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

ATLAS-A/B: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, Without Inhibitory Antibodies to Factor VIII or IX

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Hemophilia B
• Intervention / Treatment: Drug: factor concentrates; Drug: fitusiran

Detailed Description

The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, was up to 11 months for all participants in the factor on-demand arm and for participants in the fitusiran arm who enrolled in the extension study (LTE15174). The estimated total time on the study was up to 17 months for participants in the fitusiran treatment arm who did not enroll in the extension study due to the requirement for up to an additional 6 months of follow-up monitoring for antithrombin levels.

Participants who completed the study will be eligible for an open-label extension study LTE15174 (NCT03754790).

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Camperdown, Australia, 2050
    • Investigational Site Number 6101
  • Murdoch, Australia, 6961
    • Investigational Site Number 6103
  • Prahran, Australia, 3181
    • Investigational Site Number 6104
• China
  • Beijing, China, 100045
    • Investigational Site Number 8604
  • Guangzhou, China, 510515
    • Investigational Site Number 8602
  • Hangzhou, China, 89147
    • Investigational Site Number 8605
  • Shanghai, China, 200025
    • Investigational Site Number 8603
  • Tianjin, China, 300020
    • Investigational Site Number 8601
• Denmark
  • Copenhagen, Denmark, 2100
    • Investigational Site Number 4501
• France
  • Lyon, France, 69677
    • Investigational Site Number 3303
  • Paris, France, 75015
    • Investigational Site Number 3305
  • Rouen, France, 76038
    • Investigational Site Number 3301
• Germany
  • Berlin, Germany, 10249
    • Investigational Site Number 4904
  • Frankfurt Am Main, Germany, 60590
    • Investigational Site Number 4905
  • Leipzig, Germany, 4103
    • Investigational Site Number 4906
• Hungary
  • Budapest, Hungary, 1134
    • Investigational Site Number 3602
• India
  • Bangalore, India, 560034
    • Investigational Site Number 9102
  • Jaipur, India, 302017
    • Investigational Site Number 9104
  • Lucknow, India, 226003
    • Investigational Site Number 9106
  • Mumbai, India, 400012
    • Investigational Site Number 9109
  • Mumbai, India, 400022
    • Investigational Site Number 9108
  • Mumbai, India
    • Investigational Site Number 9111
  • Pune, India, 411001
    • Investigational Site Number 9103
  • Vellore, India, 632004
    • Investigational Site Number 9105
• Israel
  • Ramat-Gan, Israel, 52621
    • Investigational Site Number 9701
• Italy
  • Padova, Italy, 35128
    • Investigational Site Number 3904
• Japan
  • Isehara, Japan
    • Investigational Site Number 8105
  • Saitama, Japan
    • Investigational Site Number 8104
• Korea, Republic of
  • Busan, Korea, Republic of, 602-739
    • Investigational Site Number 8201
  • Daejeon, Korea, Republic of, 35233
    • Investigational Site Number 8202
  • Seoul, Korea, Republic of, 3722
    • Investigational Site Number 8204
• Malaysia
  • Ampang, Malaysia, 68000
    • Investigational Site Number 6004
  • Johor Bahru, Malaysia, 80100
    • Investigational Site Number 6002
  • Kota Kinabalu, Malaysia, 88586
    • Investigational Site Number 6003
• South Africa
  • Parktown, South Africa, 2193
    • Investigational Site Number 2701
  • Port Elizabeth, South Africa, 6001
    • Investigational Site Number 2702
• Spain
  • Madrid, Spain, 28046
    • Investigational Site Number 3402
• Taiwan
  • Taichung, Taiwan, 40447
    • Investigational Site Number 8807
  • Taichung, Taiwan, 40705
    • Investigational Site Number 8805
  • Taipei, Taiwan, 110
    • Investigational Site Number 8801
  • Taipei, Taiwan, 100
    • Investigational Site Number 8804
  • Taoyuan, Taiwan, 33305
    • Investigational Site Number 8808
• Turkey
  • Adana, Turkey, ?01130
    • Investigational Site Number 9002
  • Antalya, Turkey, 07059
    • Investigational Site Number 9004
  • Gaziantep, Turkey, 27100
    • Investigational Site Number 9008
  • Istanbul, Turkey, 34093
    • Investigational Site Number 9005
  • Izmir, Turkey, TR-35100
    • Investigational Site Number 9003
  • Kayseri, Turkey, 38039
    • Investigational Site Number 9009
  • Samsun, Turkey, 55200
    • Investigational Site Number 9006
• Ukraine
  • Kyiv, Ukraine, ?01135
    • Investigational Site Number 8003
  • Kyiv, Ukraine, 04060
    • Investigational Site Number 8001
  • Lviv, Ukraine, 79044
    • Investigational Site Number 8002
  • Mykolaiv, Ukraine, 54058
    • Investigational Site Number 8005
• United Kingdom
  • Glasgow, United Kingdom, G4 0SF
    • Investigational Site Number 4402
  • London, United Kingdom, E1 2ES
    • Investigational Site Number 4407
  • London, United Kingdom, SE1 9RT
    • Investigational Site Number 4401
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Investigational Site Number 0140
  • Florida
    • Gainesville, Florida, United States, 32610
      • Investigational Site Number 128
    • Tampa, Florida, United States, 33607
      • Investigational Site Number 103
  • Illinois
    • Chicago, Illinois, United States, 60612-3833
      • Investigational Site Number 102
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Investigational Site Number 119
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Investigational Site Number 125
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Investigational Site Number 111
  • Ohio
    • Akron, Ohio, United States, 44308
      • Investigational Site Number 110

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Factor On-demand; 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; by intravenous (IV) injection
Experimental: Fitusiran 80 mg Prophylaxis; 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: factor concentrates; by intravenous (IV) injection; Drug: fitusiran; by SC injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period	ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. 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 <=72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of Day 246 or last day of bleeding follow up (maximum duration of TP: from Day 1 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during TP).	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	ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1- year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: 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 last treatment for bleed, within which any symptoms of bleeding at the same location or injections <=72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when 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 TP: from Day 1 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during TP).	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	Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after 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 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 OM presents estimated results (i.e., results received by applying 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 Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period	ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. 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: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to 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 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
Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period	Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. 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 estimated results (i.e., results received by applying 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 Joint Bleeding Rate for Treated Bleeds During the Efficacy Period	Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) increasing pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: 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 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 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
Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score at Month 9	Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represented greater impairment. Change from baseline in physical health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health.	Baseline (Day 1), Month 9
Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9	Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represent greater impairment. Raw score for each domain were transformed to a scale ranged between 0 and 100, where lower scores denoted better health. Haem-A-QoL total score was average of all domain scores and ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health.	Baseline (Day 1), Month 9
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period	ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated 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. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM presents estimated results (i.e., results received by applying NB regression model on data collected during onset period).	From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment-emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the factor on-demand arm. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event.	From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up)

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Investigators: Study Director: Clinical Sciences & Operations, MD, Sanofi

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): January 26, 2021
• Study Completion (Actual): July 14, 2021

Study Registration Dates

• First Submitted: January 25, 2018
• First Submitted That Met QC Criteria: January 30, 2018
• First Posted (Actual): January 31, 2018

Study Record Updates

• Last Update Posted (Actual): March 28, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Hemophilia B; Hematologic Diseases; Genetic Diseases, Inborn; Blood Coagulation Disorders; Factor VIII; RNAi therapeutic; Factor IX; Hemorrhagic Disorders; Hemophilia A; Coagulants; Genetic Diseases, X-Linked; Coagulation Protein Disorders; Blood Coagulation Disorders, Inherited; Hemophilia A, Severe; Hemophilia B, Severe; Fitusiran
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: EFC14769; ALN-AT3SC-004 (Other Identifier: Alnylam); 2016-001464-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No