosing in study TDR14767 (ALN-AT3SC-001)
• Male aged ≥18 years
• Moderate or severe, clinically stable hemophilia A or B as evidenced by a laboratory FVIII or FIX level ≤5% at screening. Patients with a FVIII or FIX level >5% at screening will be eligible on provision of a historic laboratory report indicating a trough level ≤5%
• Willing and able to comply with the study requirements and provide written informed consent

Exclusion Criteria:

• Clinically significant liver disease
• Patients known to be human immunodeficiency virus seropositive and have a CD4 count <200 cells/μL
• History of venous thromboembolism
• Current serious mental illness that, in the judgment of the Investigator, may compromise patient safety, ability to participate in all study assessments, or study integrity
• Clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, renal, neurological, inflammatory, or other diseases that, in the judgment of the Investigator, precludes study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fitusiran; Patients will be administered subcutaneous (SC) fitusiran once monthly or every 2 months according to the dose selection rules defined in protocol.	Drug: Fitusiran (SAR439774); Pharmaceutical form: solution for injection Route of administration : subcutaneous (sc)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)	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.	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)
Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology	Blood samples were collected to determine the hematology laboratory significant abnormalities. Here, DFB = decrease from baseline, NB = non-black, and B = black.	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)
Number of Participants With Potentially Clinically Significant Abnormality: Clinical Chemistry	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.	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)
Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis	Urine samples collected to determine the significant abnormalities in urine.	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)
Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs	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.	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)
Number of Participants With Potentially Clinically Significant Abnormality: Electrocardiogram (ECG)	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.	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)
Number of Participants With Potentially Clinically Significant Abnormality: Physical Examination	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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Bleeding Rate (ABR) During the Efficacy Period	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).	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Annualized Spontaneous Bleeding Rate During the Efficacy Period	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).	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Annualized Joint Bleeding Rate During the Efficacy Period	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).	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Time Intervals Between Bleeding Events	Bleed-free duration was defined as the time interval between 2 protocol-defined treated bleeding events, excluding events that occurred during the intercurrent periods.	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Annualized Weight-Adjusted Consumption of Coagulation Factor VIII (FVIII) and Coagulation Factor IX (FIX)	Number of coagulation factor injections per bleed was determined. IU= international units, and kg= kilogram.	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Recombinant Factor VIIa (rFVIIa)	Number of BPA injections per bleed was determined.	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Annualized Weight-Adjusted Consumption of Bypassing Agent (BPA) of Activated Prothrombin Complex Concentrate (aPCC)	Number of BPA injections per bleed was determined.	From Day 29 up to end of the study, maximum of up to 76 months
Change From Baseline in EuroQoL 5-Dimension 5-level Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) Scores at Month 24	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.	Baseline and Month 24
Change From Baseline in Hemophilia Quality of Life Questionnaire (Haem-A-QoL) Total Score and Physical Health Scores at Month 24	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.	Baseline and Month 24
Antithrombin Activity Level at the End of Treatment Regimen	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.	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Thrombin Generation at the End of Treatment Regimen	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.	From Day 29 up to end of the study (SAS 1: up to 76 months and SAS 2: up to 40 months)
Maximum Observed Concentration (Cmax) of Fitusiran	Cmax was defined as maximum plasma concentration observed. The non-compartmental Pharmacokinetic (PK) analysis was performed.	Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24
Time to Reach the Maximum Concentration (Tmax) of Fitusiran	tmax was defined as time to reach Cmax. The non-compartmental PK analysis was performed.	Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24
Area Under the Concentration Versus Time Curve From Time 0 to the Real Time (AUClast) of Fitusiran	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.	Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1, and Months 12 and 24
Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of Fitusiran	AUCinf was defined as area under the concentration versus time curve extrapolated to infinity. The non-compartmental PK analysis was performed.	Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Terminal Half-Life (t1/2z) of Fitusiran	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.	Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Apparent Total Body Clearance (CL/F) of Fitusiran	CL/F was defined as apparent clearance of study drug from the body. The non-compartmental PK analysis was performed.	Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Apparent Volume of Distribution at the Steady State After Single Extravascular Dose (Vss/F) of Fitusiran	Vss/F was defined as apparent volume of distribution of study drug at steady state concentration. The non-compartmental PK analysis was performed.	Pre-dose and 0.5, 2, 4, 8 and 24 hours post-dose on Day 1 and Month 12
Recovery of Fraction of the Dose Excreted in Urine (fe) in 0-24 Hours After Fitusiran Administration	fe was defined as the amount of fitusiran excreted in urine in 0-24 hour. The non-compartmental PK analysis was performed.	Postdose, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours at Month 24

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Investigators: Study Director: Clinical Sciences & Operations, MD, Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2015
• Primary Completion (Actual): March 21, 2023
• Study Completion (Actual): March 21, 2023

Study Registration Dates

• First Submitted: September 15, 2015
• First Submitted That Met QC Criteria: September 17, 2015
• First Posted (Estimated): September 18, 2015

Study Record Updates

• Last Update Posted (Actual): June 5, 2024
• Last Update Submitted That Met QC Criteria: June 4, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: RNAi therapeutic; Hemophilia
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: LTE14762; ALN-AT3SC-002 (Other Identifier: Alnylam); 2015-001395-21 (EudraCT Number); U1111-1251-5204 (Registry Identifier: ICTRP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No