Pharmacokinetics and Safety of SAR441236

NCT03705169 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: ACTG A537738508TDU15867
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 23

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).

Conditions

HIV-1-infection

Keywords

HIV; pharmacokinetics; pharmacodynamics; broadly neutralizing antibody; antiretroviral; Phase 1

Outcome Measures

Primary Outcomes (3)

• Proportion of Participants Experiencing a Grade 3 or Higher Adverse Event (AE) That is Related to Study Treatment.

  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

  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).

• Mean Dose-normalized AUC 0-12wk of SAR441236

  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.

  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.

• 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)

  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.

  Measured at Day 0 and Day 7

Secondary Outcomes (18)

• 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 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

Study Arms (10)

Arm A: 1 mg/kg SAR441236

EXPERIMENTAL

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).

Biological: SAR441236

Arm A: 3 mg/kg for SAR441236

EXPERIMENTAL

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).

Biological: SAR441236

Arm A: 10 mg/kg SAR441236

EXPERIMENTAL

Participants continued non-study-provided ART and received 10 mg/kg of SAR441236, administered as a single IV infusion on Day 0 (Cohort 3).

Biological: SAR441236

Arm A: 30 mg/kg SAR441236

EXPERIMENTAL

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).

Biological: SAR441236

Arm A: 0 mg/kg SAR441236

PLACEBO COMPARATOR

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.

Biological: Placebo

Arm B: 1 mg/kg SAR441236

EXPERIMENTAL

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).

Biological: SAR441236

Arm B: 30 mg/kg SAR441236

EXPERIMENTAL

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).

Biological: SAR441236

Arm C: 0.3 mg/kg SAR441236

EXPERIMENTAL

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).

Biological: SAR441236

Arm C: 1 mg/kg SAR441236

EXPERIMENTAL

Participants continued non-study-provided ART and received 1 mg/kg of SAR441236, administered as an SC injection(s) on Day 0 (Cohort 11).

Biological: SAR441236

Arm C: 0 mg/kg SAR441236

PLACEBO COMPARATOR

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.

Biological: Placebo

Interventions

SAR441236 BIOLOGICAL

Administered by intravenous (IV) infusion(s) or subcutaneous (SC) injection(s)

Arm A: 1 mg/kg SAR441236; Arm A: 10 mg/kg SAR441236; Arm A: 3 mg/kg for SAR441236; Arm A: 30 mg/kg SAR441236; Arm B: 1 mg/kg SAR441236; Arm B: 30 mg/kg SAR441236; Arm C: 0.3 mg/kg SAR441236; Arm C: 1 mg/kg SAR441236

Placebo BIOLOGICAL

Administered by intravenous (IV) infusion(s) or subcutaneous (SC) injection(s)

Arm A: 0 mg/kg SAR441236; Arm C: 0 mg/kg SAR441236

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Sanofi: collaborator
• ModeX Therapeutics, An OPKO Health Company: collaborator

Study Sites (23)

Alabama CRS

Birmingham, Alabama, 35294, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90035, United States

Location

UCSD Antiviral Research Center CRS

San Diego, California, 92103, United States

Location

Ucsf Hiv/Aids Crs

San Francisco, California, 94110, United States

Location

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Rush University CRS

Chicago, Illinois, 60612, United States

Location

Massachusetts General Hospital CRS (MGH CRS)

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS

Boston, Massachusetts, 02115, United States

Location

Washington University Therapeutics (WT) CRS

St Louis, Missouri, 63110-1010, United States

Location

New Jersey Medical School Clinical Research Center CRS

Newark, New Jersey, 07103, United States

Location

Weill Cornell Chelsea CRS

New York, New York, 10010, United States

Location

Weill Cornell Uptown CRS

New York, New York, 10065, United States

Location

University of Rochester Adult HIV Therapeutic Strategies Network CRS

Rochester, New York, 14642, United States

Location

Chapel Hill CRS

Chapel Hill, North Carolina, 27599, United States

Location

Cincinnati Clinical Research Site

Cincinnati, Ohio, 45219, United States

Location

Case Clinical Research Site

Cleveland, Ohio, 44106, United States

Location

Ohio State University CRS

Columbus, Ohio, 43210, United States

Location

Penn Therapeutics, CRS

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh CRS

Pittsburgh, Pennsylvania, 15213, United States

Location

The Miriam Hospital Clinical Research Site (TMH CRS) CRS

Providence, Rhode Island, 02906, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 37204, United States

Location

University of Washington Positive Research CRS

Seattle, Washington, 98104-9929, United States

Location

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017.
• Manual for Expediated Reporting of Adverse Events to DAIDS, Version 2.0, January 2010

Limitations and Caveats

The dosing schedule for many Arm A Cohort 4 participants was interrupted by the COVID-19 pandemic and associated study pause. Enrollment in Arm B was limited. Protocol V3.0 closed the 1 mg/kg cohort and opened the 30 mg/kg cohort. Protocol V4.0 modified the eligibility criteria to boost enrollment but, despite the study remaining open through April 2023, no more participants enrolled. Neither Arm B cohort fully enrolled and the intermediate dose cohorts (3 and 10 mg/kg) did not open.

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• Athe Tsibris, MD, MS

  Brigham and Women's Hospital, Harvard Medical School

  STUDY CHAIR

• Daniel R. Kuritzkes, MD

  Brigham and Women's Hospital Therapeutics CRS, Harvard Medical School

  STUDY CHAIR

• Pablo Tebas, MD

  Penn Therapeutics CRS

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2018
• First Posted: October 15, 2018
• Study Start: May 20, 2019
• Primary Completion: April 4, 2022
• Study Completion: April 4, 2022
• Last Updated: January 12, 2024
• Results First Posted: January 12, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
• Access Criteria: * With whom? * Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group. * For what types of analyses? * To achieve aims in the proposal approved by the AIDS Clinical Trials Group. * By what mechanism will data be made available? * Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://submit.mis.s-3.net/ Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

Locations

US (23)