A PHASE 1/2, OPEN-LABEL, ADAPTIVE, DOSE-RANGING STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF SB-525 (PF-07055480) (RECOMBINANT AAV2/6 HUMAN FACTOR 8 GENE THERAPY) IN ADULT SUBJECTS WITH SEVERE HEMOPHILIA A
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 13
- 试验地点
- 22
- 主要终点
- Central FVIII Activity Levels by Chromogenic Assay at Year 2 (Week 104)
研究概览
简要总结
The purpose of the study is to evaluate the safety, tolerability and time-course profile of FVIII activity after dosing with SB-525 (PF-07055480)
详细描述
The proposed clinical study uses a recombinant adeno-associated virus 2/6 (AAV2/6) vector encoding the cDNA for the B-domain deleted human F8 (hF8). The secreted FVIII has the same amino acid sequence as approved recombinant anti hemophilic factors (Refacto® and Xyntha®). The SB-525 (PF-07055480) vector encodes a liver-specific promotor module and AAV2/6 exhibits liver tropism, thus providing the potential for long-term hepatic production of FVIII in hemophilia A subjects.
The constant production of FVIII after a single SB-525 (PF-07055480) administration may provide potential benefit in durable protection against bleeding and the complications thereof without lifelong repetitive IV factor replacement administration.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open Label
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male ≥18 years of age
- •Severe hemophilia A (past evidence of circulating FVIII activity of < 1% normal)
- •Treated or exposed to FVIII concentrates or cryoprecipitate for at least 150 exposure days
- •≥12 bleeding episodes if receiving on-demand therapy over the preceding 12 months
- •Agree to use double barrier contraceptive until at least 3 consecutive semen samples are negative for AAV 2/6 after SB-525 infusion
排除标准
- •Presence of neutralizing antibodies
- •Current inhibitor, or history of FVIII inhibitor (except for transient low titer inhibitor detected in childhood)
- •History of hypersensitivity response to FVIII
- •History of Hepatitis B or HIV-1/2 infection
- •History of Hepatitis C, unless viral assays in two samples, collected at least 6 months apart, are negative
- •Evidence of any bleeding disorder in addition to hemophilia A
- •Markers of hepatic inflammation or overt or occult cirrhosis
- •History of chronic renal disease or creatinine ≥ 1.5 mg/dL
- •Presence of liver mass on magnetic resonance imaging (MRI), or, positive alpha fetoprotein
- •Presence of > grade 2 liver fibrosis on elastography for subjects with history of treated Hepatitis C or suspicion of chronic liver disease
研究组 & 干预措施
Sequential dose escalation
SB-525 (PF-07055480) is administered as a single infusion
干预措施: SB-525 (PF-07055480) (Biological)
结局指标
主要结局
Central FVIII Activity Levels by Chromogenic Assay at Year 2 (Week 104)
时间窗: At Year 2 (Week 104)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From Baseline (1 week prior to infusion) up to 5 years post-infusion (approximately 5 Years)
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. An SAE was defined as any untoward medical occurrence that, at any dose, met one or more of the criteria as follows: death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly/birth defect and other situations per protocol. AEs included both SAEs and all non-SAEs.
Central FVIII Activity Levels by Chromogenic Assay at Year 1 (Week 52)
时间窗: At Year 1 (Week 52)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by Chromogenic Assay at Year 3 (Week 156)
时间窗: At Year 3 (Week 156)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by Chromogenic Assay at Year 4 (Week 208)
时间窗: At Year 4 (Week 208)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by Chromogenic Assay at Year 5 (Week 260)
时间窗: At Year 5 (Week 260)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 1 (Week 52)
时间窗: At Year 1 (Week 52)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 2 (Week 104)
时间窗: At Year 2 (Week 104)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 3 (Week 156)
时间窗: At Year 3 (Week 156)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 4 (Week 208)
时间窗: At Year 4 (Week 208)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 5 (Week 260)
时间窗: At Year 5 (Week 260)
FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 1 (Week 9 Through Week 53)
时间窗: Year 1 (Week 9 through Week 53)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 1 included assessments from Week 9 through Week 53). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 2 (Week 54 Through Week 108)
时间窗: Year 2 (Week 54 through Week 108)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 2 included assessments from Week 54 through Week 108). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 3 (Week 109 Through Week 160)
时间窗: Year 3 (Week 109 through Week 160)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 3 included assessments from Week 109 through Week 160). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 4 (Week 161 Through Week 212)
时间窗: Year 4 (Week 161 through Week 212)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 4 included assessments from Week 161 through Week 212). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 5 (Week 213 Through Week 264)
时间窗: Year 5 (Week 213 through Week 264)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 5 included assessments from Week 213 through Week 264). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 1 (Week 9 Through Week 53)
时间窗: Year 1 (Week 9 through Week 53)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 1 included assessments from Week 9 through Week 53). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 2 (Week 54 Through Week 108)
时间窗: Year 2 (Week 54 through Week 108)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 2 included assessments from Week 54 through Week 108). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 3 (Week 109 Through Week 160)
时间窗: Year 3 (Week 109 through Week 160)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 3 included assessments from Week 109 through Week 160). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 4 (Week 161 Through Week 212)
时间窗: Year 4 (Week 161 through Week 212)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 4 included assessments from Week 161 through Week 212). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 5 (Week 213 Through Week 264)
时间窗: Year 5 (Week 213 through Week 264)
FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 5 included assessments from Week 213 through Week 264). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
次要结局
- Total Annualized Bleeding Rate (ABR)(Pre-screening period: 12 months prior to screening; Post-infusion period: 3 weeks post-infusion up to date of day before start of prophylaxis or date of data cut or conclusion date, whichever was earlier (maximum up to 5 years))
- Total ABR by Severity(Post-infusion period: 3 weeks post-infusion up to date of day before start of prophylaxis or date of data cut or conclusion date, whichever was earlier (maximum up to 5 years))
- Annualized Infusion Rate (AIR)(Pre-infusion period: 30 days before screening up to pre-infusion (approximately up to 3.23 months); post-infusion period: 3 weeks post-infusion up to up to date of data cut or conclusion date (maximum up to 5 years))
- Change From Baseline in the EuroQol, 5 Dimensions, 5 Levels (EQ-5D-5L) Index Score at Weeks 12, 24 and 52; Months 24, 36, 48 and 60(Baseline; Weeks 12, 24, and 52; Months 24, 36, 48, and 60)
- Change From Baseline in the EQ-5D-5L- VAS Score at Week 12, 24, 52 and Month 24, 36, 48, 60(Baseline; Weeks 12, 24, and 52; Months 24, 36, 48, and 60)
- Number of Participants With Positive FVIII Inhibitor Levels During the Study(Baseline (one week prior to IP infusion) up to 5 years post-infusion)
- Peak Value of AAV2/6 (Adeno-associated Vector 2/6) Deoxyribonucleic Acid (DNA) in Plasma, Saliva, Semen, Stool and Urine(All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion)
- Time to Peak Value of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine(All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion)
- Time to Undetectable (Negative) Value of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine(All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion)
- Time to Last of 3 Consecutive Negative Values of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine(All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion)
- Time to Last Positive Value Prior to First of 3 Consecutive Negatives of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine(All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion)