Pharmacokinetics and Safety of SAR441236
- Conditions
- HIV-1-infection
- Interventions
- Biological: SAR441236Biological: Placebo
- Registration Number
- NCT03705169
- Brief Summary
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).
- Detailed Description
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.
In Arm B, two cohorts of viremic participants received a single IV dose of SAR441236 on Day 0. Cohort 5 (1 mg/kg, lowest planned Arm B dose) opened first. After reviewing the safety data from that cohort, as well as that from all Arm A cohorts (which had fully enrolled), and taking into consideration enrollment challenges, the study was redesigned to be a dose de-escalation study in Arm B only. With this redesign, the study began enrollment into the highest dose (Cohort 8, 30 mg/kg) after closing Cohort 5 enrollment. Each subsequent Arm B cohort (of lower doses) was planned to open for enrollment only after an evaluation of efficacy data from Day 14 for all participants in the previous cohort was completed. However, the highest dose cohort never fully enrolled, and no subsequent cohorts were opened. All Arm B participants were followed for up to 24 weeks.
Participants in Arm B initiated or re-initiated non-study-provided combination antiretroviral therapy (ART) (selected by their primary HIV clinician) on or before Day 28. A later version of the protocol changed the duration of SAR441236 monotherapy to no more than 14 days, however, no participants enrolled under that version.
In Arm C, two cohorts of ART-treated, virologically suppressed participants were randomized (2:1, active to placebo) to receive a single subcutaneous (SC) dose of SAR441236 or placebo on Day 0. Cohort 11 (1 mg/kg) opened for enrollment only after an evaluation of safety outcomes from Day 14 for all participants in Cohort 10 (0.3 mg/kg) and the cumulative data from that cohort indicated it was safe to dose escalate. All Arm C participants were followed for 24 weeks.
Participants in Arm C continued taking non-study-provided ART throughout the study.
The study closed to enrollment and follow-up in May 2023 due to the expiration of the available study product, despite failing to meet its enrollment targets in Arm B. There had been no enrollment to the study since October 2021, despite the team's revision of the protocol (Version 4.0) to adjust eligibility criteria to facilitate enrollment of participants with viremia. At the time of study closure, Arm A and C were fully enrolled. Two Arm B cohorts (1 mg/kg and 30 mg/kg) achieved partial enrollment. Although protocol version 4.0 was released in September 2022, the last participant was enrolled under protocol version 3.0 and completed study follow-up in April 2022.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 52
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B: 30 mg/kg SAR441236 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). Arm A: 1 mg/kg SAR441236 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). Arm A: 30 mg/kg SAR441236 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). Arm C: 1 mg/kg SAR441236 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). Arm A: 10 mg/kg SAR441236 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). Arm B: 1 mg/kg SAR441236 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). Arm A: 3 mg/kg for SAR441236 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). Arm A: 0 mg/kg SAR441236 Placebo 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. Arm C: 0.3 mg/kg SAR441236 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). Arm C: 0 mg/kg SAR441236 Placebo 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.
- Primary Outcome Measures
Name Time Method 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) 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. 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 2017Mean Dose-normalized AUC 0-12wk of SAR441236 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.
- Secondary Outcome Measures
Name Time Method 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). Half-life for each participant was calculated using regression analysis on 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 half-life.
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). Tmax for each participant was time to maximum observed SAR441236 measured 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 Tmax.
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) The maximum reduction in plasma HIV-1 RNA was calculated as the largest decline from baseline, defined as the last measurement taken prior to treatment initiation, to any post-infusion timepoint while the participant was on SAR441236 monotherapy (i.e., prior to initiating or reinitiating ART).
Attributions of Anti-SAR441236 Antibodies Among Participants in Single-dose Cohorts. Measured at Day 0 and at Week 2, 4, 12, and 24 Number of participants who were anti-drug antibody (ADA) negative, ADA positive (treatment induced), and missing were calculated at each sampled timepoint.
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 Number of participants who were anti-drug antibody (ADA) negative, ADA positive (treatment induced), and missing were calculated at each sampled timepoint.
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). Clearance (CL, in Arms A and B) or Apparent Clearance (CL/F, in Arm C) 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 CL and CL/F.
Mean SAR441236 Concentration 12 Weeks After Infusions 1, 2, 3, and 4 SAR441236 PK samples at Week 12, 24, 36, and 48. SAR441236 concentration for each participant was calculated as the observed SAR441236 concentration 12 weeks after each infusion.
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. Area Under the Concentration time curve (AUC) for multiple infusions of SAR441236 was calculated using all available SAR441236 concentrations. Standard noncompartmental techniques, using Phoenix WinNonlin, were used to determine AUC.
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) This relationship is based on measured SAR441236 concentrations and HIV-1 RNA values prior to participants initiating ART.
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 Baseline was defined as the last measurement obtained prior to treatment initiation. Change was calculated as the value of CD4 + T cell counts (cells/mm\^3) at Week 12 after each infusion minus the value at baseline.
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). Cmax for each participant was calculated as the maximum observed concentration 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 Cmax.
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). Volume of distribution (Arms A and B) or apparent volume of distribution (Arm C) 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 volume of distribution and apparent volume of distribution.
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) The Trough AI was calculated as the ratio of the SAR441236 concentration observed 12 weeks after the 4th dose and the SAR441236 concentration observed 12 weeks after the 1st dose. Standard noncompartmental techniques, using Phoenix WinNonlin, were used to determine trough AI.
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 Baseline was defined as the last measurement taken prior to treatment initiation. Change was calculated as the log10-transformed value of plasma HIV-1 RNA at the post-infusion time point minus the log10-transformed value at baseline.
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 Baseline was defined as the last measurement taken prior to treatment initiation. Change was calculated as the value of plasma HIV-1 RNA on Day 14 minus the value at baseline.
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 Baseline was defined as the last measurement obtained prior to treatment initiation. Change was calculated as the value of CD4+ T cell counts (cells/mm\^3) at Week 12 (prior to subsequent study treatment, if any) minus the value at baseline.
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. The AUC AI (12 Weeks post-Dose 1 vs 12 Weeks post-Dose 4) was calculated as the ratio of AUC 36-48 Weeks and AUC 0-12 Weeks. Standard noncompartmental techniques, using Phoenix WinNonlin, were used to determine AUC AI.
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. Cmax after the fourth infusion was calculated as the maximum observed SAR441236 concentration from SAR441236 PK samples obtained after the fourth infusion. Standard noncompartmental techniques, using Phoenix WinNonlin, were used to determine Cmax after the 4th infusion.
Trial Locations
- Locations (23)
UCLA CARE Center CRS
🇺🇸Los Angeles, California, United States
Case Clinical Research Site
🇺🇸Cleveland, Ohio, United States
Northwestern University CRS
🇺🇸Chicago, Illinois, United States
UCSD Antiviral Research Center CRS
🇺🇸San Diego, California, United States
Cincinnati Clinical Research Site
🇺🇸Cincinnati, Ohio, United States
University of Washington Positive Research CRS
🇺🇸Seattle, Washington, United States
Ucsf Hiv/Aids Crs
🇺🇸San Francisco, California, United States
Vanderbilt Therapeutics (VT) CRS
🇺🇸Nashville, Tennessee, United States
Massachusetts General Hospital CRS (MGH CRS)
🇺🇸Boston, Massachusetts, United States
Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
🇺🇸Boston, Massachusetts, United States
New Jersey Medical School Clinical Research Center CRS
🇺🇸Newark, New Jersey, United States
Alabama CRS
🇺🇸Birmingham, Alabama, United States
University of Colorado Hospital CRS
🇺🇸Aurora, Colorado, United States
Rush University CRS
🇺🇸Chicago, Illinois, United States
Washington University Therapeutics (WT) CRS
🇺🇸Saint Louis, Missouri, United States
Weill Cornell Chelsea CRS
🇺🇸New York, New York, United States
Weill Cornell Uptown CRS
🇺🇸New York, New York, United States
Chapel Hill CRS
🇺🇸Chapel Hill, North Carolina, United States
University of Rochester Adult HIV Therapeutic Strategies Network CRS
🇺🇸Rochester, New York, United States
Penn Therapeutics, CRS
🇺🇸Philadelphia, Pennsylvania, United States
Ohio State University CRS
🇺🇸Columbus, Ohio, United States
University of Pittsburgh CRS
🇺🇸Pittsburgh, Pennsylvania, United States
The Miriam Hospital Clinical Research Site (TMH CRS) CRS
🇺🇸Providence, Rhode Island, United States