A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors

NCT03417102 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: EFC147682016-001463-36ALN-AT3SC-003
• Study Type: interventional
• Target: 60
• Locations: 17 countries
• Sites: 58

Brief Summary

The purpose of this study was to determine the frequency of bleeding episodes in participants receiving fitusiran as prophylactic treatment of hemophilia compared to participants who were assigned to continue with their regular medication. In addition, the study assessed safety, quality of life, pharmacodynamics (PD), and pharmacokinetics (PK).

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; Inhibitor; Bypassing agents; 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 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) represents 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 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 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 represents observed results (i.e., descriptive statistics values based on the data which was 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 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)

Bypassing Agents (BPA) On-demand

ACTIVE COMPARATOR

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

Drug: Bypassing agents

Fitusiran 80 mg Prophylaxis

EXPERIMENTAL

Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.

Drug: fitusiran

Interventions

fitusiran DRUG

solution for injection; by subcutaneous (SC) injection

Fitusiran 80 mg Prophylaxis

Bypassing agents DRUG

solution for injection; by intravenous (IV) injection

Bypassing Agents (BPA) On-demand

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, greater than or equal to (\>=) 12 years of age.
• Severe hemophilia A or B with inhibitors.
• (Severity confirmed by a central laboratory where coagulation factor VIII (FVIII) level was less than (\<)1% or factor IX (FIX) level was less than or equal to \[\<=\]2% at Screening; Inhibitors defined as inhibitor titer of \>=0.6 Bethesda units per milliliter \[BU/mL\] or as evidenced by medical records).
• A minimum of 6 bleeding episodes requiring BPA treatment within the last 6 months prior to screening.
• Willing and able to comply 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.
• 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.
• 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 judgement.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (58)

Investigational Site Number 0117

Phoenix, Arizona, 85016, United States

Location

Investigational Site Number 0139

Los Angeles, California, 90027, United States

Location

Investigational Site Number 0135

Orange, California, 92868, United States

Location

Investigational Site Number 0137

San Diego, California, 92123, United States

Location

Investigational Site Number 0128

Gainesville, Florida, 32610, United States

Location

Investigational Site Number 0115

Jacksonville, Florida, 32207, United States

Location

Investigational Site Number 0105

Miami, Florida, 33136, United States

Location

Investigational Site Number 0103

Tampa, Florida, 33607, United States

Location

Investigational Site Number 0119

New Orleans, Louisiana, 70112, United States

Location

Investigational Site Number 0136

Baltimore, Maryland, 21205, United States

Location

Investigational Site Number 0111

Las Vegas, Nevada, 89135, United States

Location

Investigational Site Number 0104

Philadelphia, Pennsylvania, 19104-5127, United States

Location

Investigational Site Number 6101

Camperdown, 2050, Australia

Location

Investigational Site Number 6104

Clayton, 3168, Australia

Location

Investigational Site Number 1102

Montreal, H1T 2M4, Canada

Location

Investigational Site Number 8604

Beijing, 100045, China

Location

Investigational Site Number 8602

Guangzhou, 510515, China

Location

Investigational Site Number 8605

Hangzhou, 310003, China

Location

Investigational Site Number 8603

Shanghai, 200025, China

Location

Investigational Site Number 8601

Tianjin, 300020, China

Location

Investigational Site Number 3303

Lyon, 69677, France

Location

Investigational Site Number 3301

Rouen, 76038, France

Location

Investigational Site Number 4905

Frankfurt am Main, 60590, Germany

Location

Investigational Site Number 4906

Leipzig, 4103, Germany

Location

Investigational Site Number 9102

Bangalore, 560034, India

Location

Investigational Site Number 9108

India, India

Location

Investigational Site Number 9104

Jaipur, 302017, India

Location

Investigational Site Number 9106

Lucknow, 226003, India

Location

Investigational Site Number 9103

Pune, 411001, India

Location

Investigational Site Number 9111

Pune, 411004, India

Location

Investigational Site Number 9105

Vellore, 632004, India

Location

Investigational Site Number 3901

Florence, 50134, Italy

Location

Investigational Site Number 3904

Padua, 35128, Italy

Location

Investigational Site Number 8110

Japan, Japan

Location

Investigational Site Number 8103

Kita Kyushu-Shi, Japan

Location

Investigational Site Number 6003

Kota Kinabalu, 88586, Malaysia

Location

Investigational Site Number 6004

Malaysia, Malaysia

Location

Investigational Site Number 2701

Parktown, 2193, South Africa

Location

Investigational Site Number 2703

Polokwane, 699, South Africa

Location

Investigational Site Number 2702

Port Elizabeth, 6001, South Africa

Location

Investigational Site Number 8202

Daejeon, 35233, South Korea

Location

Investigational Site Number 8203

Seoul, 3722, South Korea

Location

Investigational Site Number 8204

Seoul, South Korea

Location

Investigational Site Number 3402

Madrid, 28046, Spain

Location

Investigational Site Number 8803

Changhua, 500, Taiwan

Location

Investigational Site Number 8804

Dawan, Taiwan

Location

Investigational Site Number 8805

Dawan, Taiwan

Location

Investigational Site Number 8801

Taipei, 110, Taiwan

Location

Investigational Site Number 9002

Adana, ?01130, Turkey (Türkiye)

Location

Investigational Site Number 9004

Akdeniz, 07059, Turkey (Türkiye)

Location

Investigational Site Number 9001

Ankara, 06100, Turkey (Türkiye)

Location

Investigational Site Number 9005

Istanbul, 34093, Turkey (Türkiye)

Location

Investigational Site Number 9003

Izmir, 35100, Turkey (Türkiye)

Location

Investigational Site Number 9006

Turkey, Turkey (Türkiye)

Location

Investigational Site Number 8003

Kyiv, 01135, Ukraine

Location

Investigational Site Number 8001

Kyiv, 04060, Ukraine

Location

Investigational Site Number 8002

Lviv, 79044, Ukraine

Location

Investigational Site Number 4407

London, E1 2ES, United Kingdom

Location

Related Publications (3)

• Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, Tran H, Sun J, Wu R, Poloskey S, Qiu Z, Kichou S, Andersson S, Mei B, Rangarajan S. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial. Lancet. 2023 Apr 29;401(10386):1427-1437. doi: 10.1016/S0140-6736(23)00284-2. Epub 2023 Mar 29.

  PMID: 37003287 DERIVED

• The Lancet Haematology. The role of conferences in tackling inequalities. Lancet Haematol. 2022 Feb;9(2):e81. doi: 10.1016/S2352-3026(22)00008-4. No abstract available.

  PMID: 35114155 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

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: February 14, 2018
• Primary Completion: November 25, 2020
• Study Completion: June 23, 2021
• Last Updated: March 28, 2022
• Results First Posted: December 21, 2021

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); CN (5); UA (3); MY (2); DE (2); IT (2); ES (1); AU (2); KR (3); TU (6); US (12); FR (2); GB (1); IN (7); TW (4); JP (2); ZA (3)