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Six Month lead-in Study to Evaluate Prospective Efficacy and Safety Data of Current FIX Prophylaxis Replacement Therapy in Adult Hemophilia B Subjects (FIX:C≤2%) or Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Subjects (FVIII:C≤1%)

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: NCT03587116
Recruitment Status : Recruiting
First Posted : July 16, 2018
Last Update Posted : July 21, 2020
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE June 29, 2018
First Posted Date  ICMJE July 16, 2018
Last Update Posted Date July 21, 2020
Actual Study Start Date  ICMJE July 26, 2018
Estimated Primary Completion Date September 24, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 6, 2019)
  • Annualized bleeding rate (ABR) [ Time Frame: 6 months ]
    The annualized bleeding rate (ABR) per subject will be calculated as the number of bleeds over number of days subject received FIX prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. ABR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum). The annualized bleeding rate (ABR) per subject will be calculated as the number of bleeds over number of days subject received FVIII prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. ABR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).
  • Incidence of serious adverse events [ Time Frame: 6 months ]
    The primary safety analysis will be performed on all subjects that sign the informed consent document and are subsequently identified as nAb negative and are enrolled (complete baseline visit) into the study.
  • Events of special interest (ESI):inhibitor against FIX or FVIII, thrombotic events, and FIX or FVIII hypersensitivity reactions [ Time Frame: 6 months ]
    Frequency and percentage of these ESI events will be summarized by event. In addition any events leading to discontinuation from the study will be described.
Original Primary Outcome Measures  ICMJE
 (submitted: July 2, 2018)
  • Annualized bleeding rate (ABR) [ Time Frame: 6 months ]
    The annualized bleeding rate (ABR) per subject will be calculated as the number of bleeds over number of days subject received FIX prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. ABR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).
  • Incidence of serious adverse events [ Time Frame: 6 months ]
    The primary safety analysis will be performed on all subjects that sign the informed consent document and are subsequently identified as nAb negative and are enrolled (complete baseline visit) into the study.
  • Events of special interest (ESI):inhibitor against FIX, thrombotic events, and FIX hypersensitivity reactions [ Time Frame: 6 months ]
    Frequency and percentage of these ESI events will be summarized by event. In addition any events leading to discontinuation from the study will be described.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2019)
  • Annualized infusion rate (AIR) [ Time Frame: 6 months ]
    The annualized infusion rate (AIR) per subject will be calculated as the number of infusions received over number of days subject received FIX prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. AIR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum). The annualized infusion rate (AIR) per subject will be calculated as the number of infusions received over number of days subject received FVIII prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. AIR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).
  • Dose and total factor consumption [ Time Frame: 6 months ]
    The total factor IX replacement therapy consumption and the corresponding dose will be descriptively summarized by the categories of the replacement therapy, where appropriate. Infusion diary (electronic infusion diary) of the factor IX replacement therapy will be listed. The total factor VIII replacement therapy consumption and the corresponding dose will be descriptively summarized by the categories of the replacement therapy, where appropriate. Infusion diary (electronic infusion diary) of the factor VIII replacement therapy will be listed.
  • Number of bleeding events (spontaneous and/or traumatic) [ Time Frame: 6 months ]
    The number of bleeding episodes will be summed up by spontaneous, traumatic and overall as defined as any bleed occurring >72 hours after stopping treatment from the original bleed for which treatment was initiated or a bleed occurring at a different site from the original bleed regardless of the time from last injection.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 2, 2018)
  • Annualized infusion rate (AIR) [ Time Frame: 6 months ]
    The annualized infusion rate (AIR) per subject will be calculated as the number of infusions received over number of days subject received FIX prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. AIR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).
  • Dose and total factor consumption [ Time Frame: 6 months ]
    The total factor IX replacement therapy consumption and the corresponding dose will be descriptively summarized by the categories of the replacement therapy, where appropriate. Infusion diary (electronic infusion diary) of the factor IX replacement therapy will be listed.
  • Number of bleeding events (spontaneous and/or traumatic) [ Time Frame: 6 months ]
    The number of bleeding episodes will be summed up by spontaneous, traumatic and overall as defined as any bleed occurring >72 hours after stopping treatment from the original bleed for which treatment was initiated or a bleed occurring at a different site from the original bleed regardless of the time from last injection.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Six Month lead-in Study to Evaluate Prospective Efficacy and Safety Data of Current FIX Prophylaxis Replacement Therapy in Adult Hemophilia B Subjects (FIX:C≤2%) or Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Subjects (FVIII:C≤1%)
Official Title  ICMJE AN OPEN-LABEL, NON-INVESTIGATIONAL PRODUCT, LEAD-IN STUDY TO EVALUATE AT LEAST 6 MONTHS OF PROSPECTIVE EFFICACY AND SAFETY DATA OF FACTOR IX OR FACTOR VIII PROPHYLAXIS REPLACEMENT THERAPY IN THE USUAL CARE SETTING OF MODERATELY SEVERE TO SEVERE ADULT HEMOPHILIA B SUBJECTS (FIX:C≤2%) WHO ARE NEGATIVE FOR nAb TO AAV VECTOR-SPARK100 AND MODERATELY SEVERE TO SEVERE HEMOPHILIA A ADULT SUBJECTS (FVIII:C≤1%) WHO ARE NEGATIVE FOR nAb to AAV VECTOR SB-525 CAPSID (AAV6), PRIOR TO THE RESPECTIVE THERAPEUTIC PH 3 GENE THERAPY STUDIES (See Detailed Description Section for Official Protocol Title)
Brief Summary

To establish a minimum of 6 months of prospective efficacy data of current FIX prophylaxis replacement therapy in the usual care setting of hemophilia B subjects, who are negative for nAb to AAV-Spark100, prior to the Phase 3 gene therapy study.

To establish a minimum of 6 months of prospective efficacy data of current FVIII prophylaxis replacement therapy in the usual care setting of hemophilia A subjects, who are negative for nAb to SB-525 capsid (AAV6), prior to the Phase 3 gene therapy study.

The enrollment for hemophilia B participants is completed. At this time participants are only being enrolled for hemophilia A cohort.

Detailed Description AN OPEN-LABEL, NON-INVESTIGATIONAL PRODUCT, MULTI-CENTER, LEAD-IN STUDY TO EVALUATE AT LEAST 6 MONTHS OF PROSPECTIVE EFFICACY AND SELECTED SAFETY DATA OF CURRENT FACTOR IX (FIX) OR FACTOR VIII (FVIII) PROPHYLAXIS REPLACEMENT THERAPY IN THE USUAL CARE SETTING OF MODERATELY SEVERE TO SEVERE ADULT HEMOPHILIA B SUBJECTS (FIX:C≤2%) WHO ARE NEGATIVE FOR NEUTRALIZING ANTIBODIES TO ADENO-ASSOCIATED VIRUS VECTOR-SPARK100 (BENEGENE-1) AND MODERATELY SEVERE TO SEVERE HEMOPHILIA A ADULT SUBJECTS (FVIII:C≤1%) WHO ARE NEGATIVE FOR NEUTRALIZING ANTIBODIES TO ADENO-ASSOCIATED VIRUS VECTOR SB-525 CAPSID (AAV6), PRIOR TO THE RESPECTIVE THERAPEUTIC PHASE 3 GENE THERAPY STUDIES
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
The data obtained from this 6 month lead-in study will serve as the control group for the subsequent Phase 3 gene therapy study.
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Hemophilia B
  • Hemophilia A
Intervention  ICMJE
  • Drug: Standard of Care FIX Replacement therapy
    There is no investigational product being administered. Subjects will be administering their own standard of care FIX replacement therapy.
  • Drug: Standard of Care FVIII Replacement therapy
    There is no investigational product being administered. Subjects will be administering their own standard of care FVIII replacement therapy.
Study Arms  ICMJE
  • Standard of Care FIX replacement therapy
    Intervention: Drug: Standard of Care FIX Replacement therapy
  • Standard of Care FVIII replacement therapy
    Intervention: Drug: Standard of Care FVIII Replacement therapy
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: August 6, 2019)
250
Original Estimated Enrollment  ICMJE
 (submitted: July 2, 2018)
110
Estimated Study Completion Date  ICMJE September 24, 2021
Estimated Primary Completion Date September 24, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Hemophilia B Population:

  1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  2. Willing and able to comply with scheduled visits, FIX prophylaxis treatment plan, laboratory tests and other study procedures.
  3. Males ≥ 18 and <65 years of age with moderately severe to severe hemophilia B and documented FIX activity (≤2%) prior to baseline visit.
  4. Previous experience with FIX therapy (≥50 documented exposure days to a FIX protein product such as recombinant, plasma-derived or extended half-life FIX product).
  5. Subjects on FIX prophylaxis replacement therapy (recombinant, plasma-derived or extended half-life FIX product) must have the intention to remain on FIX prophylaxis replacement therapy for the duration of the study.
  6. No known hypersensitivity to FIX replacement product.
  7. No history of FIX inhibitor (clinical or laboratory-based assessment) defined as a titer

    • 0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the upper limit of normal for the laboratory performing the assay. Clinically, no signs or symptoms of decreased response to FIX administration. Subjects will not be required to undergo diagnostic evaluation of inhibitor status to participate in the study.

Hemophilia A Population:

  1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  2. Willing and able to comply with scheduled visits, FVIII prophylaxis treatment plan, laboratory tests and other study procedures.
  3. Males ≥18 and <65 years of age with moderately severe to severe hemophilia A and documented FVIII activity (≤1%) prior to baseline visit.
  4. Previous experience with FVIII therapy (≥150 documented exposure days to a FVIII protein product such as recombinant, plasma-derived or extended half-life FVIII product).
  5. Subjects on FVIII prophylaxis replacement therapy (recombinant, plasma-derived or extended half-life FVIII product) must have the intention to remain on FVIII prophylaxis replacement therapy for the duration of the study.
  6. No known hypersensitivity to FVIII replacement product.
  7. No history of FVIII inhibitor (clinical or laboratory-based assessment) defined as a titer ≥0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the upper limit of normal for the laboratory performing the assay. Clinically, no signs or symptoms of decreased response to FVIII administration. Subjects will not be required to undergo diagnostic evaluation of inhibitor status to participate in the study.

Exclusion Criteria:

  1. Anti-AAV-Spark100 neutralizing antibody titer above or equal to 1:1 performed by a central laboratory during screening in hemophilia B subjects or Anti- SB-525 capsid (AAV6) neutralizing antibody titer (above or equal to the lowest detectable titer) performed by a central laboratory during screening in hemophilia A subjects.
  2. Lack of patient compliance with documentation of bleeds and/or prophylaxis replacement therapy administration.
  3. If there is no documentation regarding hepatitis status, as defined below, within the last 12 months prior to screening for hepatitis B and 6 months prior to screening for hepatitis C, then subjects will be required to have the following hepatitis testing performed at screening:

    1. Hepatitis B screening (acute and chronic):

      HBsAg (also referred to as Hepatitis B surface antigen), HBV-DNA viral assay (also referred to as a nucleic acid test for Hepatitis B virus DNA), and Anti-HBc (also referred to as Total Hepatitis B core antibody).

      • A subject is not eligible if either HbsAg is positive or HBV-DNA is positive/detectable.
      • Anti-HBc must be obtained in all subjects for determination of whether the subject had prior hepatitis B. If the anti-HBc is positive and both HBsAg and HBV DNA are negative this would be consistent with a prior infection and the subject would be eligible for the study. Anti-HBc must be obtained in all subjects to discriminate between those with no prior hepatitis B and those with prior infection in the event of reactivation. FDA has noted reactivation of hepatitis B virus exists.
      • One documented negative HBV-DNA viral load is sufficient to assess eligibility. A subject who is currently undergoing anti-viral therapy for hepatitis B is not eligible.
    2. Hepatitis C (acute or chronic):

      • A subject who is currently undergoing anti-viral therapy for chronic hepatitis C is not eligible.
      • Subjects treated with anti-viral therapy for chronic hepatitis C, must have completed anti-viral therapy at least 6 months prior to screening and have a negative HCV-RNA at least 6 months prior to screening.
      • All subjects (who are not currently undergoing anti-viral therapy for chronic hepatitis C) must have a single HCV-RNA load assay (also referred to as a nucleic acid test [NAT] for HCV RNA) obtained during the 6 months preceding screening. This includes subjects with prior known chronic hepatitis C who have completed treatment with anti-viral therapy.
      • A subject is not eligible if his HCV-RNA load assay result is positive/detectable.
  4. Currently on antiviral therapy for hepatitis B or C.
  5. A subject is not eligible if any of the following pre-existing diagnoses, which are indicative of significant underlying liver disease, are present in the medical record:

    • Portal hypertension; or
    • Splenomegaly; or
    • Hepatic encephalopathy.

    All subjects who do not have the listed pre-existing diagnoses above must have the following assessments performed within the last 12 months prior to screening and if not will need to be tested for liver fibrosis status at screening:

    • Measurement of serum albumin. A subject is not eligible if the serum albumin level is below the testing laboratory's lower limit of normal; and
    • One of the following diagnostic tests for liver fibrosis. The following results are indicative of fibrosis and exclude the subject from participation:
    • FibroScan, with a score >8.3 kPa units;
    • FibroTest/FibroSURE with a result >0.48*; or
    • AST-to-Platelet Ratio Index (APRI) >1.

      • Please note, if a subject has a known history of Gilbert's syndrome, a FibroTest cannot be used for fibrosis testing.
  6. Documented serological evidence of human immunodeficiency virus HIV-1 or HIV-2 with Cluster of Differentiation 4 positive (CD4+) cell count ≤200 mm3 within the last 12 months prior to screening. Subjects who are HIV positive and stable, have an adequate CD4 count (>200/mm3) and undetectable viral load (<50 gc/mL) documented within the preceding 12 months, and are on an antiretroviral drug regimen are eligible to enroll. Subjects who have not been tested within the prior 12 months of screening will need to be tested for HIV status at screening.
  7. History of chronic infection or other chronic disease that the investigator deems an unacceptable risk. Any patient with a history of thrombotic events including but not limited to stroke or myocardial infarction.
  8. Any concurrent clinically significant major disease or condition that the investigator deems unsuitable for participation or other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
  9. Participation in other studies involving investigational drug(s) within the last 3 months prior to study entry and/or during study participation or in a previous gene therapy clinical study within the last 12 months prior to screening.
  10. Any subject who previously received fidanacogene elaparvovec (SPK-9001) (hemophilia B) or SB-525 (hemophilia A) or any AAV gene-based therapy.
  11. Any subject with a planned surgical procedure requiring FIX (hemophilia B) or FVIII (hemophilia A) surgical prophylactic factor treatment in the next 24 months.
  12. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years to 64 Years   (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,   Belgium,   Brazil,   Canada,   France,   Germany,   Greece,   Israel,   Italy,   Japan,   Korea, Republic of,   Saudi Arabia,   Spain,   Sweden,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03587116
Other Study ID Numbers  ICMJE C0371004
2017-001271-23 ( EudraCT Number )
NAB PROTOCOL ( Other Identifier: Alias Study Number )
Has Data Monitoring Committee Not Provided
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 July 2020

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