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

Hemophilia A Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03370913
• Other study ID #: 270-301
• Secondary ID: 2017-003215-19
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 19, 2017
• Est. completion date: November 2024

Study information

• Verified date: December 2023
• Source: BioMarin Pharmaceutical
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 144
• Est. completion date: November 2024
• Est. primary completion date: November 16, 2020
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• valoctocogene roxaparvovec
Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A

Locations

Country	Name	City	State
Australia	The Royal Adelaide Hospital (RAH)	Adelaide
Australia	Royal Brisbane and Women's Hospital	Brisbane
Australia	Alfred Hospital	Melbourne
Australia	Fiona Stanley Hospital	Perth
Australia	Royal Prince Alfred Hospital	Sydney
Belgium	University Hospital Leuven	Leuven
Brazil	Campinas Estadual University (UNICAMP) / Campinas Hemocentro / Hematologia E Hemoterapia Center	Campinas
Brazil	Parana's Hematology And Hemotherapy Center (HEMEPAR)	Curitiba
Brazil	Arthur De Siqueira Cavalcanti Hematology State Institute	Rio De Janeiro
Brazil	Sao Paulo University Clinical Hospital	São Paulo
Brazil	Holy Spirit Hematology and Hemotherapy Center	Vitória
France	Regional University Hospital of Lille (CHRU de Lille)	Lille
France	Hopital de la Timone Marseille - Assistance Publique des Hopitaux de Marseille	Marseille
Germany	Vivantes Clinic im Friedrichshain- Landsberger Allee	Berlin
Germany	University Clinic Bonn	Bonn
Israel	Chaim Sheba Medical Center	Ramat Gan
Italy	Maggiore Polyclinic Hospital, IRCCS Ca' Granda, Center for Hemophilia and Thrombosis Angelo Bianchi Bonomi	Milan
Korea, Republic of	Department of Pediatrics, Kyung Hee University Hospital at Gangdong	Seoul
South Africa	Charlotte Maxeke Johannesburg Academic Hospital, Hemophilia Comprehensive Care Center	Johannesburg
Spain	Hospital Teresa Herrera	A Coruna
Spain	University Hospital Virgen del Rocio (HUVR)	Seville
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Addenbrookes Hospital	Cambridge
United Kingdom	Glasgow Royal Infirmary, Department of Hematology	Glasgow
United Kingdom	Barts and The London School of Medicine and Dentistry, Haemophilia Centre	London
United Kingdom	Hammersmith	London
United Kingdom	St Thomas' Hospital	London
United Kingdom	Churchill Hospital, Oxford Hemophilia and Thrombosis Center	Oxford
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United States	University of Michigan, Pediatric Hematology and Oncology	Ann Arbor	Michigan
United States	University of Colorado	Aurora	Colorado
United States	UNC Hemophilia and Thrombosis Center	Chapel Hill	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Hematology	Chicago	Illinois
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Wayne State University, Detroit Medical Center	Detroit	Michigan
United States	Los Angeles Orthopedic Hospital, Orthopedic Hemophilia Treatment Center	Los Angeles	California
United States	James Graham Brown Cancer Center	Louisville	Kentucky
United States	University of Minnesota	Minneapolis	Minnesota
United States	UC Davis Hemophilia Treatment Center	Sacramento	California
United States	Washington University School of Medicine, Department of Pediatrics, Division of Hematology/Oncology	Saint Louis	Missouri
United States	University of California San Diego, Hematology and Oncology, Hemophilia &Thrombosis Treatment Center	San Diego	California
United States	UCSF Medical Center	San Francisco	California
United States	St. Joseph's Children's Hospital, Center for Bleeding and Clotting Disorders	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
BioMarin Pharmaceutical

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  South Africa,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Annualized Number of Bleeding Episodes Irrespective of Exogenous FVIII Replacement Treatment [Annualized Bleeding Rate (ABR) for All Bleeds] in 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").	Baseline to efficacy evaluation period (EEP)
Secondary	Change From Baseline in the Annualized Number of Bleeding Episodes Requiring Exogenous FVIII Replacement Therapy (ABR for Treated Bleeds) in the 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").	Baseline to EEP
Secondary	Change From Baseline in FVIII Activity at 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.	Baseline to Week 104
Secondary	Change From Baseline in Annualized FVIII Utilization in 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").	Baseline to EEP
Secondary	Change From Baseline in Haemo-QoL-A Quality of Life: Total Score at 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.	Baseline to Week 104
Secondary	Change From Baseline in Haemo-QoL-A Quality of Life: Physical Functioning Domain Score, at 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	Baseline to Week 104
Secondary	Change From Baseline in Haemo-QoL-A Quality of Life: Consequences of Bleeding Domain Score, at 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	Baseline to Week 104
Secondary	Change From Baseline in Haemo-QoL-A Quality of Life: Role Functioning Domain Score, at 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.	Baseline to Week 104