A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors

NCT03417245 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: EFC14769ALN-AT3SC-0042016-001464-11
• Study Type: interventional
• Target: 120
• Locations: 19 countries
• Sites: 64

Brief Summary

Primary Objective:

• To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by the frequency of bleeding episodes. Secondary Objectives:
• To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by:
• The frequency of spontaneous bleeding episodes.
• The frequency of joint bleeding episodes.
• Health-related quality of life (HRQOL) in participants \>=17 years of age.
• To determine the frequency of bleeding episodes during the onset period.
• To determine the safety and tolerability of fitusiran.

Conditions

Hemophilia A; Hemophilia B

Keywords

RNAi therapeutic; Hemophilia A; Hemophilia B; Hemophilia A, Severe; Hemophilia B, Severe; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Factor VIII; Factor IX; Coagulants; Fitusiran

Outcome Measures

Primary Outcomes (2)

• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period

  ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of by-passing agents (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 outcome measure (OM) presents estimated results (i.e., results received by applying negative binomial \[NB\] regression model on data collected during EP).

  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

• Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period

  ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized 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 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on the data collected during EP).

  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

Secondary Outcomes (10)

• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period

  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

• Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period

  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

• Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period

  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

• Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period

  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

• Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period

  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

Study Arms (2)

Factor On-demand

EXPERIMENTAL

Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.

Drug: factor concentrates

Fitusiran 80 mg Prophylaxis

EXPERIMENTAL

Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.

Drug: fitusiran; Drug: factor concentrates

Interventions

fitusiran DRUG

by SC injection

Fitusiran 80 mg Prophylaxis

factor concentrates DRUG

by intravenous (IV) injection

Factor On-demand; Fitusiran 80 mg Prophylaxis

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 without inhibitors.
• Severity confirmed by a central laboratory where FVIII level was less than (\<) 1 percent (%) or Factor IX (FIX) level was less than or equal to (\<=) 2% at Screening.
• On-demand use of factor concentrate to manage bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion:
• Nijmegen modified Bethesda assay inhibitor titer of \<0.6 Bethesda units per milliliter (BU/mL) at Screening.
• No use of Bypassing agents to treat bleeding episodes for at least the last 6 months prior to Screening.
• No history of immune tolerance induction therapy within the last 3 years prior to Screening.
• A minimum of 6 bleeding episodes requiring factor concentrate treatment within the last 6 months prior to Screening.
• Willing and complied with the study requirements and to provide written informed consent and assent.

You may not qualify if:

• Known co-existing bleeding disorders other than hemophilia A or B, i.e., Von Willebrand's disease, additional factor deficiencies, or platelet disorders.
• Antithrombin (AT) activity \<60% at Screening.
• Co-existing thrombophilic disorder.
• Clinically significant liver disease.
• Active hepatitis C virus infection.
• HIV positive with a cluster of differentiation-4 count of \<200 cells/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 SC injection(s).
• Any other conditions or comorbidities that would make 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 (64)

Investigational Site Number 0140

Little Rock, Arkansas, 72202, United States

Location

Investigational Site Number 128

Gainesville, Florida, 32610, United States

Location

Investigational Site Number 103

Tampa, Florida, 33607, United States

Location

Investigational Site Number 102

Chicago, Illinois, 60612-3833, United States

Location

Investigational Site Number 119

New Orleans, Louisiana, 70112, United States

Location

Investigational Site Number 125

Ann Arbor, Michigan, 48109, United States

Location

Investigational Site Number 111

Las Vegas, Nevada, 89135, United States

Location

Investigational Site Number 110

Akron, Ohio, 44308, United States

Location

Investigational Site Number 6101

Camperdown, 2050, Australia

Location

Investigational Site Number 6103

Murdoch, 6961, Australia

Location

Investigational Site Number 6104

Prahran, 3181, Australia

Location

Investigational Site Number 8604

Beijing, 100045, China

Location

Investigational Site Number 8602

Guangzhou, 510515, China

Location

Investigational Site Number 8605

Hangzhou, 89147, China

Location

Investigational Site Number 8603

Shanghai, 200025, China

Location

Investigational Site Number 8601

Tianjin, 300020, China

Location

Investigational Site Number 4501

Copenhagen, 2100, Denmark

Location

Investigational Site Number 3303

Lyon, 69677, France

Location

Investigational Site Number 3305

Paris, 75015, France

Location

Investigational Site Number 3301

Rouen, 76038, France

Location

Investigational Site Number 4904

Berlin, 10249, Germany

Location

Investigational Site Number 4905

Frankfurt am Main, 60590, Germany

Location

Investigational Site Number 4906

Leipzig, 4103, Germany

Location

Investigational Site Number 3602

Budapest, 1134, Hungary

Location

Investigational Site Number 9102

Bangalore, 560034, India

Location

Investigational Site Number 9104

Jaipur, 302017, India

Location

Investigational Site Number 9106

Lucknow, 226003, India

Location

Investigational Site Number 9109

Mumbai, 400012, India

Location

Investigational Site Number 9108

Mumbai, 400022, India

Location

Investigational Site Number 9111

Mumbai, India

Location

Investigational Site Number 9103

Pune, 411001, India

Location

Investigational Site Number 9105

Vellore, 632004, India

Location

Investigational Site Number 9701

Ramat Gan, 52621, Israel

Location

Investigational Site Number 3904

Padua, 35128, Italy

Location

Investigational Site Number 8105

Isehara, Japan

Location

Investigational Site Number 8104

Saitama, 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 2701

Parktown, 2193, South Africa

Location

Investigational Site Number 2702

Port Elizabeth, 6001, South Africa

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 3402

Madrid, 28046, Spain

Location

Investigational Site Number 8807

Taichung, 40447, Taiwan

Location

Investigational Site Number 8805

Taichung, 40705, Taiwan

Location

Investigational Site Number 8804

Taipei, 100, Taiwan

Location

Investigational Site Number 8801

Taipei, 110, Taiwan

Location

Investigational Site Number 8808

Taoyuan District, 33305, Taiwan

Location

Investigational Site Number 9002

Adana, ?01130, 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 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 8001

Kyiv, 04060, Ukraine

Location

Investigational Site Number 8003

Kyiv, ?01135, Ukraine

Location

Investigational Site Number 8002

Lviv, 79044, Ukraine

Location

Investigational Site Number 8005

Mykolaiv, 54058, 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 4401

London, SE1 9RT, United Kingdom

Location

Related Publications (2)

• Srivastava A, Rangarajan S, Kavakli K, Klamroth R, Kenet G, Khoo L, You CW, Xu W, Malan N, Frenzel L, Bagot CN, Stasyshyn O, Chang CY, Poloskey S, Qiu Z, Andersson S, Mei B, Pipe SW. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2023 May;10(5):e322-e332. doi: 10.1016/S2352-3026(23)00037-6. Epub 2023 Mar 29.

  PMID: 37003278 DERIVED

• Del Pozo Martin Y. 2021 ASH annual meeting. Lancet Haematol. 2022 Feb;9(2):e92-e93. doi: 10.1016/S2352-3026(21)00384-7. Epub 2021 Dec 16. No abstract available.

  PMID: 34922648 DERIVED

MeSH Terms

Conditions

Hemophilia A; Hemophilia B; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked

Interventions

fitusiran; prothrombin complex concentrates

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations, MD

  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: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2018
• First Posted: January 31, 2018
• Study Start: March 1, 2018
• Primary Completion: January 26, 2021
• Study Completion: July 14, 2021
• Last Updated: March 28, 2022
• Results First Posted: February 4, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

JP (2); KR (3); CN (5); IL (1); ZA (2); IT (1); IN (8); DK (1); TW (5); FR (3); MY (3); GB (3); DE (3); ES (1); TU (7); UA (4); US (8); HU (1); AU (3)