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A Phase 1/2 Study of SHP648, an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia B Subjects

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04394286
Recruitment Status : Recruiting
First Posted : May 19, 2020
Last Update Posted : June 11, 2020
Sponsor:
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Brief Summary:
The purpose of this study is to evaluate the safety and dose escalation of SHP648 an adeno-associated viral vector for gene transfer in hemophilia B participants.

Condition or disease Intervention/treatment Phase
Hemophilia B Genetic: SHP648 Phase 1 Phase 2

Detailed Description:
This study will consists of 3 dose cohorts with 2-7 participants in each of the three ascending dose cohorts. Initially 2 participants will be dosed in Cohort 1, followed by dosing of up to 5 additional participants if the cohort is expanded. Participants in cohort 2 and 3 will receive 2-fold or 3-fold dose escalation to their respective preceding cohort doses if required.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multinational, Phase 1/2 Study of the Safety and Dose Escalation of SHP648, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing FIX Padua in Hemophilia B Subjects
Actual Study Start Date : May 13, 2020
Estimated Primary Completion Date : March 16, 2024
Estimated Study Completion Date : March 16, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1
Cohort 1 participants will receive a single intravenous (IV) infusion of SHP648 on the day of dosing (Day 0).
Genetic: SHP648
Participants will receive a single IV infusion of SHP648 in Cohort 1, 2, 3 on Day 0.
Other Names:
  • TAK748
  • AAV8.ss-3xCRM8-TTR-FIX_R338Lopt

Experimental: Cohort 2
Cohort 2 participants will receive a single IV infusion of SHP648 at a 2 to 3-fold escalation of Cohort 1 on the day of dosing (Day 0).
Genetic: SHP648
Participants will receive a single IV infusion of SHP648 in Cohort 1, 2, 3 on Day 0.
Other Names:
  • TAK748
  • AAV8.ss-3xCRM8-TTR-FIX_R338Lopt

Experimental: Cohort 3
Cohort 3 participants will receive a single IV infusion of SHP648 at a 2 to 3-fold escalation of Cohort 2 on the day of dosing (Day 0).
Genetic: SHP648
Participants will receive a single IV infusion of SHP648 in Cohort 1, 2, 3 on Day 0.
Other Names:
  • TAK748
  • AAV8.ss-3xCRM8-TTR-FIX_R338Lopt




Primary Outcome Measures :
  1. Number of Participants With SHP648 Related Serious or Non-Serious Adverse Events (AEs) [ Time Frame: From study drug administration to study completion/early termination (up to 12 months) ]
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this investigational product (IP) or medicinal product. 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. Number of participants with incidence and severity of AEs will be assessed.


Secondary Outcome Measures :
  1. Plasma FIX levels before and after SHP648 infusion [ Time Frame: From study drug administration to study completion/early termination (up to 12 months) ]
    Circulating plasma FIX activity and antigen levels before and after SHP648 administration will be reported.

  2. Annualized Bleed Rate (ABR) [ Time Frame: From study drug administration to study completion/early termination (up to 12 months) ]
    ABR will be assessed based upon each individual bleeding episode. A bleed episode is defined as subjective (e.g., pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FIX. Annualized bleed rate (ABR) before and after SHP648 administration will be reported.

  3. Number of Participants With Positive Binding Antibody Titers to Adeno-Associated Virus (AAV8) [ Time Frame: Up to study completion/early termination (up to 12 months) ]
    Number of participants with positive binding antibodies to AAV8 will be reported.

  4. Number of Participants With Positive Neutralizing Antibody Titers to Adeno-Associated Virus (AAV8) [ Time Frame: Up to study completion/early termination (up to 12 months) ]
    Number of participants with positive neutralizing antibodies to AAV8 will be reported.

  5. Number of Participants with T-cell Response to Adeno-Associated Virus (AAV8) [ Time Frame: Up to study completion/early termination (up to 12 months) ]
    Number of participants with T-cell response to AAV8 will be reported.

  6. Number of Participants with T-cell Response to Factor IX (FIX) Transgene Products [ Time Frame: Up to study completion/early termination (up to 12 months) ]
    Number of participants with T-cell response to FIX transgene products will be reported.

  7. Duration of SHP648 Genomes Present in Bodily Fluids [ Time Frame: Up to study completion/early termination (up to 12 months) ]
    Duration of SHP648 genomes present in bodily fluids such as serum, blood, saliva, urine, stool, and semen will be reported.

  8. Percent Change in Consumption of Exogenous Factor IX (FIX) Before and After Gene Transfer [ Time Frame: Up to study completion/early termination (up to 12 months) ]
    Percent change in consumption of exogenous FIX before and after gene transfer will be reported.



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 or moderately severe hemophilia B (plasma FIX activity lesser than or equal to [<=] 2 percent (%) measured following greater than or equal to [>=] 5 half-lives of most recent exposure to exogenous FIX) and either >= 3 hemorrhages per year requiring treatment with exogenous FIX or use of prophylactic therapy.
  • History of greater than (>) 50 exposure days to exogenously administered FIX concentrates or cryoprecipitates.
  • 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 SHP648, or until SHP648 genomes are no longer detected in the semen (whichever is sooner).
  • Signed informed consent.

Exclusion Criteria:

  • Bleeding disorder(s) other than hemophilia B.
  • Documented laboratory evidence of having developed inhibitors (>= 0.6 Bethesda Units [BU] on any single test) to FIX proteins at any time.
  • Documented prior allergic reaction to any FIX product.
  • Anti-AAV8 neutralizing antibody titer >= 1:5.
  • 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, severe labile hypertension, and brittle diabetes).
  • Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease:

    • Anti-smooth muscle antibody (ASMA) titer >= 1:40. Values of 1:31 to 1:39 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 ribonucleic acid (HCV RNA) by polymerase chain reaction (PCR).
  • Hepatitis B: If surface hepatitis B virus (HBV) antigen is positive.
  • Receiving chronic 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 lesser than < 1000 cells per cubic millimetre (cells/mm^3).
  • Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following:

    • Platelet count < 150,000/microliter (μL)
    • Albumin <= 3.5 gram per deciliter (g/dL)
    • Total bilirubin > 1.5x ULN and direct bilirubin >= 0.5 milligram per deciliter (mg/dL)
    • ALT or Aspartate aminotransferase (AST) > 1.0x ULN
    • Alkaline phosphatase > 2.0x ULN
    • History of liver biopsy or imaging indicating moderate or severe fibrosis (Metavir staging of F2 or greater)
    • History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy
    • FibroSURE Score >= 0.4
    • Prothrombin time international normalized ratio (INR) >= 1.4
  • Serum creatinine > 1.5 mg/dL.
  • Human immunodeficiency virus (HIV) if cluster of differentiation 4 (CD4)+ cell count <= 200 mm^3 and/or viral load > 20 copies per milliliter (copies/mL).
  • Urine protein > 30 mg/dL.
  • Body mass index > 38.
  • Orthopedic or other major surgery 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.
  • 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).
  • History of arterial or venous thrombosis / thromboembolism, or a known pro-thrombotic condition.
  • 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.
  • Participation in another study involved with an investigational agent.
  • Participant is 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): NCT04394286


Contacts
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Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

Locations
Show Show 17 study locations
Sponsors and Collaborators
Baxalta 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: NCT04394286    
Other Study ID Numbers: SHP648-101
2018-004024-11 ( EudraCT Number )
First Posted: May 19, 2020    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

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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
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked