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A Gene Therapy Study for 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. Read our disclaimer for details. Identifier: NCT02484092
Recruitment Status : Completed
First Posted : June 29, 2015
Results First Posted : May 19, 2020
Last Update Posted : June 16, 2020
Information provided by (Responsible Party):

Tracking Information
First Submitted Date  ICMJE June 18, 2015
First Posted Date  ICMJE June 29, 2015
Results First Submitted Date  ICMJE April 4, 2020
Results First Posted Date  ICMJE May 19, 2020
Last Update Posted Date June 16, 2020
Actual Study Start Date  ICMJE November 18, 2015
Actual Primary Completion Date April 8, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 5, 2020)
  • Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings [ Time Frame: Baseline up to Week 52 ]
    Physical examination included examination of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.
  • Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to Week 52 ]
    Vital signs (temperature, respiratory rate, pulse rate, height, weight, systolic and diastolic blood pressure) were obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Clinical significance of vital signs was determined at the investigator's discretion.
  • Number of Participants With Clinical Laboratory Abnormalities Reported as TEAE [ Time Frame: Baseline up to Week 52 ]
    Following parameters were analyzed for laboratory examination: hematology (neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell [RBC] count, hemoglobin, hematocrit, platelet count); liver function (albumin, total bilirubin, total protein, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, GGT); Lipid panel (HDL, VLDL, triglycerides, total cholesterol); clinical chemistry (sodium, potassium, chloride, bicarbonate, glucose, phosphate, serum creatinine, BUN); urinalysis (specific gravity, pH, glucose, protein, blood, ketones; coagulation, immunology, etc. Investigators determined which laboratory abnormalities were reported as treatment-emergent adverse events (TEAEs).
  • Number of Participants With Drug -Related TEAEs and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 52 ]
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. An AE was regarded as TEAE if the start date was on or after the infusion of SPK-9001 but before participant's last visit on study (or the date of withdrawal/the date of being lost to follow-up). Severe TEAEs were TEAEs that interfered significantly with participants' usual function. Treatment-related TEAEs were determined by the investigator.
  • Number of Participants With Positive Immune Reponses Against Adeno-associated Virus Vector (AAV) Capsid [ Time Frame: Baseline up to Week 52 ]
    Peripheral blood mononuclear cells (PBMC) results by interferon gamma enzyme-linked immunospot assay (ELISPOT) to assess cellular immune responses to AAV capsid and to FIX were presented. The ELISPOT is a type of assay that focuses on quantitatively measuring the frequency of cytokine secretion for a single cell. The positive ELISPOT results suggested a T-cell reaction to capsid protein.
  • Number of Participants Who Reached > 150% Vector-derived FIX:C Activity Level After SPK-9001 Infusion [ Time Frame: Baseline up to Week 52 ]
    Based on non-clinical studies in non-human primates (NHPs), it was not predicted that vector-derived FIX:C activity levels >150% of normal would be achieved in this study. However, thrombin antithrombin (TAT) levels as thrombotic potential were to be measured if vector derived FIX:C activity levels >150% of normal were achieved in any participant during the study. Blood samples for TAT at Day 0 visit (prior to FIX protein product infusion) were used to establish baseline value.
  • Number of Participants With FIX Inhibitor [ Time Frame: Baseline up to Week 52 ]
    FIX inhibitors were measured using the Bethesda assay from the central and local laboratory. The Bethesda assay measures the amount of factor (FIX) inactivated when the plasma from the patient is incubated with an external source of factor for 2 hours at 37ºC. Inhibitor levels are quantified in Bethesda units (BU). An inhibitor titer of ≥ 0.6 BU/ml is to be taken as clinically significant.
  • Incremental Recovery of FIX Product [ Time Frame: Day 0 and Week 52 ]
    Incremental recovery was determined as the peak factor level recorded within the first 3 hours after infusion and was reported as (IU/ml)/(IU/kg), using the formula:([Activity IU/mL peak post infusion] - [Activity IU/mL pre-infusion]) / (IU/kg infused).
Original Primary Outcome Measures  ICMJE
 (submitted: June 24, 2015)
Number of participants experiencing drug-related adverse events [ Time Frame: 1 year ]
As assessed by physical exam, vital signs, standard clinical labs, and Bethesda assay for FIX inhibitor
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 5, 2020)
  • FIX:C Activity [ Time Frame: Baseline up to Week 52 ]
    All samples collected from participants for plasma FIX activity levels were analyzed and used to determine peak and steady-state vector-derived circulating FIX activity levels. The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity levels were characterized by post-treatment population mean. Dose escalation and dose level expansion strategies were employed in the study based on vector-derived FIX activity levels as well as any immune responses against AAV capsid. Steady-state levels were based on 2 separate vector-derived FIX:C activity level measurements (at least 2 weeks apart) starting from Week 8-12 with adequate washout.
  • Change From Baseline in FIX:C Antigen Level at Steady State [ Time Frame: Week 12 up to Week 52 ]
    The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity antigen levels were characterized by post-treatment population mean.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2015)
Changes from baseline in circulating FIX activity (IU/dL or % normal) [ Time Frame: 1 Year ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE A Gene Therapy Study for Hemophilia B
Official Title  ICMJE Gene Therapy, Open-label, Dose-escalation Study of PF-06838435 (SPK-9001) [Adeno-associated Viral Vector With Human Factor IX Gene] in Subjects With Hemophilia B
Brief Summary A Phase 1/2, Open-Label, Non-Randomized, Dose-Escalation Study of SPK-9001 in Subjects with Hemophilia B.
Detailed Description

Hemophilia B, or Christmas disease, is a genetic bleeding disorder resulting in the lack of ability to produce blood-clotting factor IX (FIX). Individuals with hemophilia B suffer repeated bleeding events, which can cause chronic joint disease and sometimes leads to death due to the inability for blood to clot efficiently. This chronic joint disease can have significant physical, psychosocial, and quality-of-life effects, including financial burden. The current treatment is intravenous infusion of FIX protein products, either prophylactically or in response to bleeding.

The approach being tested in this study uses a novel recombinant adeno-associated virus (AAV), which in nature causes no disease, to deliver the human factor IX (hFIX) gene to the liver cells where FIX is normally made. Recent data of a gene therapy study showed preliminary encouraging results with the approach of using an AAV vector carrying the factor IX gene. This study will seek to determine the safety and kinetics of a single IV infusion of SPK-9001 (a novel AAV vector carrying a high specific activity factor IX variant).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia B
Intervention  ICMJE Biological: SPK-9001
A novel, bioengineered adeno-associated viral vector carrying human factor IX variant
Study Arms  ICMJE Experimental: SPK-9001
Single intravenous (i.v.) infusion of SPK-9001 [an adeno-associated viral (AAV) vector with human factor IX gene] Intervention: Gene Therapy / Gene Transfer
Intervention: Biological: SPK-9001
Publications * George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, Cuker A, Sullivan LM, Majumdar S, Teitel J, McGuinn CE, Ragni MV, Luk AY, Hui D, Wright JF, Chen Y, Liu Y, Wachtel K, Winters A, Tiefenbacher S, Arruda VR, van der Loo JCM, Zelenaia O, Takefman D, Carr ME, Couto LB, Anguela XM, High KA. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med. 2017 Dec 7;377(23):2215-2227. doi: 10.1056/NEJMoa1708538.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 24, 2015)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 8, 2019
Actual Primary Completion Date April 8, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Able to provide informed consent and comply with requirements of the study
  • Males ≥18 y.o. with confirmed diagnosis of hemophilia B (≤2 IU/dL or ≤2% endogenous factor IX)
  • Received ≥50 exposure days to factor IX products
  • A minimum average of 4 bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions
  • No measurable factor IX inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor IX protein
  • Agree to use reliable barrier contraception until 3 consecutive samples are negative for vector sequences

Exclusion Criteria:

  • Evidence of active hepatitis B or C
  • Currently on antiviral therapy for hepatitis B or C
  • Have significant underlying liver disease
  • Have serological evidence* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 (* subjects who are HIV+ and stable with CD4 count >200/mm3 and undetectable viral load are eligible to enroll)
  • Neutralizing antibodies reactive with AAV-Spark100 above and/or below a defined titre
  • Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational drug within the last 12 weeks
  • Unable or unwilling to comply with study assessments
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Gender Eligibility Description: Genetic Males
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries Canada
Administrative Information
NCT Number  ICMJE NCT02484092
Other Study ID Numbers  ICMJE C0371005
SPK-9001-101 ( 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:
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer Call Center Pfizer
PRS Account Pfizer
Verification Date June 2020

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