A Phase I, First-in-Human Study of SAR441236, a Tri-specific Broadly Neutralizing Antibody, in Participants With HIV
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 52
- 试验地点
- 44
- 主要终点
- Mean Change in Plasma HIV-1 RNA (log10 Copies/mL) From Baseline to Day 7 of SAR441236 Monotherapy for Viremic Participants With HIV (Arm B Cohorts)
研究概览
简要总结
The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of SAR441236, a tri-specific broadly neutralizing antibody against the human immunodeficiency virus (HIV).
详细描述
This study evaluated the safety, tolerability, pharmacokinetics, and antiviral activity of SAR441236, a tri-specific broadly neutralizing antibody against HIV.
The study included three arms.
In Arm A, three dose cohorts (1, 3, and 10 mg/kg) of antiretroviral-treated, virologically suppressed participants were randomized (2:1, active to placebo) to receive a single intravenous (IV) dose of SAR441236 or placebo on Day 0. After Cohort 1 (1 mg/kg, lowest Arm A dose), each subsequent, higher-dose, cohort opened for enrollment only after an evaluation of safety outcomes for all participants in the previous cohort indicated it was safe to increase the dose of SAR441236. All participants in Cohorts 1-3 were followed for up to 24 weeks.
In Arm A, Cohort 4, participants were randomized (2:1, active to placebo) to receive an IV infusion of 30 mg/kg SAR441236 or placebo once every 12 weeks beginning at entry, for a total of 4 infusions. The first six Cohort 4 participants were enrolled after the safety evaluation of Cohort 3 participants and the rest of the Cohort 4 participants were accrued after a safety evaluation of the first 6 participants. The time between infusions was prolonged for some participants due to the COVID-19 pandemic, which occurred during the course of the study. Participants in this cohort were followed for up to 36 weeks after their final infusion.
Participants in Arm A continued taking non-study-provided antiretroviral treatment throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Mean Change in Plasma HIV-1 RNA (log10 Copies/mL) From Baseline to Day 7 of SAR441236 Monotherapy for Viremic Participants With HIV (Arm B Cohorts)
时间窗: Measured at Day 0 and Day 7
Baseline was defined as the last measurement taken prior to treatment initiation. Change was calculated as the log10-transformed value on Day 7 minus the log10-transformed value at baseline.
Proportion of Participants Experiencing a Grade 3 or Higher Adverse Event (AE) That is Related to Study Treatment.
时间窗: Measured from Day 0 through entire study follow-up, up to 24 weeks post study treatment administration for single dose cohorts (all arms) and up to 36 weeks after the fourth study treatment administration for the multi-dose cohort (Arm A only).
The proportion of participants reporting a grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 (death) adverse event, that was judged by the core safety team (blinded to active/placebo treatment in Arms A and C) to be at least possibly related to study treatment. Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017
Mean Dose-normalized AUC 0-12wk of SAR441236
时间窗: SAR441236 PK samples at pre-dose, Hours 0, 2 (Arm A, B only) , 4 (Arm A, B only), 6 (Arm A, B only), and 10, Days 1, 2, 3, 4 (Arm B only), 7, 10 (Arm B only), and Weeks 2, 4, 8 (single dose only), 10 (multi dose only), and 12.
Dose-normalized Area Under the Concentration time curve (AUC) for each participant was calculated from all available SAR441236 concentrations measured prior to and after first treatment and prior to any subsequent treatment instances (Arm A: 30 mg/kg only). Standard noncompartmental techniques, using Phoenix WinNonlin, were used to determine AUC 0-12WK.
次要结局
- Half-life (T1/2) of SAR441236 After a Single IV Infusion or SC Injection.(SAR441236 PK samples at pre-dose, Hours 0, 2 (Arm A, B only) , 4 (Arm A, B only), 6 (Arm A, B only), and 10, Days 1, 2, 3, 4 (Arm B only), 7, 10 (Arm B only), and Weeks 2, 4, 8 (single dose only), 10 (multi dose only), 12, and 24 (single dose only).)
- Time to Maximum Concentration (Tmax) of SAR441236 After a Single IV Infusion of SC Injection.(SAR441236 PK samples at pre-dose, Hours 0, 2 (Arm A, B only) , 4 (Arm A, B only), 6 (Arm A, B only), and 10, Days 1, 2, 3, 4 (Arm B only), 7, 10 (Arm B only), and Weeks 2, 4, 8 (single dose only), 10 (multi dose only), 12, and 24 (single dose only).)
- Mean Maximum Reduction of Plasma HIV-1 RNA During up to 28 Days of SAR441236 Monotherapy for Viremic Participants With HIV (Arm B Cohorts)(Measured at Day 0 and at up to Day 28 (while on SAR441236 monotherapy))
- Attributions of Anti-SAR441236 Antibodies Among Participants in Single-dose Cohorts.(Measured at Day 0 and at Week 2, 4, 12, and 24)
- Attributions of Anti-SAR441236 Antibodies Among Participants in Multi-dose Cohort.(Measured at Day 0, at Weeks 2 and 4 after Infusion 1, at Infusion 2, at Infusion 3, at Infusion 4, and at Weeks 12 and 36 post-Infusion 4)
- Clearance or Apparent Clearance of SAR441236 After a Single IV Infusion of SC Injection.(SAR441236 PK samples at pre-dose, Hours 0, 2 (Arm A, B only) , 4 (Arm A, B only), 6 (Arm A, B only), and 10, Days 1, 2, 3, 4 (Arm B only), 7, 10 (Arm B only), and Weeks 2, 4, 8 (single dose only), 10 (multi dose only), 12, and 24 (single dose only).)
- Mean SAR441236 Concentration 12 Weeks After Infusions 1, 2, 3, and 4(SAR441236 PK samples at Week 12, 24, 36, and 48.)
- Mean AUC After Multiple Infusions of SAR441236(Intensive SAR441236 PK samples taken at Hours 0, 2, 4, 6, and 10 and Days 1 and 2 after infusions 1 and 4 and non-intensive sampling at pre-dose (Weeks 0, Week 12, 24, 36) and Weeks 2, 4 , 8, 10, 13, 14, 16, 22, 26, 28, 34, 37, 38, 40, and 48.)
- Dose-response Relationship Between SAR441236 Exposure and Changes in Plasma HIV-1 RNA(Day 0 and at all study visits prior to ART initiation/re-initiation (up to Week 4))
- Mean Change From Baseline in CD4+ T Cell Counts Following Each Infusion for Cohort 4(Measured at Day 0 and at Week 12 after each infusion)
- Mean Maximum Concentration (Cmax) of SAR441236 After a Single IV Infusion or SC Injection.(SAR441236 PK samples at pre-dose, Hours 0, 2 (Arm A, B only) , 4 (Arm A, B only), 6 (Arm A, B only), and 10, Days 1, 2, 3, 4 (Arm B only), 7, 10 (Arm B only), and Weeks 2, 4, 8 (single dose only), 10 (multi dose only), 12, and 24 (single dose only).)
- Volume of Distribution of SAR441236 After a Single IV Infusion or SC Injection(SAR441236 PK samples at pre-dose, Hours 0, 2 (Arm A, B only) , 4 (Arm A, B only), 6 (Arm A, B only), and 10, Days 1, 2, 3, 4 (Arm B only), 7, 10 (Arm B only), and Weeks 2, 4, 8 (single dose only), 10 (multi dose only), 12, and 24 (single dose only).)
- Mean Trough Accumulative Index (12 Weeks Post-Dose 1 vs 12 Weeks Post-Dose 4)(SAR441236 PK samples taken at Week 12 (pre-dose #2) and at Week 48 (12 weeks after dose #4))
- Mean Change in Plasma HIV-1 RNA (log10 Copies/mL) From Baseline to Post-infusion Time Points During SAR441236 Monotherapy for Viremic Participants With HIV (Arm B Cohorts)(Measured at Day 0 and at Day 1, 2, 3, and 4, and Week 1, 2, and 3)
- Mean Change in Plasma HIV-1 RNA (log10 Copies/mL) From Baseline to Day 14 of SAR441236 Monotherapy for Viremic Participants With HIV (Arm B Cohorts)(Measured at Day 0 and Day 14)
- Mean Change From Baseline in CD4+ T Cell Counts Following the First Treatment of SAR441236 or Placebo for All Cohorts(Measured at Day 0 and Week 12)
- Mean AUC Accumulation Index (AI) (12 Weeks Post-Dose 1 vs 12 Weeks Post-Dose 4).(Intensive SAR441236 PK samples taken at Hours 0, 2, 4, 6, and 10 and Days 1 and 2 after infusions 1 and 4 and non-intensive sampling at pre-dose (Weeks 0, Week 12, 24, 36) and Weeks 2, 4 , 8, 10, 13, 14, 16, 22, 26, 28, 34, 37, 38, 40, and 48.)
- Mean Maximum Concentration (Cmax) of SAR441236 After the Fourth IV Infusion(Intensive SAR441236 PK samples after Infusion 4 (Week 36) at Hours 0, 2, 4, 6, and 10, Days 1 and 2, and at non-intensive sampling at Weeks 37, 38, 40, 48, 60, and 72.)