Clinical trial NCT03417245: A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-01-31
Enrollment: 120
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
timeFrame: 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
measure: Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
timeFrame: 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:
measure: Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
timeFrame: 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
measure: Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
timeFrame: 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
measure: Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period
timeFrame: 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
measure: Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period
timeFrame: 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
measure: Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
timeFrame: 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
measure: Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
timeFrame: 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
measure: 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
timeFrame: Baseline (Day 1), Month 9
measure: Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9
timeFrame: Baseline (Day 1), Month 9
measure: Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period
timeFrame: 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
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
timeFrame: From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up)
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Investigational Site Number 0140
state: Arkansas
city: Gainesville
country: United States
facility: Investigational Site Number 128
state: Florida
city: Tampa
country: United States
facility: Investigational Site Number 103
state: Florida
city: Chicago
country: United States
facility: Investigational Site Number 102
state: Illinois
city: New Orleans
country: United States
facility: Investigational Site Number 119
state: Louisiana
city: Ann Arbor
country: United States
facility: Investigational Site Number 125
state: Michigan
city: Las Vegas
country: United States
facility: Investigational Site Number 111
state: Nevada
city: Akron
country: United States
facility: Investigational Site Number 110
state: Ohio
city: Camperdown
country: Australia
facility: Investigational Site Number 6101
city: Murdoch
country: Australia
facility: Investigational Site Number 6103
city: Prahran
country: Australia
facility: Investigational Site Number 6104
city: Beijing
country: China
facility: Investigational Site Number 8604
city: Guangzhou
country: China
facility: Investigational Site Number 8602
city: Hangzhou
country: China
facility: Investigational Site Number 8605
city: Shanghai
country: China
facility: Investigational Site Number 8603
city: Tianjin
country: China
facility: Investigational Site Number 8601
city: Copenhagen
country: Denmark
facility: Investigational Site Number 4501
city: Lyon
country: France
facility: Investigational Site Number 3303
city: Paris
country: France
facility: Investigational Site Number 3305
city: Rouen
country: France
facility: Investigational Site Number 3301
city: Berlin
country: Germany
facility: Investigational Site Number 4904
city: Frankfurt Am Main
country: Germany
facility: Investigational Site Number 4905
city: Leipzig
country: Germany
facility: Investigational Site Number 4906
city: Budapest
country: Hungary
facility: Investigational Site Number 3602
city: Bangalore
country: India
facility: Investigational Site Number 9102
city: Jaipur
country: India
facility: Investigational Site Number 9104
city: Lucknow
country: India
facility: Investigational Site Number 9106
city: Mumbai
country: India
facility: Investigational Site Number 9109
city: Mumbai
country: India
facility: Investigational Site Number 9108
city: Mumbai
country: India
facility: Investigational Site Number 9111
city: Pune
country: India
facility: Investigational Site Number 9103
city: Vellore
country: India
facility: Investigational Site Number 9105
city: Ramat-Gan
country: Israel
facility: Investigational Site Number 9701
city: Padova
country: Italy
facility: Investigational Site Number 3904
city: Isehara
country: Japan
facility: Investigational Site Number 8105
city: Saitama
country: Japan
facility: Investigational Site Number 8104
city: Busan
country: Korea, Republic of
facility: Investigational Site Number 8201
city: Daejeon
country: Korea, Republic of
facility: Investigational Site Number 8202
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 8204
city: Ampang
country: Malaysia
facility: Investigational Site Number 6004
city: Johor Bahru
country: Malaysia
facility: Investigational Site Number 6002
city: Kota Kinabalu
country: Malaysia
facility: Investigational Site Number 6003
city: Parktown
country: South Africa
facility: Investigational Site Number 2701
city: Port Elizabeth
country: South Africa
facility: Investigational Site Number 2702
city: Madrid
country: Spain
facility: Investigational Site Number 3402
city: Taichung
country: Taiwan
facility: Investigational Site Number 8807
city: Taichung
country: Taiwan
facility: Investigational Site Number 8805
city: Taipei
country: Taiwan
facility: Investigational Site Number 8804
city: Taipei
country: Taiwan
facility: Investigational Site Number 8801
city: Taoyuan
country: Taiwan
facility: Investigational Site Number 8808
city: Adana
country: Turkey
facility: Investigational Site Number 9002
city: Antalya
country: Turkey
facility: Investigational Site Number 9004
city: Gaziantep
country: Turkey
facility: Investigational Site Number 9008
city: Istanbul
country: Turkey
facility: Investigational Site Number 9005
city: Izmir
country: Turkey
facility: Investigational Site Number 9003
city: Kayseri
country: Turkey
facility: Investigational Site Number 9009
city: Samsun
country: Turkey
facility: Investigational Site Number 9006
city: Kyiv
country: Ukraine
facility: Investigational Site Number 8001
city: Kyiv
country: Ukraine
facility: Investigational Site Number 8003
city: Lviv
country: Ukraine
facility: Investigational Site Number 8002
city: Mykolaiv
country: Ukraine
facility: Investigational Site Number 8005
city: Glasgow
country: United Kingdom
facility: Investigational Site Number 4402
city: London
country: United Kingdom
facility: Investigational Site Number 4407
city: London
country: United Kingdom
facility: Investigational Site Number 4401
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations, MD
role: STUDY_DIRECTOR
References:
citation: 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.