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

NCT03549871 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: EFC151102016-004087-19ALN-AT3SC-009U1111-1217-3270
• Study Type: interventional
• Target: 80
• Locations: 15 countries
• Sites: 35

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.

Conditions

Hemophilia

Outcome Measures

Primary Outcomes (2)

• Estimated Annualized Bleeding Rate (ABR)

  Bleeding episodes (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/total number of days in the respective period\*365.25. Estimated data were derived by using repeated measures negative binomial (NB) regression model.

  Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest

• Observed Annualized Bleeding Rate (ABR)

  A bleeding episode (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as 1 BE towards ABR. Any bleeding that began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/number of days in the respective period \*365.25.

  Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest

Secondary Outcomes (13)

• Estimated Annualized Spontaneous Bleeding Rate

  Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest

• Observed Annualized Spontaneous Bleeding Rate

  Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest

• Estimated Annualized Joint Bleeding Rate

  Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest

• Observed Annualized Joint Bleeding Rate

  Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest

• Change in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period

  Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period

Study Arms (1)

Fitusiran

EXPERIMENTAL

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.

Drug: Fitusiran; Drug: BPA prophylaxis; Drug: Factor (FVIII or FIX) prophylaxis

Interventions

Fitusiran DRUG

Pharmaceutical form: solution for injection Route of administration: subcutaneous

Fitusiran

BPA prophylaxis DRUG

Pharmaceutical form: solution for injection Route of administration: Intravenous

Fitusiran

Factor (FVIII or FIX) prophylaxis DRUG

Pharmaceutical form: solution for injection Route of administration: Intravenous

Fitusiran

Eligibility Criteria

• Age: 12 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (35)

Investigational Site Number 0139

Los Angeles, California, 90027, United States

Location

Investigational Site Number 6104

Prahran, 3181, Australia

Location

Investigational Site Number 8604

Beijing, 100045, China

Location

Investigational Site Number 4501

Copenhagen, 2100, Denmark

Location

Investigational Site Number 3303

Lyon, 69677, France

Location

Investigational Site Number 5301

Crumlin, 12, Ireland

Location

Investigational Site Number 9701

Ramat Gan, 52621, Israel

Location

Investigational Site Number 3902

Milan, 20122, Italy

Location

Investigational Site Number 8101

Nagoya, Japan

Location

Investigational Site Number 8102

Nishinomiya, Japan

Location

Investigational Site Number 8104

Saitama, Japan

Location

Investigational Site Number 8109

Tokyo, Japan

Location

Investigational Site Number 6004

Ampang, 68000, Malaysia

Location

Investigational Site Number 6002

Johor Bahru, 80100, Malaysia

Location

Investigational Site Number 6003

Kota Kinabalu, 88586, Malaysia

Location

Investigational Site Number 5201

San Pablo, Mexico

Location

Investigational Site Number 8201

Busan, 602-739, South Korea

Location

Investigational Site Number 8202

Daejeon, 35233, South Korea

Location

Investigational Site Number 8204

Seoul, 3722, South Korea

Location

Investigational Site Number 9002

Adana, ?01130, Turkey (Türkiye)

Location

Investigational Site Number 9001

Ankara, 06100, Turkey (Türkiye)

Location

Investigational Site Number 9004

Antalya, 07059, Turkey (Türkiye)

Location

Investigational Site Number 9008

Gaziantep, 27100, Turkey (Türkiye)

Location

Investigational Site Number 9005

Istanbul, 34093, Turkey (Türkiye)

Location

Investigational Site Number 9010

Izmir, 35040, Turkey (Türkiye)

Location

Investigational Site Number 9003

Izmir, TR-35100, Turkey (Türkiye)

Location

Investigational Site Number 9009

Kayseri, 38039, Turkey (Türkiye)

Location

Investigational Site Number 9006

Samsun, 55200, Turkey (Türkiye)

Location

Investigational site number 9013

Van, 65080, Turkey (Türkiye)

Location

Investigational Site Number 8003

Kyiv, ?01135, Ukraine

Location

Investigational Site Number 8002

Lviv, 79044, Ukraine

Location

Investigational Site Number 4402

Glasgow, G4 0SF, United Kingdom

Location

Investigational Site Number 4407

London, E1 2ES, United Kingdom

Location

Investigational Site Number 4403

London, NW3 2QG, United Kingdom

Location

Investigational Site Number 4401

London, SE1 9RT, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 38452197 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

fitusiran

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi ( Genzyme, a Sanofi Company )

Contact-US@Sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 25, 2018
• First Posted: June 8, 2018
• Study Start: July 25, 2018
• Primary Completion: January 20, 2022
• Study Completion: March 25, 2022
• Last Updated: February 6, 2023
• Results First Posted: February 6, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share

Locations

MY (3); AU (1); DK (1); US (1); UA (2); GB (4); TU (10); KR (3); IT (1); FR (1); IL (1); ME (1); JP (4); IE (1); CN (1)