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Long-term Safety and Efficacy Study and Dose-Escalation Substudy of PF 06838435 in Individuals With Hemophilia B

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: NCT03307980
Recruitment Status : Recruiting
First Posted : October 12, 2017
Last Update Posted : January 11, 2021
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE September 29, 2017
First Posted Date  ICMJE October 12, 2017
Last Update Posted Date January 11, 2021
Actual Study Start Date  ICMJE June 22, 2017
Estimated Primary Completion Date November 10, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 6, 2021)
  • Dose-Escalation Substudy: Number of participants with clinically significant changes from baseline in physical examination [ Time Frame: Baseline up to 52 weeks ]
    A complete physical examination will be performed at scheduled visits. Findings considered to be clinically significant are based on investigator's decision and are to be recorded as adverse events.
  • Dose-Escalation Substudy: Number of participants with clinically significant changes from baseline in vital signs [ Time Frame: Baseline up to 52 weeks ]
    Vital signs measurements including blood pressure, pulse rate, respiratory rate, and temperature. Changes considered to be clinically significant are based on investigator's decision and are to be recorded as adverse events.
  • Dose-Escalation Substudy: Number of participants with clinically significant changes from baseline in laboratory values [ Time Frame: Baseline up to 52 weeks ]
    Laboratory assessments include but not limited to hematology, chemistry, liver function tests, and coagulation assays. Changes considered to be clinically significant are based on investigator's decision and are to be recorded as adverse events.
  • Dose-Escalation Substudy: Number of participants with PF-06838435-related adverse events [ Time Frame: Baseline up to 52 weeks ]
    Related adverse events
  • Dose-Escalation Substudy: Immune response against AAV capsid protein and hFIX transgene [ Time Frame: Baseline up to 52 weeks ]
    Positive immune response based on peripheral blood mononuclear cell (PBMC) results by interferon gamma enzyme-linked immunospot assay (ELISPOT)
  • Dose-Escalation Substudy: Number of participants PF-06838435-related elevated hepatic transaminases that fail to improve or resolve [ Time Frame: Baseline up to 52 weeks ]
    PF-06838435-related elevated hepatic transaminases that fail to improve or resolve
  • Dose-Escalation Substudy: Number of participants with clinical thrombotic events [ Time Frame: Baseline up to 52 weeks ]
    Clinical thrombotic events
  • Dose-Escalation Substudy: Number of participants with FIX inhibitor development [ Time Frame: Baseline up to 52 weeks ]
    FIX inhibitor development by Nijmegen assay (>/= 0.6 BU/mL, central laboratory)
  • Dose-Escalation Substudy: Number of participants with hypersensitivity reaction [ Time Frame: Baseline up to 52 weeks ]
    Hypersensitivity reaction will be reported as an adverse event.
  • Dose-Escalation Substudy: Number of participants with hepatic malignancy [ Time Frame: Baseline up to 52 weeks ]
    Hepatic malignancy will be reported as an adverse event
  • Dose-Escalation Substudy: Number of participants with PF-06838435-related mailgnancy [ Time Frame: Baseline up to 52 weeks ]
    PF-06838435-related mailgnancy will be reported as an adverse event.
  • LTFU: Number of participants with PF-06838435-related adverse advents [ Time Frame: Year 2 through Year 6 ]
    adverse events
Original Primary Outcome Measures  ICMJE
 (submitted: October 6, 2017)
SPK-9001-related adverse advents [ Time Frame: up to 5 years ]
adverse events
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 6, 2021)
  • Dose-Escalation Substudy: Mean and standard deviation of vector-derived FIX Activity levels [ Time Frame: up to 52 weeks ]
    Mean and standard deviation of peak and steady-state FIX Activity
  • Dose-Escalation Substudy: Mean and standard deviation of FIX Antigen levels [ Time Frame: up to 52 weeks ]
    Mean and standard deviation of FIX Antigen levels
  • LTFU: Coagulation Clotting Assay for FIX activity levels [ Time Frame: Year 2 through Year 6 ]
    Coagulation Clotting assays to assess FIX activity levels (percent of normal)
  • LTFU: Annualized (factor FIX) infusion rate [ Time Frame: Year 2 through Year 6 ]
    AIR (not including those for surgery)
  • LTFU: Total factor consumption (IU) [ Time Frame: Year 2 through Year 6 ]
    total quantity of factor infused annually (not including those for surgery) as recorded on the infusion log
  • LTFU: Total factor consumption (volume) [ Time Frame: Year 2 through Year 6 ]
    total quantity of factor infused annually (not including those for surgery) as recorded on the infusion log
  • LTFU: Annualized bleeding rate [ Time Frame: Year 2 through Year 6 ]
    ABR (not including those for surgery)
  • LTFU: Total number of bleeding events [ Time Frame: Year 2 through Year 6 ]
    spontaneous and traumatic
  • LTFU: Haem-A-QoL [ Time Frame: Year 2 through Year 6 ]
    Quality-of-life (QoL) assessment
  • LTFU: EQ-5D-5L [ Time Frame: Year 2 through Year 6 ]
    Quality-of-life (QoL) assessment
  • LTFU: Brief Pain Inventory [ Time Frame: Year 2 through Year 6 ]
    Quality-of-life (QoL) assessment
Original Secondary Outcome Measures  ICMJE
 (submitted: October 6, 2017)
  • Coagulation Clotting Assay for FIX activity levels [ Time Frame: up to 5 years ]
    Coagulation Clotting assays to assess FIX activity levels (percent of normal)
  • Annualized (factor FIX) infusion rate [ Time Frame: up to 5 years ]
    AIR (not including those for surgery)
  • Total factor consumption (IU and volume) [ Time Frame: up to 5 years ]
    total quantity of factor infused annually (not including those for surgery) as recorded on the infusion log
  • Annualized bleeding rate [ Time Frame: up to 5 years ]
    ABR (not including those for surgery)
  • Total number of bleeding events [ Time Frame: up to 5 years ]
    (spontaneous and traumatic)
  • Haem-A-QoL [ Time Frame: up to 5 years ]
    Quality-of-life (QoL) assessment
  • EQ-5D-5L [ Time Frame: up to 5 years ]
    Quality-of-life (QoL) assessment
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Long-term Safety and Efficacy Study and Dose-Escalation Substudy of PF 06838435 in Individuals With Hemophilia B
Official Title  ICMJE A FACTOR IX (FIX) GENE TRANSFER, MULTI CENTER EVALUATION OF THE LONG TERM SAFETY AND EFFICACY STUDY OF PF 06838435 AND A DOSE ESCALATION SUBSTUDY IN INDIVIDUALS WITH HEMOPHILIA B
Brief Summary Long-term safety and efficacy follow-up for participants with Hemophilia B who were previously treated in the C0371005 (formerly SPK-9001-101) study, and a dose-escalation substudy evaluating safety, tolerability, and kinetics of a higher dose with long-term safety and efficacy follow-up.
Detailed Description Evaluation of the long-term level of persistence and potential late or delayed adverse events associated with PF-06838435 (formerly SPK-9001), assessment of the durability of the transgene expression, and determination of the effects of PF-06838435 on clinical outcomes in individuals who have previously received a single administration of PF-06838435 in the C0371005 study. Amendment 2 of this study incorporates a dose-escalation substudy to evaluate the safety, tolerability, and kinetics of a single IV infusion of PF-06838435 at a higher dose than that used in the C0371005 study. The dose-escalation participants will also be followed for long-term safety and efficacy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Intervention Model Description:

This study was originally designed as a long-term follow up study for individuals dosed in Study C0371005 to evaluate the overall long-term safety, durability of transgene expression, and effect on clinical outcomes of PF-06838435 mediated gene transfer. For these individuals this study will last for 5 years providing a minimum of 6 years of follow up post vector administration.

Amendment 2 of this study introduces a dose-escalation substudy to evaluate the safety, tolerability, and kinetics of a single IV infusion of PF-06838435 at a higher dose(s) than that used in the C0371005 study. For these participants this study will last for a total of 6 years post vector administration.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia B
Intervention  ICMJE Biological: PF-06838435 (formerly SPK-9001)
Gene Therapy: A novel, bioengineered adeno-associated viral vector carrying human factor IX variant
Study Arms  ICMJE Experimental: PF-06838435 Dose-Escalation
Single intravaneous infusion of PF-06838435. After 2 participants receive initial dose, data will be evaluated and a decision will be made to escalate or reduce the dose being evaluated, increase the number of participants receiving the dose, or stop dosing. Multiple iterations may be undertaken.
Intervention: Biological: PF-06838435 (formerly SPK-9001)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 6, 2021)
55
Original Estimated Enrollment  ICMJE
 (submitted: October 6, 2017)
11
Estimated Study Completion Date  ICMJE November 10, 2027
Estimated Primary Completion Date November 10, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

This study is currently only enrolling into the dose-escalation substudy with subsequent long-term follow-up. The Eligibility Criteria for entry into the dose-escalation substudy is presented below:

Inclusion Criteria:

  1. Able to provide informed consent and comply with requirements of the study
  2. Males age 18 to 65 years with confirmed diagnosis of hemophilia B (≤2 IU/dL or ≤2% endogenous factor IX)
  3. Received ≥50 exposure days to factor IX products
  4. No measurable factor IX inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor IX protein
  5. Agree to refrain from donating sperm and either abstain from intercourse or use reliable barrier contraception until 3 consecutive semen samples are negative for vector sequences

Exclusion Criteria:

  1. Evidence of active hepatitis B or C
  2. Currently on antiviral therapy for hepatitis B or C
  3. Have significant underlying liver disease
  4. Serological evidence* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 (* participants who are HIV+ and stable with CD4 count >200/mm3 and undetectable viral load are eligible to enroll)
  5. Neutralizing antibody titers to the capsid portion of PF-06838435 above the established threshold
  6. Sensitivity to heparin or heparin induced thrombocytopenia; sensitivity to any of the study interventions, or components thereof, or drug or other allergy
  7. Previously dosed in a gene therapy research trial at any time or in an interventional clinical study within 3 months of screening visit
  8. Any concurrent clinically significant major disease or condition
  9. Unable or unwilling to comply with the study procedures
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Gender Eligibility Description: Genetic males
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03307980
Other Study ID Numbers  ICMJE C0371003
SPK-9001-LTFU-101 ( Other Identifier: Alias Study Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP