A Study of Fitusiran in Severe Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis

NCT ID: NCT03549871

Last Updated: 2023-02-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-25
• Study Completion Date: 2022-03-25

Brief Summary

Primary Objective:

To characterize the frequency of bleeding episodes (BE) while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor concentrate or bypassing agent (BPA) prophylaxis.

Secondary Objectives:

• To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis:
• the frequency of spontaneous bleeding episodes
• the frequency of joint bleeding episodes
• health related quality of life (HRQOL) in participants greater than or equal to (>=) 17 years of age
• To characterize the frequency of bleeding episodes during the onset and treatment periods in participants receiving fitusiran.
• To characterize the safety and tolerability of fitusiran.
• To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis.

Detailed Description

The estimated total time on study, inclusive of Screening, for each participant was up to 15 months for participants who were enrolled in the extension study except for participants in the subgroup of Cohort A, for whom it was up to 9 months. The estimated total time on study was up to 21 months (up to 15 months in participants in the subgroup of Cohort A) in participants who did not enroll in the extension study due to the requirement for an additional up to 6 months of follow-up for monitoring of antithrombin (AT) levels.

Conditions

Hemophilia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Fitusiran

Cohort A \[inhibitor\]: participants with severe hemophilia A/B and inhibitory antibodies to coagulation factor VIII (FVIII)/factor IX (FIX) previously received BPA prophylaxis. Cohort B \[non-inhibitor\]: participants with severe hemophilia A/B without inhibitory antibodies to FVIII/FIX previously received factor prophylaxis. Participants from both cohorts was enrolled into 6-month factor/BPA prophylaxis period and continued their pre-study, regularly scheduled prophylaxis regimen with factor/BPAs. This period could be skipped by subgroup of Cohort A (hemophilia B with inhibitors to FIX and historical annualized bleeding rate \[ABR\] \>=20) that started directly with fitusiran. Post completing factor/BPA prophylaxis period, participants entered 7-month fitusiran treatment period (1-month onset+6-month efficacy) followed by AT follow-up/roll-over into LTE15174 (NCT03754790). Throughout study, participants could receive on-demand treatment for breakthrough BE with factor/BPAs, as appropriate.

Group Type: EXPERIMENTAL

Fitusiran

Intervention Type: DRUG

Pharmaceutical form: solution for injection Route of administration: subcutaneous

BPA prophylaxis

Intervention Type: DRUG

Pharmaceutical form: solution for injection Route of administration: Intravenous

Factor (FVIII or FIX) prophylaxis

Intervention Type: DRUG

Pharmaceutical form: solution for injection Route of administration: Intravenous

Interventions

Fitusiran

Pharmaceutical form: solution for injection Route of administration: subcutaneous

Intervention Type: DRUG

BPA prophylaxis

Pharmaceutical form: solution for injection Route of administration: Intravenous

Intervention Type: DRUG

Factor (FVIII or FIX) prophylaxis

Pharmaceutical form: solution for injection Route of administration: Intravenous

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Males, >=12 years of age.
• Severe hemophilia A or B (as evidenced by a central laboratory measurement at screening or documented medical record evidence of FVIII less than (<) 1 percent (%) or FIX level less than or equal to (<=) 2%).
• A minimum of 2 bleeding episodes required BPA treatment within the last 6 months prior to screening for participants with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode required factor treatment within the last 12 months prior to screening for participants without inhibitory antibodies to factor VIII or factor IX (Cohort B).
• Met either the definition of inhibitor or non-inhibitor participant as below:
• Inhibitor: Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met one of the following Nijmegen-modified Bethesda assay results criteria:
• Inhibitor titer of >=0.6 Bethesda Unit per milliliter (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 anamnestic response
• The subgroup of participants in Cohort A participants might additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period:

• Hemophilia B with inhibitory antibody to Factor IX as defined above
• Not responding adequately to BPA treatment (historical ABR >=20) prior to enrollment
• In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6-month BPA prophylaxis period should be omitted.
• Non-inhibitor: Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met each of the following criterion:
• Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at screening and
• No use of BPAs to treat bleeding episodes for at least the last 6 months prior to screening and
• No history of immune tolerance induction therapy within the past 3 years prior to screening.
• Documented prophylactic treatment with factor concentrates or BPAs for the treatment of hemophilia A or B for at least 6 months prior to screening.
• Adherent to the prescribed prophylactic therapy for at least 6 months prior to screening per Investigator assessment.
• Willed and complied with the study requirements and to provide written informed consent and assent.

Exclusion Criteria

• Known co-existing bleeding disorders other than hemophilia A or B.
• 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.
• HIV positive with a CD4 count of <200 cells per microliter.
• History of arterial or venous thromboembolism.
• Inadequate renal function.
• History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine (GalNAc).
• History of intolerance to subcutaneous injection(s).
• Any other conditions or comorbidities that made the participant unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment.

• Minimum Eligible Age: 12 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

Investigational Site Number 0139

Los Angeles, California, United States

Investigational Site Number 6104

Prahran, , Australia

Investigational Site Number 8604

Beijing, , China

Investigational Site Number 4501

Copenhagen, , Denmark

Investigational Site Number 3303

Lyon, , France

Investigational Site Number 5301

Crumlin, , Ireland

Investigational Site Number 9701

Ramat Gan, , Israel

Investigational Site Number 3902

Milan, , Italy

Investigational Site Number 8101

Nagoya, , Japan

Investigational Site Number 8102

Nishinomiya, , Japan

Investigational Site Number 8104

Saitama, , Japan

Investigational Site Number 8109

Tokyo, , Japan

Investigational Site Number 6004

Ampang, , Malaysia

Investigational Site Number 6002

Johor Bahru, , Malaysia

Investigational Site Number 6003

Kota Kinabalu, , Malaysia

Investigational Site Number 5201

San Pablo, , Mexico

Investigational Site Number 8201

Busan, , South Korea

Investigational Site Number 8202

Daejeon, , South Korea

Investigational Site Number 8204

Seoul, , South Korea

Investigational Site Number 9002

Adana, , Turkey (Türkiye)

Investigational Site Number 9001

Ankara, , Turkey (Türkiye)

Investigational Site Number 9004

Antalya, , Turkey (Türkiye)

Investigational Site Number 9008

Gaziantep, , Turkey (Türkiye)

Investigational Site Number 9005

Istanbul, , Turkey (Türkiye)

Investigational Site Number 9010

Izmir, , Turkey (Türkiye)

Investigational Site Number 9003

Izmir, , Turkey (Türkiye)

Investigational Site Number 9009

Kayseri, , Turkey (Türkiye)

Investigational Site Number 9006

Samsun, , Turkey (Türkiye)

Investigational site number 9013

Van, , Turkey (Türkiye)

Investigational Site Number 8003

Kyiv, , Ukraine

Investigational Site Number 8002

Lviv, , Ukraine

Investigational Site Number 4402

Glasgow, , United Kingdom

Investigational Site Number 4407

London, , United Kingdom

Investigational Site Number 4403

London, , United Kingdom

Investigational Site Number 4401

London, , United Kingdom

Countries

United States; Australia; China; Denmark; France; Ireland; Israel; Italy; Japan; Malaysia; Mexico; South Korea; Turkey (Türkiye); Ukraine; United Kingdom

References

Kenet G, Nolan B, Zulfikar B, Antmen B, Kampmann P, Matsushita T, You CW, Vilchevska K, Bagot CN, Sharif A, Peyvandi F, Young G, Negrier C, Chi J, Kittner B, Sussebach C, Shammas F, Mei B, Andersson S, Kavakli K. Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial. Blood. 2024 May 30;143(22):2256-2269. doi: 10.1182/blood.2023021864.

Reference Type: DERIVED

PMID: 38452197 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-004087-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ALN-AT3SC-009

Identifier Type: OTHER

Identifier Source: secondary_id

U1111-1217-3270

Identifier Type: REGISTRY

Identifier Source: secondary_id

EFC15110

Identifier Type: -

Identifier Source: org_study_id