Clinical Trials Logo

Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03370172
Other study ID # 201501
Secondary ID 2015-005576-22
Status Active, not recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date March 31, 2018
Est. completion date April 24, 2025

Study information

Verified date June 2023
Source Takeda
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 21
Est. completion date April 24, 2025
Est. primary completion date April 24, 2025
Accepts healthy volunteers No
Gender Male
Age group 18 Years to 75 Years
Eligibility 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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
BAX 888
Participants will receive a single peripheral IV infusion of BAX 888 in Cohort 1, 2, 3 on Day 0.

Locations

Country Name City State
Austria AKH - Medizinische Universität Wien Vienna
France Hôpital Morvan Brest Cedex Finistere
France Groupement Hospitalier Est- Hôpital Louis Pradel Bron cedex Rhone
France Hôpital Bicêtre Le Kremlin Bicêtre cedex Val De Marne
France Hopital Jeanne de Flandre - CHU Lille Lille Nord
France Hôpital de la Timone Marseille Cedex 05 Bouches-du-Rhône
France CHU de Nantes Site Hotel Dieu Nantes Cedex 1 Loire Atlantique
France CHU Rennes - Hopital Pontchaillou Rennes cedex 09 Ille Et Vilaine
France CHU Tours - Hôpital Trousseau Tours cedex 9 Indre Et Loire
Germany Vivantes Klinikum im Friedrichshain Berlin
Germany Universitaetsklinikum Carl Gustav Carus TU Dresden Dresden Sachsen
Germany Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt Hessen
Hungary Semmelweis Egyetem Budapest
Italy Azienda Ospedaliera Universitaria Careggi Firenze
Italy Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico Milano
Spain Hospital Universitari Vall d'Hebron Barcelona
Spain Hospital Universitario La Paz Madrid
Spain Hospital Regional Universitario de Malaga Malaga
Spain Hospital Clinico Universitario de Salamanca Salamanca
Spain Hospital Universitari i Politecnic La Fe Valencia
United States University of Colorado Hemophilia & Thrombosis Center Aurora Colorado
United States Medical University of South Carolina (MUSC) Charleston South Carolina
United States Cincinnati Children's Hospital Medical Center Cincinnati Ohio
United States Gulf States Hemophilia and Thrombophilia Center Houston Texas
United States Orthopaedic Hospital DBA Orthopaedic Hemophilia Treatment Center Los Angeles California
United States Mount Sinai Medical Center New York New York
United States Phoenix Childrens Hospital Phoenix Arizona
United States UC Davis Medical Center Sacramento California

Sponsors (3)

Lead Sponsor Collaborator
Baxalta now part of Shire Baxalta Innovations GmbH, now part of Shire, Takeda Development Center Americas, Inc.

Countries where clinical trial is conducted

United States,  Austria,  France,  Germany,  Hungary,  Italy,  Spain, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
See also
  Status Clinical Trial Phase
Completed NCT03834727 - Characterizing the Impact and Treatment of Reproductive Tract Bleeding on Women and Post-menarchal Girls With Bleeding Disorders
Completed NCT03191799 - A Study to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors Phase 3
Completed NCT01599819 - BAX 855 Dose-Escalation Safety Study Phase 1
Terminated NCT04541628 - Safety & Efficacy of Encapsulated Allogeneic FVIII Cell Therapy in Haemophilia A Phase 1/Phase 2
Completed NCT02847637 - A Clinical Trial to Evaluate Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants Without Inhibitors Phase 3
Completed NCT04072237 - Study of Coagulation Faction VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia Phase 1
Completed NCT04085458 - Study to Gain More Information on How Safe and Effective Jivi Works in Patients With Severe Hemophilia A (Post-marketing Investigation) Phase 4
Completed NCT04565236 - A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A Phase 4
Recruiting NCT05987449 - A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of NXT007 in Persons With Severe or Moderate Hemophilia A Phase 1/Phase 2
Active, not recruiting NCT04621916 - Preventing Inhibitor Recurrence Indefinitely Phase 4
Not yet recruiting NCT02888223 - Pharmacokinetic Study of SCT800 in Previously Treated Patients With Hemophilia A Phase 1
Completed NCT02528968 - National Study of a Pharmacokinetic-Focused Educational Package for Patients With Severe Haemophilia A N/A
Completed NCT02225483 - Phenotypic Heterogeneity in Hemophilia A: An Investigation of the Role of Platelet Function N/A
Completed NCT02199717 - An Institutional Pilot Study to Investigate Physical Activity Patterns in Boys With Hemophilia N/A
Completed NCT01217255 - Comparing the Burden of Illness of Hemophilia in the Developing and the Developed World
Terminated NCT00995046 - Individually Tailored Prophylaxis in Patients With Severe Hemophilia A N/A
Completed NCT00969319 - Effekt-2 - Efficacy and Safety of Long-term Treatment With KOGENATE® FS in Latin America N/A
Completed NCT00868530 - Study Evaluating On-Demand Treatment Of Xyntha In Chinese Subjects Phase 3
Completed NCT00839202 - Activity and Content of Factor VIII (FVIII) in Human Plasma: The Assessment of a Novel Immunoassay N/A
Completed NCT00629837 - Pharmacokinetics and Safety of a Single Intravenous Infusion of BAY 79-4980 Phase 1