A Study of Fitusiran in Severe Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis

Hemophilia Clinical Trial

— ATLAS-PPX  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03549871
• Other study ID #: EFC15110
• Secondary ID: 2016-004087-19AL
• Status: Completed
• Phase: Phase 3
• Start date: July 25, 2018
• Est. completion date: March 25, 2022

Study information

• Verified date: January 2023
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: March 25, 2022
• Est. primary completion date: January 20, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemophilia
• Hemophilia A

Intervention

Drug:
• Fitusiran
Pharmaceutical form: solution for injection Route of administration: subcutaneous
• BPA prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous
• Factor (FVIII or FIX) prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous

Locations

Country	Name	City	State
Australia	Investigational Site Number 6104	Prahran
China	Investigational Site Number 8604	Beijing
Denmark	Investigational Site Number 4501	Copenhagen
France	Investigational Site Number 3303	Lyon
Ireland	Investigational Site Number 5301	Crumlin
Israel	Investigational Site Number 9701	Ramat-Gan
Italy	Investigational Site Number 3902	Milano
Japan	Investigational Site Number 8101	Nagoya
Japan	Investigational Site Number 8102	Nishinomiya
Japan	Investigational Site Number 8104	Saitama
Japan	Investigational Site Number 8109	Tokyo
Korea, Republic of	Investigational Site Number 8201	Busan
Korea, Republic of	Investigational Site Number 8202	Daejeon
Korea, Republic of	Investigational Site Number 8204	Seoul
Malaysia	Investigational Site Number 6004	Ampang
Malaysia	Investigational Site Number 6002	Johor Bahru
Malaysia	Investigational Site Number 6003	Kota Kinabalu
Mexico	Investigational Site Number 5201	San Pablo
Turkey	Investigational Site Number 9002	Adana
Turkey	Investigational Site Number 9001	Ankara
Turkey	Investigational Site Number 9004	Antalya
Turkey	Investigational Site Number 9008	Gaziantep
Turkey	Investigational Site Number 9005	Istanbul
Turkey	Investigational Site Number 9003	Izmir
Turkey	Investigational Site Number 9010	Izmir
Turkey	Investigational Site Number 9009	Kayseri
Turkey	Investigational Site Number 9006	Samsun
Turkey	Investigational site number 9013	Van
Ukraine	Investigational Site Number 8003	Kyiv
Ukraine	Investigational Site Number 8002	Lviv
United Kingdom	Investigational Site Number 4402	Glasgow
United Kingdom	Investigational Site Number 4401	London
United Kingdom	Investigational Site Number 4403	London
United Kingdom	Investigational Site Number 4407	London
United States	Investigational Site Number 0139	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Australia,  China,  Denmark,  France,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Mexico,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Estimated Annualized Bleeding Rate (ABR)	Bleeding episodes (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/total number of days in the respective period*365.25. Estimated data were derived by using repeated measures negative binomial (NB) regression model.	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
Primary	Observed Annualized Bleeding Rate (ABR)	A bleeding episode (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as 1 BE towards ABR. Any bleeding that began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/number of days in the respective period *365.25.	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	Estimated Annualized Spontaneous Bleeding Rate	BE: any occurrence of hemorrhage that might require administration of factor/BPA infusion. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. Spontaneous BE: BE occurrence for no apparent/known reason, particularly into joints, muscles, and soft tissues. ABR = total number of qualifying BE/number of days in respective period *365.25. Estimated data was derived using repeated measures NB regression model.	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	Observed Annualized Spontaneous Bleeding Rate	BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Spontaneous BE: bleeding event occurred for no apparent or known reason, particularly into joints, muscles and soft tissues. ABR = total number of qualifying BE/number of days in respective period *365.25.	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	Estimated Annualized Joint Bleeding Rate	BE: any hemorrhage that required administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection to treat BE at that location was considered part of original BE; counted as 1 BE towards ABR. Bleeding after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint ("aura") + increasing swelling/warmth over joint skin, increasing pain/progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of qualifying BE/number of days in respective period *365.25. Estimated data were derived by using repeated measures NB regression model.	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	Observed Annualized Joint Bleeding Rate	BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint (aura) increasing swelling/warmth over joint skin, increasing pain or progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of joint BE/number of days in respective period*365.25.	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	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	Haem-A-QoL: participant-reported questionnaire for adults aged >=17 years with hemophilia and comprised of 46 items covering 10 domains. Physical health domain (PHD) is assessed with 5 items rated on 5-point Likert scale: never, rarely, sometimes, often or all the time. Raw score for PHD were transformed to scale ranged from 0 to 100, where lower scores = better physical health. Least square (LS) mean and 95% confidence interval (CI) by mixed model for repeated measure (MMRM) analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis & fitusiran treatment) & Baseline score (Month -6) as fixed effects.	Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
Secondary	Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period	Haem-A-QoL: questionnaire for adults aged >= 17 years with hemophilia; and comprised of 46 items covering 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 on 5-point Likert scale: never, rarely, sometimes, often or all time. Domain raw score was transformed to scale ranged from 0 to 100, where lower scores=better health. LS mean & 95% CI by MMRM analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis & fitusiran treatment) & Baseline score (Month -6) as fixed effects.	Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
Secondary	Estimated Annualized Bleeding Rate in the Fitusiran Onset Period	BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Estimated ABR and 95% CI was derived by using repeated measures NB regression model with logarithm of duration (years) that each participant spends in 1-Month fitusiran onset period matching BE data being analyzed as offset variable. ABR = total number of qualifying BE/number of days in respective period *365.25.	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
Secondary	Observed Annualized Bleeding Rate in the Fitusiran Onset Period	BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and was counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in the 1-month onset period *365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in 1-month onset period and excluded any bleeding events in period of intercurrent events.	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
Secondary	Estimated Annualized Bleeding Rate in the Fitusiran Treatment Period	BE: defined as any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in the period of intercurrent events. ABR = total number of qualifying BE/number of days in respective period *365.25.	From Day 1 up to Day 190
Secondary	Observed Annualized Bleeding Rate in the Fitusiran Treatment Period	BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original bleeding event and was counted as one BE towards ABR. Any bleeding that began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in treatment period *365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in period of intercurrent events.	from Day 1 up to Day 190
Secondary	Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates)	Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: [Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period]*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agent: aPCC (unit per kilogram [U/kg]) were reported.	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	Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa)	Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: rFVIIa (unit: micrograms per kg [mcg/kg]) were reported. Combined data of annualized weight-adjusted BPA consumption (mcg/kg) for both treated bleeds and prophylaxis purpose were reported in this outcome measure.	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	Cohort B: Annualized Weight-adjusted Consumption of Factor	Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: FVIII and FIX (unit: international Units [IU] per kg [IU/kg]) were reported.	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