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

• ClinicalTrials.gov Identifier: NCT03417102
• Recruitment Status: Completed
• First Posted: January 31, 2018
• Results First Posted: December 21, 2021
• Last Update Posted: March 28, 2022
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Hemophilia A; Hemophilia B	Drug: fitusiran; Drug: Bypassing agents	Phase 3

Detailed Description:

The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, for each participant was up to 11 months for all participants who enroll in the extension study and participants in the on-demand arm who did not enroll in the extension study. The estimated total time on study was up to 17 months in fitusiran treatment arm participants 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: ATLAS-INH: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, With Inhibitory Antibodies to Factor VIII or IX
• Actual Study Start Date: February 14, 2018
• Actual Primary Completion Date: November 25, 2020
• Actual Study Completion Date: June 23, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Bypassing Agents (BPA) On-demand; 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; solution for injection; by intravenous (IV) injection
Experimental: Fitusiran 80 mg Prophylaxis; 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; solution for injection; by subcutaneous (SC) injection

Outcome Measures

Primary Outcome Measures :

1. Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period [ Time Frame: 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 ]
   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).
2. Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period [ Time Frame: 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 ]
   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).

Secondary Outcome Measures :

1. Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period [ Time Frame: 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 ]
   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 less than or equal to 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 represents estimated results (i.e., results received by applying NB regression model on data collected during TP).
2. Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period [ Time Frame: 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 ]
   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 less than or equal to 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 represents observed results (i.e., descriptive statistics values based on data collected during TP).
3. Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period [ Time Frame: 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 ]
   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 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 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 represents estimated results (i.e., results received by applying NB regression model on data collected during EP).
4. Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period [ Time Frame: 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 ]
   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 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: 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 represents observed results (i.e., descriptive statistics values based on data collected during EP).
5. Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period [ Time Frame: 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 ]
   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) increased 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).
6. Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period [ Time Frame: 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 ]
   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) increased 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).
7. Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9 [ Time Frame: Baseline (Day 1), 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). Items were rated along five response options: never, rarely, sometimes, often, or all the time. 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 to 100, where lower scores denoted better physical health.
8. Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 [ Time Frame: Baseline (Day 1), 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). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for each domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores denoted better quality of life.
9. Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period [ Time Frame: 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 ]
   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 may 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. 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 represents estimated results (i.e., results received by applying NB regression model on data collected during onset period).
10. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: From Baseline (Day 1) up to 15 months (i.e. 9 months treatment period + 6-months follow-up) ]
    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 BPA 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.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Contacts and Locations

Locations

United States, Arizona

Investigational Site Number 0117

Phoenix, Arizona, United States, 85016

United States, California

Investigational Site Number 0139

Los Angeles, California, United States, 90027

Investigational Site Number 0135

Orange, California, United States, 92868

Investigational Site Number 0137

San Diego, California, United States, 92123

United States, Florida

Investigational Site Number 0128

Gainesville, Florida, United States, 32610

Investigational Site Number 0115

Jacksonville, Florida, United States, 32207

Investigational Site Number 0105

Miami, Florida, United States, 33136

Investigational Site Number 0103

Tampa, Florida, United States, 33607

United States, Louisiana

Investigational Site Number 0119

New Orleans, Louisiana, United States, 70112

United States, Maryland

Investigational Site Number 0136

Baltimore, Maryland, United States, 21205

United States, Nevada

Investigational Site Number 0111

Las Vegas, Nevada, United States, 89135

United States, Pennsylvania

Investigational Site Number 0104

Philadelphia, Pennsylvania, United States, 19104-5127

Australia

Investigational Site Number 6101

Camperdown, Australia, 2050

Investigational Site Number 6104

Clayton, Australia, 3168

Canada

Investigational Site Number 1102

Montreal, Canada, H1T 2M4

China

Investigational Site Number 8604

Beijing, China, 100045

Investigational Site Number 8602

Guangzhou, China, 510515

Investigational Site Number 8605

Hangzhou, China, 310003

Investigational Site Number 8603

Shanghai, China, 200025

Investigational Site Number 8601

Tianjin, China, 300020

France

Investigational Site Number 3303

Lyon, France, 69677

Investigational Site Number 3301

Rouen, France, 76038

Germany

Investigational Site Number 4905

Frankfurt Am Main, Germany, 60590

Investigational Site Number 4906

Leipzig, Germany, 4103

India

Investigational Site Number 9102

Bangalore, India, 560034

Investigational Site Number 9108

India, India

Investigational Site Number 9104

Jaipur, India, 302017

Investigational Site Number 9106

Lucknow, India, 226003

Investigational Site Number 9103

Pune, India, 411001

Investigational Site Number 9111

Pune, India, 411004

Investigational Site Number 9105

Vellore, India, 632004

Italy

Investigational Site Number 3901

Florence, Italy, 50134

Investigational Site Number 3904

Padua, Italy, 35128

Japan

Investigational Site Number 8110

Japan, Japan

Investigational Site Number 8103

Kita Kyushu-Shi, Japan

Korea, Republic of

Investigational Site Number 8202

Daejeon, Korea, Republic of, 35233

Investigational Site Number 8203

Seoul, Korea, Republic of, 3722

Investigational Site Number 8204

Seoul, Korea, Republic of

Malaysia

Investigational Site Number 6003

Kota Kinabalu, Malaysia, 88586

Investigational Site Number 6004

Malaysia, Malaysia

South Africa

Investigational Site Number 2701

Parktown, South Africa, 2193

Investigational Site Number 2703

Polokwane, South Africa, 699

Investigational Site Number 2702

Port Elizabeth, South Africa, 6001

Spain

Investigational Site Number 3402

Madrid, Spain, 28046

Taiwan

Investigational Site Number 8803

Changhua, Taiwan, 500

Investigational Site Number 8801

Taipei, Taiwan, 110

Investigational Site Number 8804

Taiwan, Taiwan

Investigational Site Number 8805

Taiwan, Taiwan

Turkey

Investigational Site Number 9002

Adana, Turkey, ?01130

Investigational Site Number 9004

Akdeniz, Turkey, 07059

Investigational Site Number 9001

Ankara, Turkey, 06100

Investigational Site Number 9005

Istanbul, Turkey, 34093

Investigational Site Number 9003

Izmir, Turkey, 35100

Investigational Site Number 9006

Turkey, Turkey

Ukraine

Investigational Site Number 8003

Kyiv, Ukraine, 01135

Investigational Site Number 8001

Kyiv, Ukraine, 04060

Investigational Site Number 8002

Lviv, Ukraine, 79044

United Kingdom

Investigational Site Number 4407

London, United Kingdom, E1 2ES

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations, MD; Sanofi

  Study Documents (Full-Text)

Documents provided by Sanofi ( Genzyme, a Sanofi Company ):

Study Protocol  [PDF] June 27, 2018

Statistical Analysis Plan  [PDF] July 16, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT03417102
• Other Study ID Numbers: EFC14768; 2016-001463-36 ( EudraCT Number ); ALN-AT3SC-003 ( Other Identifier: Alnylam )
• First Posted: January 31, 2018
• Results First Posted: December 21, 2021
• Last Update Posted: March 28, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sanofi ( Genzyme, a Sanofi Company ):

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

Additional relevant MeSH terms:

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