A Study of Fitusiran in Severe Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis (ATLAS-PPX)

• ClinicalTrials.gov Identifier: NCT03549871
• Recruitment Status: Completed
• First Posted: June 8, 2018
• Results First Posted: February 6, 2023
• Last Update Posted: February 6, 2023
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia	Drug: Fitusiran; Drug: BPA prophylaxis; Drug: Factor (FVIII or FIX) prophylaxis	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 80 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: July 25, 2018
• Actual Primary Completion Date: January 20, 2022
• Actual Study Completion Date: March 25, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Fitusiran; Cohort A [inhibitor]: participants with severe hemophilia A/B and inhibitory antibodies to coagulation factor VIII (FVIII)/factor IX (FIX) previously received BPA prophylaxis. Cohort B [non-inhibitor]: participants with severe hemophilia A/B without inhibitory antibodies to FVIII/FIX previously received factor prophylaxis. Participants from both cohorts was enrolled into 6-month factor/BPA prophylaxis period and continued their pre-study, regularly scheduled prophylaxis regimen with factor/BPAs. This period could be skipped by subgroup of Cohort A (hemophilia B with inhibitors to FIX and historical annualized bleeding rate [ABR] >=20) that started directly with fitusiran. Post completing factor/BPA prophylaxis period, participants entered 7-month fitusiran treatment period (1-month onset+6-month efficacy) followed by AT follow-up/roll-over into LTE15174 (NCT03754790). Throughout study, participants could receive on-demand treatment for breakthrough BE with factor/BPAs, as appropriate.

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

Outcome Measures

Primary Outcome Measures :

1. Estimated Annualized Bleeding Rate (ABR) [ Time Frame: 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 ]
   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.
2. Observed Annualized Bleeding Rate (ABR) [ Time Frame: 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 ]
   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.

Secondary Outcome Measures :

1. Estimated Annualized Spontaneous Bleeding Rate [ Time Frame: 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 ]
   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.
2. Observed Annualized Spontaneous Bleeding Rate [ Time Frame: 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 ]
   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.
3. Estimated Annualized Joint Bleeding Rate [ Time Frame: 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 ]
   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.
4. Observed Annualized Joint Bleeding Rate [ Time Frame: 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 ]
   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.
5. 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 [ Time Frame: Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment 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.
6. Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period [ Time Frame: Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment 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.
7. Estimated Annualized Bleeding Rate in the Fitusiran Onset Period [ Time Frame: 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 ]
   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.
8. Observed Annualized Bleeding Rate in the Fitusiran Onset Period [ Time Frame: 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 ]
   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.
9. Estimated Annualized Bleeding Rate in the Fitusiran Treatment Period [ Time Frame: From Day 1 up to Day 190 ]
   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.
10. Observed Annualized Bleeding Rate in the Fitusiran Treatment Period [ Time Frame: from Day 1 up to Day 190 ]
    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.
11. Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates) [ Time Frame: 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 ]
    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.
12. Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa) [ Time Frame: 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 ]
    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.
13. Cohort B: Annualized Weight-adjusted Consumption of Factor [ Time Frame: 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 ]
    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.

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, >=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.

Contacts and Locations

Locations

United States, California

Investigational Site Number 0139

Los Angeles, California, United States, 90027

Australia

Investigational Site Number 6104

Prahran, Australia, 3181

China

Investigational Site Number 8604

Beijing, China, 100045

Denmark

Investigational Site Number 4501

Copenhagen, Denmark, 2100

France

Investigational Site Number 3303

Lyon, France, 69677

Ireland

Investigational Site Number 5301

Crumlin, Ireland, 12

Israel

Investigational Site Number 9701

Ramat-Gan, Israel, 52621

Italy

Investigational Site Number 3902

Milano, Italy, 20122

Japan

Investigational Site Number 8101

Nagoya, Japan

Investigational Site Number 8102

Nishinomiya, Japan

Investigational Site Number 8104

Saitama, Japan

Investigational Site Number 8109

Tokyo, Japan

Korea, Republic of

Investigational Site Number 8201

Busan, Korea, Republic of, 602-739

Investigational Site Number 8202

Daejeon, Korea, Republic of, 35233

Investigational Site Number 8204

Seoul, Korea, Republic of, 3722

Malaysia

Investigational Site Number 6004

Ampang, Malaysia, 68000

Investigational Site Number 6002

Johor Bahru, Malaysia, 80100

Investigational Site Number 6003

Kota Kinabalu, Malaysia, 88586

Mexico

Investigational Site Number 5201

San Pablo, Mexico

Turkey

Investigational Site Number 9002

Adana, Turkey, ?01130

Investigational Site Number 9001

Ankara, Turkey, 06100

Investigational Site Number 9004

Antalya, Turkey, 07059

Investigational Site Number 9008

Gaziantep, Turkey, 27100

Investigational Site Number 9005

Istanbul, Turkey, 34093

Investigational Site Number 9010

İzmir, Turkey, 35040

Investigational Site Number 9003

Izmir, Turkey, TR-35100

Investigational Site Number 9009

Kayseri, Turkey, 38039

Investigational Site Number 9006

Samsun, Turkey, 55200

Investigational site number 9013

Van, Turkey, 65080

Ukraine

Investigational Site Number 8003

Kyiv, Ukraine, ?01135

Investigational Site Number 8002

Lviv, Ukraine, 79044

United Kingdom

Investigational Site Number 4402

Glasgow, United Kingdom, G4 0SF

Investigational Site Number 4407

London, United Kingdom, E1 2ES

Investigational Site Number 4403

London, United Kingdom, NW3 2QG

Investigational Site Number 4401

London, United Kingdom, SE1 9RT

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

  Study Documents (Full-Text)

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

Study Protocol  [PDF] December 8, 2020

Statistical Analysis Plan  [PDF] January 12, 2022

More Information

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT03549871
• Other Study ID Numbers: EFC15110; 2016-004087-19 ( EudraCT Number ); ALN-AT3SC-009 ( Other Identifier: Alnylam ); U1111-1217-3270 ( Registry Identifier: WHO Universal Trial Number (UTN) )
• First Posted: June 8, 2018
• Results First Posted: February 6, 2023
• Last Update Posted: February 6, 2023
• Last Verified: January 2023

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
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn