A Study of BAX 888 in Male Adults With Severe Hemophilia A

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: BAX 888


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Cohort 1 participants will receive a single peripheral intravenous (IV) infusion of BAX 888 at a dose of 2.0*10^12 capsid particles per kilogram (cp/kg) on the day of dosing (Day 0). | Drug: BAX 888<br>* Participants will receive a single peripheral IV infusion of BAX 888 in Cohort 1, 2, 3 on Day 0.<br>* Other names: BAX888;|
| Experimental: Cohort 2<br>Cohort 2 participants will receive a single peripheral IV infusion of BAX 888 at a dose of 6.0*10^12 cp/kg on the day of dosing (Day 0). | Drug: BAX 888<br>* Participants will receive a single peripheral IV infusion of BAX 888 in Cohort 1, 2, 3 on Day 0.<br>* Other names: BAX888;|
| Experimental: Cohort 3<br>Cohort 3 participants will receive a single peripheral IV infusion of BAX 888 at a dose of 1.2*10^13 cp/kg on the day of dosing (Day 0). | Drug: BAX 888<br>* Participants will receive a single peripheral IV infusion of BAX 888 in Cohort 1, 2, 3 on Day 0.<br>* Other names: BAX888;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With BAX 888-Related Adverse Events (AEs) | An AE is defined as any untoward medical occurrence in a participant administered an investigational product (IP) that does not necessarily have a causal relationship with the treatment. A Serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; life-threatening event; required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. AEs include both serious and non-serious adverse events including development of FVIII inhibitory antibodies, clinically significant changes in standard laboratory parameters, physical exam, and vital signs. | From study drug administration to 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Circulating Plasma FVIII Activity Level | Change from baseline in circulating plasma FVIII activity level, based on one-stage clotting assay will be assessed. | Baseline, up to approximately 5 years per participant | 
| Change from Baseline in Circulating Plasma FVIII Antigen Level | Change from baseline in circulating plasma FVIII antigen (protein) levels will be assessed. | Baseline, up to approximately 5 years per participant | 
| Annualized Bleed Rate (ABR) | ABR in comparison to before gene transfer will be assessed. A bleed is defined as subjective or objective evidence of bleeding which may or may not require treatment with FVIII. ABR will be calculated as (number of bleeding episodes/observed treatment period in days)*365.25. | Up to 5 years per participant | 
| Percentage of Participants With a Redaction Consumption of Exogenous FVIII | The percentage of participants with a reduction in exogenous FVIII consumption from 12 months prior to study enrollment and up to 5 years post-infusion compared to the historical consumption (consumption of exogenous FVIII during the 12 month period prior to BAX 888 infusion). | Historical data from 12 months prior to study enrollment and 5 years post-infusion | 
| Number of Participants Develop Inhibitory Antibodies to FVIII | Number of participants develop inhibitory antibodies to FVIII will be assessed. | Up to 5 years per participant | 
| Number of Participants Develop Total Binding Antibodies to FVIII | Number of participants develop total binding antibodies to FVIII (Immunoglobulin G [IgG], Immunoglobulin M [IgM]) and antibody titers will be assessed. | Up to 5 years per participant | 
| Number of Participants With Humoral and Cell-Mediated Immune Response to AAV8 and FVIII Proteins | Number of participants with humoral (antibody-mediated) and cell-mediated immune response to adeno-associated virus (AAV8) (the vector), FVIII protein and antibody titers will be assessed. | Up to 5 years per participant | 
| Surveillance of AAV8 Genome Shedding | Surveillance of AAV8 genome shedding in blood, saliva, semen, urine and stool will be assessed. | Until 2 consecutive measurements are negative or up to 5 years, whichever is sooner |