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Safety and Dose Escalation Study of an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia A Participants

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03370172
Recruitment Status : Active, not recruiting
First Posted : December 12, 2017
Last Update Posted : June 11, 2020
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Brief Summary:
The purpose of this study is to evaluate the safety and determine the dose of BAX 888.

Condition or disease Intervention/treatment Phase
Hemophilia A Drug: BAX 888 Phase 1 Phase 2

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 FVIII expression 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 percent (%), then dose escalation to cohort 2 will be triggered with no further dosing in cohort 1. If FVIII expression (greater than or equal to [>=] 2%) is 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 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 expression 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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
Actual Study Start Date : March 31, 2018
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Cohort 1
Cohort 1 participants will receive a single peripheral intravenous (IV) infusion of BAX 888 at a dose of 2.0 x 10^12 capsid particles per kilogram (cp/kg) on the day of dosing (Day 0).
Drug: BAX 888
Participants will receive a single peripheral IV infusion of BAX 888 in Cohort 1, 2, 3 on Day 0.
Other Names:
  • Adeno-associated virus serotype 8 (AAV8) vector expressing B-domain deleted Factor VIII (BDD-FVIII)
  • BAX888

Experimental: Cohort 2
Cohort 2 participants will receive a single peripheral IV infusion of BAX 888 at a dose of 6.0 x 10^12 cp/kg on the day of dosing (Day 0).
Drug: BAX 888
Participants will receive a single peripheral IV infusion of BAX 888 in Cohort 1, 2, 3 on Day 0.
Other Names:
  • Adeno-associated virus serotype 8 (AAV8) vector expressing B-domain deleted Factor VIII (BDD-FVIII)
  • BAX888

Experimental: Cohort 3
Cohort 3 participants will receive a single peripheral IV infusion of BAX 888 at a dose of 1.2 x 10^13 cp/kg on the day of dosing (Day 0).
Drug: BAX 888
Participants will receive a single peripheral IV infusion of BAX 888 in Cohort 1, 2, 3 on Day 0.
Other Names:
  • Adeno-associated virus serotype 8 (AAV8) vector expressing B-domain deleted Factor VIII (BDD-FVIII)
  • BAX888




Primary Outcome Measures :
  1. Number of Participants With BAX 888-Related Adverse Events (AEs) [ Time Frame: From study drug administration to 3 Years ]
    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) was 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.


Secondary Outcome Measures :
  1. Change from Baseline in Circulating Plasma FVIII Activity Level [ Time Frame: Baseline, up to approximately 3 years per participant ]
    Change from baseline in circulating plasma FVIII activity level, based on one-stage clotting assay will be assessed.

  2. Change from Baseline in Circulating Plasma FVIII Antigen Level [ Time Frame: Baseline, up to approximately 3 years per participant ]
    Change from baseline in circulating plasma FVIII antigen (protein) levels will be assessed.

  3. Annualized bleed rate (ABR) [ Time Frame: Throughout the study period of approximately 3 years per participant ]
    Annualized bleed rate (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. Annualized bleed rate (ABR) was calculated as (number of bleeding episodes/observed treatment period in days)*365.25.

  4. Percentage of Participants with a Redaction Consumption of Exogenous Factor VIII (FVIII) [ Time Frame: Historical data from 12 months prior to study enrollment; and 12 months post-infusion and 3 years post-infusion ]
    The percentage of participants with a reduction in exogenous FVIII consumption 12 months post-infusion and 3 years post-infusion compared to the historical consumption (consumption of exogenous FVIII during the 12 month period prior to BAX 888 infusion).

  5. Number of Participants Develop Inhibitory Antibodies to FVIII [ Time Frame: Throughout the study period of approximately 3 years per participant ]
    Number of participants develop inhibitory antibodies to FVIII will be assessed.

  6. Number of Participants Develop Total Binding Antibodies to FVIII [ Time Frame: Throughout the study period of approximately 3 years per participant ]
    Number of participants develop total binding antibodies to FVIII (Immunoglobulin G [IgG] and Immunoglobulin M [IgM]) will be assessed.

  7. Number of Participants With Humoral and Cell-Mediated Immune Response to AAV8 and Factor VIII (FVIII) Proteins [ Time Frame: Throughout the study period of approximately 3 years per participant ]
    Number of participants with humoral (antibody-mediated) and cell-mediated immune response to adeno-associated virus (AAV8) (the vector) and FVIII proteins will be assessed.

  8. Surveillance of AAV8 Genome Shedding [ Time Frame: Throughout the study period of approximately 3 years per participant,or until 2 consecutive measurements are negative, which ever is sooner ]
    Surveillance of adeno-associated virus (AAV8) genome shedding in blood, saliva, semen, urine and stool will be assessed.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male, aged 18 to 75 years at the time of screening.
  • Established severe hemophilia A (factor VIII procoagulant activity (FVIII:C) lesser than (<) 1 percent (%), measured following greater than or equal to (> or =) 5 days without factor VIII (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 > or = 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 lesser 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) > 1.5x 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 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 (μL).
    • 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 >1.5x upper limit of normal (ULN) and direct bilirubin >= 0.5 milligram per deciliter (mg/dL).
    • ALT or aspartate aminotransferase (AST) >1.0x ULN.
    • Alkaline phosphatase (AP) > 2.0x 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.
  • 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.
  • Sensitivity to penicillin.
  • Participant is a family member or employee of the investigator.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03370172


Locations
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United States, Arizona
Phoenix Childrens Hospital
Phoenix, Arizona, United States, 85016
United States, California
Orthopaedic Hemophilia Treatment Center
Los Angeles, California, United States, 90007
United States, Colorado
University of Colorado Hemophilia & Thrombosis Center
Aurora, Colorado, United States, 80045
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, South Carolina
Medical University of South Carolina (MUSC)
Charleston, South Carolina, United States, 29425
United States, Texas
Gulf States Hemophilia and Thrombophilia Center City
Houston, Texas, United States, 77030-4009
Austria
AKH - Medizinische Universität Wien
Vienna, Austria, 1090
France
Hôpital de la Timone
Marseille Cedex 05, Bouches-du-Rhône, France, 13385
CHU de Nantes Site Hotel Dieu
Nantes Cedex 1, Loire Atlantique, France, 44093
Hopital Jeanne de Flandre - CHU Lille
Lille Cedex, Nord, France, 59037
Groupement Hospitalier Est- Hôpital Louis Pradel
Bron cedex, Rhone, France, 69677
Groupement Hospitalier Sud - Hôpital Bicêtre
Le Kremlin Bicêtre cedex, Val De Marne, France, 94275
Hungary
Semmelweis Egyetem
Budapest, Hungary, 1083
Spain
Hospital Universitario La Paz
Madrid, Spain, 28046
Hospital Regional Universitario de Malaga
Malaga, Spain, 29010
Hospital Universitario de Salamanca
Salamanca, Spain, 37007
Sponsors and Collaborators
Baxalta now part of Shire
Baxalta Innovations GmbH, now part of Shire
Investigators
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Study Director: Study Director Shire
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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT03370172    
Other Study ID Numbers: 201501
2015-005576-22 ( EudraCT Number )
First Posted: December 12, 2017    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Shire does not provide access to Individual Participant Data (IPD) when a study is in a very limited (small) study population due to participant privacy concerns such as potential reidentification of study participants.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants