Clinical trial NCT03370172: A Study of BAX 888 in Male Adults With Severe Hemophilia A
Official title: A Global, Open-Label, Multicenter, Phase 1/2 Study of the Safety and Dose Escalation of BAX 888, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII) in Severe Hemophilia A Subjects Administered a Single Intravenous Infusion
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Baxalta Innovations GmbH, now part of Shire
name: Takeda Development Center Americas, Inc.
First posted: 2017-12-12
Enrollment: 21
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: The main aim of this study is to check if there are side effects from BAX 888 and to determine the dose of BAX 888 for treating severe hemophilia A in male adults.

Participants will receive one infusion with BAX 888 at the hemophilia treatment center. During the study, participants will visit their study clinic multiple times.

Detailed description: This study consists of 3 cohorts. Participants will be assigned to 1 of 3 dose cohorts with a minimum of 24 hours between dosing of each participant. Initially, 2 participants will be dosed in a cohort, with up to a total of 5 participants if the cohort is expanded based on safety and activity levels data.

Dose escalation: After dosing first 2 participants in cohort 1 the decision will be made on the following: If week 4 FVIII activity levels of both participants are less than (\<) 2%, then dose escalation to cohort 2 will be triggered with no further dosing in cohort 1. If FVIII activity levels \>=2% are observed in at least 1 participant among the 2 participants the decision to escalate dose or expand the cohort with dosing of additional participants will be based on all available data through Week 14.

Dose expansion: After dose escalation and administration of BAX 888 to the first 2 participants in 3 cohorts: If sustained Week 14 FVIII activity levels are \>=30% are not achieved in both participants (first 2 participants in cohorts 1 and 2) then escalation to immediate next cohort will be triggered after Data Monitoring Committee (DMC) review of all available safety and FVIII activity levels data. For cohort 3 dosing of additional participants will be paused until further review of available data. If sustained Week 14 FVIII levels are \>=30% in at least 1 of the 2 participants (first 2 participant in cohort 1, 2, 3) then expansion of cohorts 1, 2 (with up to 5 participants), 3 (with up to 3 additional participants) will be initiated with dosing or study could be completed with no further dosing.

23 APRIL 2020: Enrollment of new patients into this study has been paused due to the COVID-19 situation. The duration of this pause is dependent on the leveling and control of the COVID-19 pandemic.

Eligibility criteria: Inclusion Criteria:

* Male, aged 18 to 75 years at the time of screening.
* Established severe hemophilia A (FVIII:C \<1%, measured following \>=5 days without FVIII treatment) and/or documented intron 1 inversion or intron 22 inversion mutation in the F8 gene, consistent with severe hemophilia A , and documented evidence of \>=3 hemorrhages over the previous 12 months requiring treatment with exogenous FVIII or use of FVIII prophylaxis because of history of frequent bleeding episodes.
* History of greater than (\>) 150 exposure days to exogenously administered FVIII concentrates or cryoprecipitate.
* Sexually active men must agree to use barrier contraception (combination of a condom and spermicide) or limit sexual intercourse to post-menopausal, surgically sterilized, or contraception-practicing partners for a minimum of 6 months after administration of BAX 888, or until BAX 888 genomes are no longer detected in the semen, whichever is sooner.
* Participant is willing and able to comply with the requirements of the protocol, including provision of semen samples, maintenance of a diary of bleeding episodes and FVIII protein use.
* Signed informed consent.

Exclusion Criteria:

* Bleeding disorder(s) other than hemophilia A.
* Personal laboratory evidence of having developed inhibitors to FVIII protein at any time (\>=0.6 Bethesda units \[BU\] on any single test).
* Documented prior allergic reaction to any FVIII product.
* Anti-Adeno-associated virus, serotype 8 (AAV8) neutralizing antibody titer \>=1:5. Participants whose laboratory assessments are less than or equal to (\<=) 1:10 may be re-tested within the same screening window and, if eligibility criterion is met on retest, may be enrolled after confirmation by the Sponsor Medical Monitor.
* Known hypersensitivity to prednisolone or prednisone, or to any of the excipients.
* Having a disease in which treatment with prednisolone or prednisone is not tolerated (including but not limited to osteoporosis with vertebral fractures, difficult to control hypertension, and difficult to control diabetes).
* Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease:

  * Anti-smooth muscle antibody assay results \>=40 (Inova QUANTA LiteTM Actin IgG enzyme-linked immunosorbent assay \[ELISA\]); values of 31 to 39 will be flagged as possibly abnormal and the Investigator and Medical Monitor will evaluate the participant for eligibility.
  * Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers.
  * Total immunoglobulin G (IgG) \>1.5\*upper limit of normal (ULN).
  * Antinuclear antibody (ANA) titer \>1:320; OR ANA titer \>1:80 if demonstrated concurrently with alanine aminotransferase (ALT) that is \>ULN.
* Active Hepatitis virus (Hepatitis C): As indicated by detectable hepatitis C virus (HCV) ribonucleic acid (RNA) by polymerase chain reaction (PCR).
* Hepatitis B: If surface antigen is positive.
* Seropositive for Human Immunodeficiency Virus (HIV).
* Receiving systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment.
* Clinically significant infections (e.g. systemic fungal infections) requiring systemic treatment.
* Known immune disorder (including myeloma and lymphoma).
* Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders.
* An absolute neutrophil count \<1000 cells per cubic millimeter (cells/mm\^3).
* Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following:

  * Platelet count of \<150,000/microliter (mcL).
  * Serum albumin level is below the central laboratory's lower limit of normal and FibroSURE is \>=0.48 (i.e., Metavir staging of F2 or greater). Of note, in participants with a known history of Gilbert's syndrome, a Fibrotest cannot be used for fibrosis testing.
  * Total bilirubin \>1.5\*ULN and direct bilirubin \>=0.5 milligram per deciliter (mg/dL).
  * ALT or aspartate aminotransferase (AST) \>1.0\*ULN.
  * Alkaline phosphatase (AP) \>2.0\*ULN.
  * History of liver biopsy indicating moderate or severe fibrosis (Metavir staging of F2 or greater).
  * History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy.
  * Any findings on screening ultrasound that would preclude the safe use of AAV gene therapy.
* Prothrombin time (PT) international normalized ratio (INR) \>=1.4.
* Serum creatinine \>1.5 mg/dL.
* Urine protein \>30 mg/dL or \>0.5 gram per day (g/day).
* Body mass index \>38.
* Major surgery or an orthopedic surgical procedure planned within 6 months after enrollment.
* Acute or chronic disease that, in the opinion of the investigator, would adversely affect participant safety or compliance or interpretation of study results.
* Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0.
* Received an investigational intervention or participated in another clinical trial within 4 weeks prior to enrollment or within 5 half-lives of the investigational drug administration, whichever is longer.
* Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease).
* Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol abuse) that in the opinion of the investigator, is likely to impair participants ability to comply with protocol mandated procedures.
* Participant is a family member or employee of the investigator.

Primary outcomes:
measure: Number of Participants With BAX 888-Related Adverse Events (AEs)
timeFrame: From study drug administration to 5 Years
Secondary outcomes:
measure: Change from Baseline in Circulating Plasma FVIII Activity Level
timeFrame: Baseline, up to approximately 5 years per participant
measure: Change from Baseline in Circulating Plasma FVIII Antigen Level
timeFrame: Baseline, up to approximately 5 years per participant
measure: Annualized Bleed Rate (ABR)
timeFrame: Up to 5 years per participant
measure: Percentage of Participants With a Redaction Consumption of Exogenous FVIII
timeFrame: Historical data from 12 months prior to study enrollment and 5 years post-infusion
measure: Number of Participants Develop Inhibitory Antibodies to FVIII
timeFrame: Up to 5 years per participant
measure: Number of Participants Develop Total Binding Antibodies to FVIII
timeFrame: Up to 5 years per participant
measure: Number of Participants With Humoral and Cell-Mediated Immune Response to AAV8 and FVIII Proteins
timeFrame: Up to 5 years per participant
measure: Surveillance of AAV8 Genome Shedding
timeFrame: Until 2 consecutive measurements are negative or up to 5 years, whichever is sooner
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Orthopaedic Hospital DBA Orthopaedic Hemophilia Treatment Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hemophilia & Thrombosis Center
state: Colorado
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Houston
country: United States
facility: Gulf States Hemophilia and Thrombophilia Center
state: Texas
city: Vienna
country: Austria
facility: AKH - Medizinische Universität Wien
city: Marseille Cedex 05
country: France
facility: Hôpital de la Timone
state: Bouches-du-Rhône
city: Brest Cedex
country: France
facility: Hôpital Morvan
state: Finistere
city: Rennes cedex 09
country: France
facility: CHU Rennes - Hopital Pontchaillou
state: Ille Et Vilaine
city: Tours cedex 9
country: France
facility: CHU Tours - Hôpital Trousseau
state: Indre Et Loire
city: Nantes Cedex 1
country: France
facility: CHU de Nantes Site Hotel Dieu
state: Loire Atlantique
city: Lille
country: France
facility: Hopital Jeanne de Flandre - CHU Lille
state: Nord
city: Bron cedex
country: France
facility: Groupement Hospitalier Est- Hôpital Louis Pradel
state: Rhone
city: Le Kremlin Bicêtre cedex
country: France
facility: Hôpital Bicêtre
state: Val De Marne
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universitaet
state: Hessen
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus TU Dresden
state: Sachsen
city: Berlin
country: Germany
facility: Vivantes Klinikum im Friedrichshain
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References: