Clinical trial NCT03549871: A Study of Fitusiran in Severe Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis
Official title: ATLAS-PPX: an Open-label, Multinational, Switching Study to Describe the Efficacy and Safety of Fitusiran Prophylaxis in Patients With Hemophilia A and B Previously Receiving Factor or Bypassing Agent Prophylaxis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-06-08
Enrollment: 80
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To characterize the frequency of bleeding episodes (BE) while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor concentrate or bypassing agent (BPA) prophylaxis.

Secondary Objectives:

* To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis:
* the frequency of spontaneous bleeding episodes
* the frequency of joint bleeding episodes
* health related quality of life (HRQOL) in participants greater than or equal to (\>=) 17 years of age
* To characterize the frequency of bleeding episodes during the onset and treatment periods in participants receiving fitusiran.
* To characterize the safety and tolerability of fitusiran.
* To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis.

Detailed description: The estimated total time on study, inclusive of Screening, for each participant was up to 15 months for participants who were enrolled in the extension study except for participants in the subgroup of Cohort A, for whom it was up to 9 months. The estimated total time on study was up to 21 months (up to 15 months in participants in the subgroup of Cohort A) in participants who did not enroll in the extension study due to the requirement for an additional up to 6 months of follow-up for monitoring of antithrombin (AT) levels.

Eligibility criteria: Inclusion Criteria:

* Males, \>=12 years of age.
* Severe hemophilia A or B (as evidenced by a central laboratory measurement at screening or documented medical record evidence of FVIII less than (\<) 1 percent (%) or FIX level less than or equal to (\<=) 2%).
* A minimum of 2 bleeding episodes required BPA treatment within the last 6 months prior to screening for participants with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode required factor treatment within the last 12 months prior to screening for participants without inhibitory antibodies to factor VIII or factor IX (Cohort B).
* Met either the definition of inhibitor or non-inhibitor participant as below:
* Inhibitor: Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met one of the following Nijmegen-modified Bethesda assay results criteria:
* Inhibitor titer of \>=0.6 Bethesda Unit per milliliter (BU/mL) at screening, or
* Inhibitor titer of \<0.6 BU/mL at screening with medical record evidence of 2 consecutive titers \>=0.6 BU/mL, or
* Inhibitor titer of \<0.6 BU/mL at screening with medical record evidence of anamnestic response
* The subgroup of participants in Cohort A participants might additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period:

  * Hemophilia B with inhibitory antibody to Factor IX as defined above
  * Not responding adequately to BPA treatment (historical ABR \>=20) prior to enrollment
  * In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6-month BPA prophylaxis period should be omitted.
* Non-inhibitor: Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met each of the following criterion:
* Nijmegen-modified Bethesda assay inhibitor titer of \<0.6 BU/mL at screening and
* No use of BPAs to treat bleeding episodes for at least the last 6 months prior to screening and
* No history of immune tolerance induction therapy within the past 3 years prior to screening.
* Documented prophylactic treatment with factor concentrates or BPAs for the treatment of hemophilia A or B for at least 6 months prior to screening.
* Adherent to the prescribed prophylactic therapy for at least 6 months prior to screening per Investigator assessment.
* Willed 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.
* AT activity \<60% at screening.
* Co-existing thrombophilic disorder.
* Clinically significant liver disease.
* Active Hepatitis C virus infection.
* Acute or chronic Hepatitis B virus infection.
* HIV positive with a CD4 count of \<200 cells per 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 subcutaneous injection(s).
* Any other conditions or comorbidities that made 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)
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
measure: Observed Annualized Bleeding Rate (ABR)
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Secondary outcomes:
measure: Estimated Annualized Spontaneous Bleeding Rate
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
measure: Observed Annualized Spontaneous Bleeding Rate
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
measure: Estimated Annualized Joint Bleeding Rate
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
measure: Observed Annualized Joint Bleeding Rate
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
measure: Change in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period
timeFrame: Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
measure: Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period
timeFrame: Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
measure: Estimated Annualized Bleeding Rate in the Fitusiran Onset Period
timeFrame: Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest
measure: Observed Annualized Bleeding Rate in the Fitusiran Onset Period
timeFrame: Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest
measure: Estimated Annualized Bleeding Rate in the Fitusiran Treatment Period
timeFrame: From Day 1 up to Day 190
measure: Observed Annualized Bleeding Rate in the Fitusiran Treatment Period
timeFrame: from Day 1 up to Day 190
measure: Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates)
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
measure: Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa)
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
measure: Cohort B: Annualized Weight-adjusted Consumption of Factor
timeFrame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Investigational Site Number 0139
state: California
city: Prahran
country: Australia
facility: Investigational Site Number 6104
city: Beijing
country: China
facility: Investigational Site Number 8604
city: Copenhagen
country: Denmark
facility: Investigational Site Number 4501
city: Lyon
country: France
facility: Investigational Site Number 3303
city: Crumlin
country: Ireland
facility: Investigational Site Number 5301
city: Ramat-Gan
country: Israel
facility: Investigational Site Number 9701
city: Milano
country: Italy
facility: Investigational Site Number 3902
city: Nagoya
country: Japan
facility: Investigational Site Number 8101
city: Nishinomiya
country: Japan
facility: Investigational Site Number 8102
city: Saitama
country: Japan
facility: Investigational Site Number 8104
city: Tokyo
country: Japan
facility: Investigational Site Number 8109
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: San Pablo
country: Mexico
facility: Investigational Site Number 5201
city: Adana
country: Turkey
facility: Investigational Site Number 9002
city: Ankara
country: Turkey
facility: Investigational Site Number 9001
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: İzmir
country: Turkey
facility: Investigational Site Number 9010
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: Van
country: Turkey
facility: Investigational site number 9013
city: Kyiv
country: Ukraine
facility: Investigational Site Number 8003
city: Lviv
country: Ukraine
facility: Investigational Site Number 8002
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 4403
city: London
country: United Kingdom
facility: Investigational Site Number 4401
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: