2022-502844-11-00招募中3 期
C0371002 - Phase 3, open label, single arm study to evaluate efficacy and safety of FIX gene transfer with PF-06838435 (rAAV-Spark100-hFIX-R338L) in adult male participants with moderately severe to severe hemophilia B (FIX:C≤2%) (BeneGene-2)
干预措施
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- Pfizer Inc.
- 入组人数
- 26
- 试验地点
- 14
- 主要终点
- Non-inferiority on annualized bleeding rate (ABR) for total bleeds (treated and untreated) from Week 12 to Month 15 versus usual care FIX prophylaxis replacement regimen, comparing pre- and post-IP infusion
研究概览
简要总结
To demonstrate the efficacy of a single infusion of PF-06838435 in male participants ≥18 years of age with moderately severe to severe hemophilia B (FIX:C ≤2%).
入排标准
- 年龄范围
- 18 years 至 64 years（18-64 Years）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •1 Participants must have completed at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy as per their usual care during the lead-in study (C0371004) prior to providing consent at the screening visit for this study.
- •2 Participants who have documented moderately severe to severe hemophilia B, defined as FIX:C ≤2%.
- •3 Participants who have 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).
- •4 Participants must agree to suspend prophylaxis therapy for hemophilia B after administration of the IP. FIX replacement therapy is allowed as needed
- •5 Acceptable screening laboratory values as follows: • Hemoglobin ≥11 g/dL; • Platelets ≥100,000 cells/µL; • Creatinine ≤2.0 mg/dL.
- •6 Sex: Male. Participants are eligible to participate if they agree to the following requirements starting on Day 1/Visit 3 (IP infusion visit) and continue until at least 3 consecutive ejaculate samples test negative for vector shedding: • Refrain from donating sperm. PLUS either: • Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR •Must agree to use contraception/barrier as detailed below: •Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person
- •7 Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol. • For German sites please refer to Germany Appendix
- •8 Participants between the ages of 18 (or the minimum country specific age of consent if >18) and ≤65 years, inclusive, at Visit 1 (Screening Period).
排除标准
- •1 Anti-AAVRh74var nAb titer above the established threshold (ie, positive for nAb), performed by a central laboratory during screening. nAb testing may be repeated, if necessary. In such cases, a new sample must be drawn for re-testing.
- •5 Any participant with conditions associated with increased thromboembolic risk, such as known inherited or acquired thrombophilia, or a history of thrombotic events including but not limited to: stroke, myocardial infarction, and/or venous thromboembolism.
- •11 Any participant with a planned surgical procedure requiring FIX surgical prophylactic factor treatment in the next 15 months.
- •10 Currently on antiviral therapy for hepatitis B or C
- •12 Participants using therapies that are restricted
- •13 Previously dosed in a gene therapy research trial at any time or in an interventional clinical study within the last 12 weeks, excluding participation in Study C0371004
- •14 Active hepatitis B or C; HBsAg, HBVDNA positivity, or HCVRNA positivity.
- •15 Significant liver disease, as defined by preexisting diagnosis of portal hypertension, splenomegaly, or hepatic encephalopathy. Additionally, during screening, a serum albumin level below normal limits and/or significant liver fibrosis by one of the following diagnostic modalities (please note only 1 test is needed for screening purposes): FibroScan median stiffness score >8 kPa units OR Fibro Test/FibroSURE >0.48*. A FibroScan is preferred if available. If there is concern regarding the FibroTest or the FibroScan results due to a confounding medical history (eg, proteinuria can impact FibroTest result), or in the event of conflicting results between the modalities, the investigator should contact the sponsor. *Please note: if a participant has a known history of Gilbert's syndrome, a FibroTest cannot be used for fibrosis testing. However, the participant could be tested using FibroScan.
- •16 Serological evidence of HIV1 or HIV2 infection with either CD4+ cell count ≤200 mm3 and/or a viral load >20 copies/mL, and remain on highly active antiretroviral therapy (HAART) throughout the study.
- •17 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 participants who are Pfizer employees, including their family members, directly involved in the conduct of the study.
- •18 Unable to comply with scheduled visits, treatment plan (participants must agree to suspend prophylaxis therapy for hemophilia B after administration of the study intervention), laboratory tests, and other study procedures for up to six years postinfusion of PF-06838435 in the investigator’s judgement.
- •19 Sensitivity to heparin or heparin induced thrombocytopenia.
- •9 Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, hepatic encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, is acceptable if the participant otherwise meets entry criteria).
- •7 Alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) >2 × upper limit of normal (ULN), based on central laboratory results
- •20 Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or the sponsor’s medical monitor, contraindicates participation in the study.
- •2 Prior history of inhibitor to FIX or positive inhibitor testing as measured by the central laboratory ≥0.6 Bethesda Units (BU) during screening. Clinical signs or symptoms of decreased response to FIX.
- •3 Known hypersensitivity to FIX replacement product or intravenous immunoglobulin administration
- •4 History of chronic infection or other chronic disease that investigator deems as an unacceptable risk
- •6 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 (including alcoholism) 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 participant inappropriate for entry into this study. In addition, any participant with a history of a neoplasm (including hepatic malignancy) that required treatment (eg, chemotherapy, radiotherapy, immunotherapy), is excluded, except for adequately treated basal or squamous cell carcinoma of the skin or a surgically removed benign neoplasm not requiring chemotherapy, radiotherapy, and/or immunotherapy. Any other neoplasm that has been cured by resection should be discussed between the investigator and sponsor.
- •8 Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%), based on central laboratory results
研究组 & 干预措施
fidanacogene elaparvovec
Experimental
Participants receiving fidanacogene elaparvovec
干预措施: fidanacogene elaparvovec (Drug)
结局指标
主要结局
Non-inferiority on annualized bleeding rate (ABR) for total bleeds (treated and untreated) from Week 12 to Month 15 versus usual care FIX prophylaxis replacement regimen, comparing pre- and post-IP infusion
Non-inferiority on annualized bleeding rate (ABR) for total bleeds (treated and untreated) from Week 12 to Month 15 versus usual care FIX prophylaxis replacement regimen, comparing pre- and post-IP infusion
次要结局
- Non-inferiority on ABR for treated bleeds from Week 12 to Month 15 versus usual care FIX prophylaxis replacement regimen, comparing pre- and post-IP infusion
- Annualized infusion rate (AIR) of exogenous FIX from Week 12 to Month 15 versus AIR of FIX with usual care FIX replacement regimen pre IP infusion
- Vector derived FIX:C level at steady state (from Week 12 to 15 months) demonstrated to be greater than 5%. FIX:C will also be summarized descriptively by study visit
- The following parameters will be compared with usual care FIX replacement regimen, comparing pre- and post-IP infusion from Week 12 to Month 15: •Annualized FIX consumption. • Annualized number of bleeding events of specific type: spontaneous and traumatic, and untreated. •Frequency of target joint bleeds. •Percentage of the participants without bleeds.
- The following parameters will be compared with usual care FIX replacement regimen, comparing pre- and post-IP infusion at 12 months: •Change in joint health as measured by the Hemophilia Joint Health Score (HJHS) instrument. •PRO instruments: •Haem A QoL Physical Health domain;•HAL Complex Lower Extremity Activities Component Score
- Incidence and severity of adverse events collected during the study.
- Adverse Events of special interest: •Hypersensitivity reactions; • Clinical thrombotic events; • FIX inhibitors, • Hepatic malignancies. • Drug related elevated hepatic transaminases that fail to improve or resolve • Malignancy assessed as having reasonable possibility of being related to study drug
- Other immunogenicity-based laboratory data including: immune response (presumed T-cell activation) to AAV capsid protein and/or FIX transgene
- The following parameters will be assessed throughout the 6-year study period according to the SoA. Summaries will be provided for the overall follow-up period, as well as by yearly intervals: •Annualized Bleeding Rate for total bleeds (treated and untreated). • ABR for treated bleeds. •AIR of exogenous FIX. • Vector-derived FIX:C level by study visit and the geometric mean at each yearly interval.
- (continued from endpoint no. 9) • Annualized FIX consumption. • Annualized number of bleeding events of specific type: spontaneous and traumatic, and untreated. • HJHS total score. • Frequency of target joint bleeds. • PROs instruments. • Haem A QoL Physical Health domain. • HAL Complex Lower Extremity Activities Component Score.
研究者
Clinical Trials.gov Call Centre
Scientific
Pfizer Inc.
研究点 (14)
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