Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301) (BMN 270-301)

• ClinicalTrials.gov Identifier: NCT03370913
• Recruitment Status: Active, not recruiting
• First Posted: December 13, 2017
• Results First Posted: November 28, 2023
• Last Update Posted: December 20, 2023
• Sponsor: BioMarin Pharmaceutical
• Information provided by (Responsible Party): BioMarin Pharmaceutical

Tracking Information

• First Submitted Date: November 27, 2017
• First Posted Date: December 13, 2017
• Results First Submitted Date: July 17, 2023
• Results First Posted Date: November 28, 2023
• Last Update Posted Date: December 20, 2023
• Actual Study Start Date: December 19, 2017
• Actual Primary Completion Date: November 16, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 17, 2023)

Change From Baseline in Annualized Number of Bleeding Episodes Irrespective of Exogenous FVIII Replacement Treatment [Annualized Bleeding Rate (ABR) for All Bleeds] in EEP. [ Time Frame: Baseline to efficacy evaluation period (EEP) ]

All bleeds comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. All bleeds are any reported bleeding events regardless of the use of FVIII or other treatments. ABR for all bleeds= Number of bleeding episodes for all bleeds during the calculation period / total number of days during the calculation period * 365.25. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis. EEP: From Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit").

• Original Primary Outcome Measures (submitted: December 7, 2017): Change of the median FVIII activity [ Time Frame: 52 weeks ]

Current Secondary Outcome Measures (submitted: November 6, 2023)

• Change From Baseline in the Annualized Number of Bleeding Episodes Requiring Exogenous FVIII Replacement Therapy (ABR for Treated Bleeds) in the EEP. [ Time Frame: Baseline to EEP ]
  ABR for treated bleeds=Number of bleeding episodes for treated bleeds during the calculation period/total number of days during the calculation period * 365.25 Bleeds that were treated with FVIII replacement therapy (recorded as "treatment for bleed") within 72 hours and were not associated with surgery or a procedure were included. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis. EEP: From Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit").
• Change From Baseline in FVIII Activity at Week 104 [ Time Frame: Baseline to Week 104 ]
  The change from baseline (assuming no treatment for severe hemophilia A) in FVIII activity, as measured by chromogenic substrate assay, at Weeks 104 post-BMN 270 infusion. Each subject's FVIII activity level at Week 104 is defined as the median of the values obtained at Week 104 with the analysis window defined. The baseline value is imputed as 1 IU/dL for each subject. Note: One of the subject's wk104 duplicate data issue was corrected in the 3 year analysis per which the mean (standard deviation) values are reported in outcome measure table. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis.
• Change From Baseline in Annualized FVIII Utilization in EEP. [ Time Frame: Baseline to EEP ]
  The change from baseline in the annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy in the Post FVIII Prophylaxis to Last Visit in the EEP. The annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy is defined as Sum of FVIII use (IU/kg) during calculation period/Total number of days during the calculation period ×365.25. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis. EEP: From Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit").
• Change From Baseline in Haemo-QoL-A Quality of Life: Total Score at Week 104 [ Time Frame: Baseline to Week 104 ]
  The change from baseline(assuming no treatment for severe hemophilia A) in Haemo-Qol-A score, at wk104 post-BMN 270 infusion.The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life(HRQoL)questionnaire for adults consisting of 41 items covering 6 domains(Physical Functioning,Role Functioning,Worry,Consequences of Bleeding,Emotional Impact &Treatment Concerns). The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0(none of the time)to 5 (all of the time).The recall period for the Haemo-Qol-A is one month (4-weeks). The Haemo-QoL-A domain(physical functioning, role functioning, worry, consequences of bleeding, emotional impact, treatment concern) scores range from 0 to 5 and the total score is derived by summing each domain score (range, 0 to 30). Domain and total scores are transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia related quality of life.
• Change From Baseline in Haemo-QoL-A Quality of Life: Physical Functioning Domain Score, at Week 104 [ Time Frame: Baseline to Week 104 ]
  The change from baseline (assuming no treatment for severe hemophilia A) in Haemo-Qol-A score, at week 104 post-BMN 270 infusion. The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life (HRQoL) questionnaire for adults consisting of 41 items covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns).The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0 (none of the time) to 5 (all of the time).The recall period for the Haemo-Qol-A is one month (4-weeks). The Haemo-Qol-A physical functioning domain score is an average of each item value within a domain.The range of domain scores is 0 to 5; higher scores mean better HRQoL or less impairment for the domain. The physical functioning domain score is transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia-related physical functioning
• Change From Baseline in Haemo-QoL-A Quality of Life: Consequences of Bleeding Domain Score, at Week 104 [ Time Frame: Baseline to Week 104 ]
  The change from baseline(assuming no treatment for severe hemophilia A)in Haemo-Qol-A score, at week 104 post-BMN 270 infusion. The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life(HRQoL)questionnaire for adults consisting of 41 items covering 6 domains(Physical Functioning,Role Functioning,Worry,Consequences of Bleeding,Emotional Impact and Treatment Concerns). The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0(none of the time) to 5(all of the time). The recall period for the Haemo-Qol-A is one month (4-wks). The Haemo-Qol-A consequences of bleeding domain score is an average of each item value within a domain. The range of domain scores is 0 to 5; higher scores mean better HRQoL or less impairment for the domain. The consequences of bleeding domain score is transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia-related consequences of bleeding
• Change From Baseline in Haemo-QoL-A Quality of Life: Role Functioning Domain Score, at Week 104 [ Time Frame: Baseline to Week 104 ]
  The change from baseline (assuming no treatment for severe hemophilia A) in Haemo-Qol-A score, at week 104 post-BMN 270 infusion. The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life (HRQoL) questionnaire for adults consisting of 41 items covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns).The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0 (none of the time) to 5 (all of the time). The recall period for the Haemo-Qol-A is one month (4-weeks). The Haemo-Qol-A role functioning domain score is an average of each item value within a domain. The range of domain scores is 0 to 5; higher scores mean better HRQoL or less impairment for the domain. The role functioning domain score is transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia-related role functioning.

Original Secondary Outcome Measures (submitted: December 7, 2017)

• Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy [ Time Frame: 52 weeks ]
• Change in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment [ Time Frame: 52 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: December 7, 2017)

• Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemo-QoL-A. [ Time Frame: 52 weeks ]
  Haemo-QoL-A is a hemophilia-specific, health-related quality of life questionnaire for adults
• Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) EQ-5D-5L [ Time Frame: 52 weeks ]
  EQ-5D-5L is a general questionnaire designed to measure health status
• Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemophilia Activities List (HAL) [ Time Frame: 52 weeks ]
  HAL is a questionnaire that measures the impact of hemophilia on functional abilities in adults
• Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) [ Time Frame: 52 weeks ]
  WPAI+CIQ:HS is a questionnaire that is designed to measure the effect of symptom severity due to hemophilia on work productivity and activity/classroom impairment
• Percentage of participants with treatment-related adverse events, as assessed by CTCAE v4.03 in the first 52 weeks following valoctocogene roxaparvovec infusion [ Time Frame: 52 weeks ]
• Percentage of participants with treatment-related adverse events, as assessed by de novo development of FVIII inhibitors in the first 52 weeks following valoctocogene roxaparvovec infusion [ Time Frame: 52 weeks ]
• Percentage of participants with treatment-related adverse events, as assessed by CTCAE v4.03 during years 2-5 following valoctocogene roxaparvovec infusion. [ Time Frame: 5 years ]
• Percentage of participants with treatment-related adverse events, as assessed by de novo development of FVIII inhibitors during years 2-5 following valoctocogene roxaparvovec infusion. [ Time Frame: 5 years ]

Descriptive Information

• Brief Title: Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301)
• Official Title: A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL Receiving Prophylactic FVIII Infusions
• Brief Summary: This Phase III clinical study will assess the impact of BMN 270 (compared to FVIII prophylaxis) on the number of bleeding episodes irrespective of exogenous FVIII replacement treatment in the efficacy evaluation period (EEP) (from Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit"). The study will also assess the impact of BMN 270 (compared to FVIII prophylaxis) on: the number of bleeding episodes requiring exogenous FVIII treatment in "Post FVIII Prophylaxis to Last Visit", FVIII activity as measured by chromogenic sustrate assay at Week 104 following intravenous infusion of BMN 270, usage of exogenous FVIII replacement therapy in "Post FVIII Prophylaxis to Last Visit", health-related quality of life patient-reported outcomes at week 104 following intravenous infusion of BMN 270. The study will also evaluate the safety of the BMN 270.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia A

Intervention

Biological: valoctocogene roxaparvovec

Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A

Other Name: BMN 270

Study Arms

Experimental: valoctocogene roxaparvovec Open Label

Single administration of valoctocogene roxaparvovec at a dose of 6E13 vg/kg

Intervention: Biological: valoctocogene roxaparvovec

Publications *

• Quinn J, Delaney KA, Wong WY, Miesbach W, Bullinger M. Psychometric Validation of the Haemo-QOL-A in Participants with Hemophilia A Treated with Gene Therapy. Patient Relat Outcome Meas. 2022 Jul 18;13:169-180. doi: 10.2147/PROM.S357555. eCollection 2022.
• Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, Symington E, Quon DV, Wang JD, Peerlinck K, Pipe SW, Madan B, Key NS, Pierce GF, O'Mahony B, Kaczmarek R, Henshaw J, Lawal A, Jayaram K, Huang M, Yang X, Wong WY, Kim B; GENEr8-1 Trial Group. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022 Mar 17;386(11):1013-1025. doi: 10.1056/NEJMoa2113708.
• Rosen S, Tiefenbacher S, Robinson M, Huang M, Srimani J, Mackenzie D, Christianson T, Pasi KJ, Rangarajan S, Symington E, Giermasz A, Pierce GF, Kim B, Zoog SJ, Vettermann C. Activity of transgene-produced B-domain-deleted factor VIII in human plasma following AAV5 gene therapy. Blood. 2020 Nov 26;136(22):2524-2534. doi: 10.1182/blood.2020005683.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 17, 2023): 144
• Original Estimated Enrollment (submitted: December 7, 2017): 40
• Estimated Study Completion Date: November 2024
• Actual Primary Completion Date: November 16, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent.
2. Must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry.
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs).
4. No previous documented history of a detectable FVIII inhibitor, and results from a Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 12 months.

Exclusion Criteria:

1. Detectable pre-existing antibodies to the adeno-associated virus 5 (AAV5) capsid.
2. Any evidence of active infection or any immunosuppressive disorder, except for HIV infection
3. Any evidence of active infection or any immunosuppressive disorder, including HIV infection (effective as of Protocol Amendment 3)
4. Significant liver dysfunction.
5. Prior liver biopsy showing significant fibrosis.
6. Evidence of any bleeding disorder not related to hemophilia A.
7. Platelet count of < 100 x 10^9/L.
8. Creatinine ≥ 1.5 mg/dL.
9. Liver cirrhosis of any etiology as assessed by liver ultrasound.
10. Chronic or active hepatitis B.
11. Active Hepatitis C.
12. Active malignancy, except non-melanoma skin cancer.
13. History of hepatic malignancy.
14. History of arterial or venous thromboembolic events.
15. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Biological males only

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, France, Germany, Israel, Italy, Korea, Republic of, South Africa, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Japan

Administrative Information

• NCT Number: NCT03370913
• Other Study ID Numbers: 270-301; 2017-003215-19 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: BioMarin Pharmaceutical
• Original Responsible Party: Same as current
• Current Study Sponsor: BioMarin Pharmaceutical
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Monitor, MD; BioMarin Pharmaceutical

• PRS Account: BioMarin Pharmaceutical
• Verification Date: December 2023