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

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

Tracking Information

• First Submitted Date: September 29, 2017
• First Posted Date: October 12, 2017
• Last Update Posted Date: January 11, 2021
• Actual Study Start Date: June 22, 2017
• Estimated Primary Completion Date: November 10, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (submitted: October 6, 2017)

SPK-9001-related adverse advents [ Time Frame: up to 5 years ]

adverse events

Current Secondary Outcome Measures (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 (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: Long-term Safety and Efficacy Study and Dose-Escalation Substudy of PF 06838435 in Individuals With Hemophilia B
• Official Title: 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: Interventional
• Study Phase: Phase 2

Study Design

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: Hemophilia B

Intervention

Biological: PF-06838435 (formerly SPK-9001)

Gene Therapy: A novel, bioengineered adeno-associated viral vector carrying human factor IX variant

Study Arms

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

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 6, 2021): 55
• Original Estimated Enrollment (submitted: October 6, 2017): 11
• Estimated Study Completion Date: November 10, 2027
• Estimated Primary Completion Date: November 10, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Genetic males

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

• Listed Location Countries: Australia, United States

Administrative Information

• NCT Number: NCT03307980
• Other Study ID Numbers: 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

• 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: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: January 2021