Clinical trial NCT03370913: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Keywords: Gene Therapy
Clotting Disorders
Blood Disorder
Blood Coagulation Disorders
Inherited Blood Coagulation disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases
Inborn
Factor VIII
Coagulants
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2017-12-13
Enrollment: 144
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Change From Baseline in Annualized Number of Bleeding Episodes Irrespective of Exogenous FVIII Replacement Treatment [Annualized Bleeding Rate (ABR) for All Bleeds] in EEP.
timeFrame: Baseline to efficacy evaluation period (EEP)
Secondary outcomes:
measure: Change From Baseline in the Annualized Number of Bleeding Episodes Requiring Exogenous FVIII Replacement Therapy (ABR for Treated Bleeds) in the EEP.
timeFrame: Baseline to EEP
measure: Change From Baseline in FVIII Activity at Week 104
timeFrame: Baseline to Week 104
measure: Change From Baseline in Annualized FVIII Utilization in EEP.
timeFrame: Baseline to EEP
measure: Change From Baseline in Haemo-QoL-A Quality of Life: Total Score at Week 104
timeFrame: Baseline to Week 104
measure: Change From Baseline in Haemo-QoL-A Quality of Life: Physical Functioning Domain Score, at Week 104
timeFrame: Baseline to Week 104
measure: Change From Baseline in Haemo-QoL-A Quality of Life: Consequences of Bleeding Domain Score, at Week 104
timeFrame: Baseline to Week 104
measure: Change From Baseline in Haemo-QoL-A Quality of Life: Role Functioning Domain Score, at Week 104
timeFrame: Baseline to Week 104
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Los Angeles Orthopedic Hospital, Orthopedic Hemophilia Treatment Center
state: California
city: Sacramento
country: United States
facility: UC Davis Hemophilia Treatment Center
state: California
city: San Diego
country: United States
facility: University of California San Diego, Hematology and Oncology, Hemophilia &Thrombosis Treatment Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Tampa
country: United States
facility: St. Joseph's Children's Hospital, Center for Bleeding and Clotting Disorders
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Hematology
state: Illinois
city: Louisville
country: United States
facility: James Graham Brown Cancer Center
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Hematology & Medical Oncology
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan, Pediatric Hematology and Oncology
state: Michigan
city: Detroit
country: United States
facility: Wayne State University, Detroit Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine, Department of Pediatrics, Division of Hematology/Oncology
state: Missouri
city: Chapel Hill
country: United States
facility: UNC Hemophilia and Thrombosis Center
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Adelaide
country: Australia
facility: The Royal Adelaide Hospital (RAH)
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Melbourne
country: Australia
facility: Alfred Hospital
city: Perth
country: Australia
facility: Fiona Stanley Hospital
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Campinas
country: Brazil
facility: Campinas Estadual University (UNICAMP) / Campinas Hemocentro / Hematologia E Hemoterapia Center
city: Curitiba
country: Brazil
facility: Parana's Hematology And Hemotherapy Center (HEMEPAR)
city: Rio De Janeiro
country: Brazil
facility: Arthur De Siqueira Cavalcanti Hematology State Institute
city: São Paulo
country: Brazil
facility: Sao Paulo University Clinical Hospital
city: Vitória
country: Brazil
facility: Holy Spirit Hematology and Hemotherapy Center
city: Lille
country: France
facility: Regional University Hospital of Lille (CHRU de Lille)
city: Marseille
country: France
facility: Hopital de la Timone Marseille - Assistance Publique des Hopitaux de Marseille
city: Berlin
country: Germany
facility: Vivantes Clinic im Friedrichshain- Landsberger Allee
city: Bonn
country: Germany
facility: University Clinic Bonn
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Milan
country: Italy
facility: Maggiore Polyclinic Hospital, IRCCS Ca' Granda, Center for Hemophilia and Thrombosis Angelo Bianchi Bonomi
city: Seoul
country: Korea, Republic of
facility: Department of Pediatrics, Kyung Hee University Hospital at Gangdong
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Academic Hospital, Hemophilia Comprehensive Care Center
city: A Coruna
country: Spain
facility: Hospital Teresa Herrera
city: Seville
country: Spain
facility: University Hospital Virgen del Rocio (HUVR)
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary, Department of Hematology
city: London
country: United Kingdom
facility: Barts and The London School of Medicine and Dentistry, Haemophilia Centre
city: London
country: United Kingdom
facility: Hammersmith
city: London
country: United Kingdom
facility: St Thomas' Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital, Oxford Hemophilia and Thrombosis Center
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: BioMarin Pharmaceutical
name: Medical Monitor, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.