Open-Label Multinational Study of Fitusiran Prophylaxis in Pediatric Patients Aged 1 to <12 Years with Severe Hemophilia A or B

Trial ID: 2024-512501-76-00
Protocol: EFC15467
Sponsor: Genzyme Corp.

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Diseases & Conditions

Haemophilia

Objectives

The primary objective of this study is to confirm the appropriate **dose levels** of **fitusiran** when administered to male pediatric participants aged 1 to less than 12 years with severe **hemophilia A** or **B**. This is clinically relevant as determining the correct dosage is crucial for ensuring the efficacy and safety of fitusiran as a prophylactic treatment in this vulnerable population, potentially reducing bleeding episodes and improving quality of life.

Secondary objectives include:

To characterize the safety and tolerability of fitusiran, which is essential for understanding the risk profile and managing potential adverse effects in pediatric patients.
To determine fitusiran plasma concentrations at selected time points, providing insights into the pharmacokinetics of the drug and aiding in optimizing dosing regimens.

Participants

The clinical trial involves a total of **29 male pediatric participants** aged 1 to less than 12 years, all diagnosed with severe **hemophilia** A or B. The study population was selected based on specific inclusion criteria, including the presence of inhibitory antibodies to Factor VIII or IX, and adequate peripheral venous access. Participants are required to weigh between 8 to less than 45 kg at the time of enrollment. The trial does not include female subjects and focuses solely on a vulnerable population of young males. Participants and their guardians must be willing and able to comply with study requirements, with informed consent obtained from parents or legal guardians, and assent from the participants as per local and national regulations. The trial aims to confirm appropriate dose levels of fitusiran for this specific demographic.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **fitusiran** in male pediatric participants aged 1 to less than 12 years with severe **hemophilia** A or B. This study is structured as an open-label, multinational trial with the primary objective of confirming appropriate dose levels of fitusiran. The trial will assess plasma antithrombin activity levels as the primary endpoint, while secondary endpoints include the number of participants reported with adverse events and fitusiran plasma concentrations. The trial is expected to run from January 28, 2020, to December 31, 2025, with a maximum treatment period of 63 days for each participant.

Participants will be administered fitusiran as a **solution for injection** via the subcutaneous route. The study will begin with a screening visit to confirm eligibility based on criteria such as age, weight, and the presence of inhibitory antibodies to Factor VIII or IX. Participants must have adequate peripheral venous access and meet specific inhibitor titer criteria. Following the screening, eligible participants will undergo regular follow-up visits to monitor safety and efficacy parameters, including blood draws for plasma antithrombin activity and fitusiran concentration measurements. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any adverse events are addressed.

The expected length of participant involvement is determined by the maximum treatment period of 63 days, although early termination may occur if participants experience significant adverse events or fail to comply with study requirements. The trial is not categorized as low intervention and is conducted under the auspices of Sanofi Aventis Recherche et Développement. The study's design and procedures are meticulously structured to ensure the collection of robust data while maintaining participant safety throughout the trial duration.

Treatment

The clinical trial involves the administration of **fitusiran**, an experimental medication, under the product name SAR439774. Fitusiran is formulated as a **solution for injection** and is administered via the **subcutaneous** route. The medication is designed for pediatric subjects aged 1 to less than 12 years with severe **hemophilia A** or **B**. The maximum daily dose of fitusiran is 30 mg, with a total maximum dose of 1860 mg over a treatment period of 63 days. The active substance, fitusiran, is a synthetic double-stranded siRNA oligonucleotide directed against antithrombin mRNA and is covalently linked to a ligand containing three N-acetylgalactosamine residues. This substance is classified as a nucleic acid and is developed by Sanofi Aventis Recherche et Développement (SAR).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to confirm appropriate dose levels of fitusiran in the specified pediatric population. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen. The trial is conducted as an open-label, multinational study, allowing for the observation of fitusiran's effects in the target demographic without the use of blinding.

Efficacy

Efficacy in the clinical trial titled "ATLAS-PEDS: An open-label, multinational study of fitusiran prophylaxis in pediatric subjects ages 1 to less than 12 years with hemophilia A or B" will be assessed using specific endpoints. The primary endpoint for evaluating efficacy is the measurement of **plasma antithrombin (AT) activity levels**. This parameter will be used to confirm the appropriate dose levels of fitusiran in the target population. Secondary endpoints include the number of participants reported with adverse events and the measurement of fitusiran plasma concentrations. These endpoints will provide additional insights into the safety and pharmacokinetics of the treatment. The trial is designed to ensure that the data collected will be robust and reliable, contributing to the understanding of fitusiran's efficacy in managing severe hemophilia A or B in pediatric patients.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male, aged 1 to <12 years at the time of enrollment.
Severe hemophilia A or B (Factor VIII (FVIII) <1% or Factor IX (FIX) ≤2%)
Participants must have inhibitory antibodies to FVIII or FIX and must meet one of the following Nijmegen-modified Bethesda assay results criteria: - Inhibitor titer of ≥0.6 BU/mL at screening, OR - Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of 2 consecutive titers ≥0.6 BU/mL, OR - Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of 1 inhibitor titer ≥0.6 BU/mL and a history of anamnestic response or severe allergic reaction (anaphylaxis or nephrotic syndrome)
Adequate peripheral venous access, as determined by the Investigator, to allow the blood draws required by the study protocol
Weight requirements at the time of enrollment: 8 to <45 kg
Willing and able to comply with the study requirements and to provide signed written informed consent obtained from parent(s)/legal guardian (hereinafter the “parent”) and written or oral assent obtained from participant, per local and national requirements

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Exclusion Criteria

Known co-existing bleeding disorders other than hemophilia A or B
Antithrombin (AT) activity <60% at Screening
Co-existing thrombophilic disorder
Clinically significant liver disease
Active Hepatitis C virus infection
Acute or chronic Hepatitis B virus infection
Acute Hepatitis A or hepatitis E infection
HIV positive with a CD4 count of <400 cells/μL
History of arterial or venous thromboembolism, unrelated to an indwelling venous access
Inadequate renal function
History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine (GalNAc)
Subjects with central or peripheral indwelling catheters, with history of venous access complications leading to hospitalization and/or systemic anticoagulation therapy.
History of intolerance to subcutaneous (SC) injection(s)
Use of emicizumab (Hemlibra®) within 6 months prior to screening
Any other conditions or comorbidities that would make the patient unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment