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
- 23
- 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
- •Note: The following inclusion and
排除标准
- •reflect those in protocol version 3.0, the last protocol version under which participants enrolled. Although a protocol version 4.0 was released, no participants enrolled under that version.
- •Inclusion Criteria, Arms A, B, and C
- •HIV-1 infection, documented by any licensed rapid HIV-1 test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot, Geenius assay, or a second antibody test by a method other than the initial rapid HIV-1 and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
- •NOTE: The term "licensed" refers to a US Food and Drug Administration (FDA)-approved kit.
- •WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot, Geenius assay, or a plasma HIV-1 RNA viral load.
- •The following laboratory values obtained within 45 days prior to entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
- •Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm^3
- •Hemoglobin greater than or equal to 12.0 g/dL for men and greater than or equal to 11.0 g/dL for women
- •Platelet count greater than or equal to 120,000/mm^3
- •Creatinine clearance (CrCl) greater than 60 mL/min
- •Refer to the calculator located on the FSTRF website (at https://www.frontierscience.org/): Calculated Creatinine Clearance - Cockcroft-Gault Equation (Adult).
- •Aspartate aminotransferase (AST) (SGOT) less than 1.25 x upper limit of normal (ULN)
- •Alanine aminotransferase (ALT) (SGPT) less than 1.25 x ULN
- •Alkaline phosphatase less than 2.0 x ULN
- •Total bilirubin less than 1.1 x ULN
- •Hepatitis C virus (HCV) antibody negative result within 45 days prior to study entry or, for study candidates who are HCV antibody positive (based on testing performed at any time prior to study entry), a negative HCV RNA result obtained within 45 days prior to study entry.
- •NOTE: A negative HCV RNA level may result from either spontaneous clearance or from HCV therapy. Participants must have completed any HCV therapy at least 6 months prior to enrollment.
- •Negative HBsAg result obtained within 45 days prior to study entry, or documented hepatitis B immunity, defined as positive hepatitis B surface antibody testing, at any time.
- •Female study candidates of reproductive potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL performed at screening and again within 24 hours before study entry by any US clinic or laboratory that has a CLIA certification or its equivalent, or is using a point of care (POC)/CLIA-waived test.
- •NOTE: Reproductive potential is defined as girls who have reached menarche, and women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, and women who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy.
- •All study candidates must agree not to participate in an assisted conception process (e.g., sperm donation, intrauterine insemination, in vitro fertilization) from screening until 12 weeks after the final study visit.
- •If participating in sexual activity that could lead to pregnancy, all study candidates must agree to use at least one reliable method of contraception from study entry until 12 weeks after the final study visit. At least one of the following methods must be used appropriately:
- •Condoms (male or female) with or without a spermicidal agent. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV transmission.
- •Diaphragm or cervical cap with spermicide.
- •Intrauterine device.
- •Hormone-based contraceptive.
- •Study candidates who are not of reproductive potential are eligible without requiring the use of a contraceptive method. Acceptable documentation of sterilization, menopause, and reproductive potential is specified below.
- •Written documentation or oral communication from a clinician or clinician's staff documented in source documents of one of the following:
- •Physician report/letter
- •Operative report or other source documentation in the patient record
- •Discharge summary
- •Laboratory report of azoospermia (is required to document successful vasectomy)
- •Follicle-stimulating hormone (FSH) measurement elevated into the menopausal range as established by the reporting laboratory.
- •NOTE A: Female reproductive potential is defined in the criteria above.
- •NOTE B: Male candidates who are not of reproductive potential are defined as having documented azoospermia.
- •NOTE C: A female study candidate's oral report of her male partner's lack of reproductive potential should be recorded in the source documents if written proof is not available.
- •Ability and willingness of participant to provide informed consent.
- •Additional Arms A- and C-specific Inclusion Criteria
- •Receiving combination ART for at least 12 months prior to study entry with no changes in ART regimen within the 12 weeks prior to entry.
- •NOTE A: Use of a two-drug ART regimen within the 12 months prior to entry is exclusionary.
- •NOTE B: Although ritonavir or cobicistat may be included in a combination ART regimen, neither of these "counts" in a tally of antiretroviral agents.
- •CD4+ cell count of greater than or equal to 200 cells/mm^3 obtained within 45 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent.
- •Within 45 days prior to study entry, plasma HIV-1 RNA <50 copies/mL on any FDA-approved assay with a limit of quantification of <50 copies/mL by a US laboratory that has a CLIA certification or its equivalent.
- •Within 12 months prior to study entry and before screening, at least one documented plasma HIV-1 RNA <50 copies/mL on any FDA-approved assay with a limit of quantification of <50 copies/mL by a US laboratory that has a CLIA certification or its equivalent.
- •NOTE: A single plasma HIV-1 RNA ≥50 but <200 copies/mL at least 6 months prior to screening is permitted if followed within 2 months by an HIV-1 RNA <50 copies/mL.
- •Additional Arm B-specific Inclusion Criteria
- •Plasma HIV-1 RNA >5000 and ≤200,000 copies/mL within 45 days prior to study entry.
- •CD4+ cell count of greater than or equal to 350 cells/mm^3 obtained within 45 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent.
- •Willingness and ability to start or re-start combination ART by or on Day 28 of the study.
- •Exclusion Criteria, Arms A, B, and C
- 另有 15 项未显示
研究组 & 干预措施
Arm A: 30 mg/kg SAR441236
Participants continued non-study-provided ART and received 30 mg/kg of SAR441236, administered as an IV infusion on Day 0 and then every 12 weeks for a total of four doses (Cohort 4).
干预措施: SAR441236 (Biological)
Arm C: 1 mg/kg SAR441236
Participants continued non-study-provided ART and received 1 mg/kg of SAR441236, administered as an SC injection(s) on Day 0 (Cohort 11).
干预措施: SAR441236 (Biological)
Arm B: 1 mg/kg SAR441236
Participants received 1 mg/kg of SAR441236, administered as a single IV infusion on Day 0. Antiretroviral treatment was initiated or re-initiated by Day 28 (Cohort 5).
干预措施: SAR441236 (Biological)
Arm A: 0 mg/kg SAR441236
Placebo participants were pooled across those receiving:
- 1 mg/kg dose volume-equivalent administered as a single IV infusion (Cohort 1).
- 3 mg/kg dose volume-equivalent administered as a single IV infusion (Cohort 2).
- 10 mg/kg dose volume-equivalent administered as a single IV infusion (Cohort 3)
- 30 mg/kg dose volume-equivalent administered as an IV infusion on Day 0 and then every 12 weeks for a total of four doses (Cohort 4)
All continued on non-study provided ART.
干预措施: Placebo (Biological)
Arm C: 0 mg/kg SAR441236
Placebo participants were pooled across those receiving:
- 0.3 mg/kg dose volume-equivalent administered as an SC injection(s) (Cohort 10).
- 1 mg/kg dose volume-equivalent administered as an SC injection(s) (Cohort 11).
All continued on non-study provided ART.
干预措施: Placebo (Biological)
Arm C: 0.3 mg/kg SAR441236
Participants continued non-study-provided ART and received 0.3 mg/kg of SAR441236, administered as a subcutaneous (SC) injection(s) on Day 0 (Cohort 10).
干预措施: SAR441236 (Biological)
Arm B: 30 mg/kg SAR441236
Participants received 30 mg/kg of SAR441236, administered as a single IV infusion on Day 0. Antiretroviral treatment was initiated or re-initiated by Day 28 (Cohort 8).
干预措施: SAR441236 (Biological)
Arm A: 10 mg/kg SAR441236
Participants continued non-study-provided ART and received 10 mg/kg of SAR441236, administered as a single IV infusion on Day 0 (Cohort 3).
干预措施: SAR441236 (Biological)
Arm A: 3 mg/kg for SAR441236
Experimental: Arm A: 3 mg/kg SAR441236 Participants continued on non-study-provided ART, and received 3 mg/kg of SAR441236, administered as a single IV infusion on Day 0 (Cohort 2).
干预措施: SAR441236 (Biological)
Arm A: 1 mg/kg SAR441236
Participants continued on non-study-provided ART and received 1 mg/kg of SAR441236, administered as a single intravenous (IV) infusion on Day 0 (Cohort 1).
干预措施: SAR441236 (Biological)
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
- 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).)
- 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).)
- 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.)