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Pharmacokinetics of SAR441236

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ClinicalTrials.gov Identifier: NCT03705169
Recruitment Status : Not yet recruiting
First Posted : October 15, 2018
Last Update Posted : October 15, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of SAR441236, a tri-specific broadly neutralizing antibody against the human immunodeficiency virus (HIV).

Condition or disease Intervention/treatment Phase
HIV-1-infection Biological: SAR441236 Biological: Placebo Drug: Antiretroviral treatment Phase 1

Detailed Description:

This study will evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of SAR441236, a tri-specific broadly neutralizing antibody against HIV.

The study includes two arms. In Arm A, three cohorts of antiretroviral-treated, virologically suppressed participants will be randomized to receive a single intravenous (IV) dose of SAR441236 or placebo on Day 0. After Cohort 1, each subsequent cohort will open for enrollment only after an evaluation of safety outcomes for all participants in the previous cohort indicates that it is safe to increase the dose of SAR441236. All participants in Cohorts 1-3 will be followed for 24 weeks.

In Arm A, Cohort 4, participants will be randomized to receive an IV infusion of SAR441236 or placebo once every 12 weeks beginning at entry, for a total of 4 infusions. Participants in this cohort will be followed for 72 weeks.

Participants in Arm A will continue taking non-study-provided antiretroviral treatment throughout the study.

In Arm B, four cohorts of ART naïve, viremic participants will each receive a single IV dose of SAR441236 on Day 0. After Cohort 5, each subsequent cohort will be opened for enrollment after an evaluation of safety outcomes for all participants in the previous cohort indicates that it is safe to increase the dose of SAR441236.

Based on an evaluation of virologic study data, an additional Arm B cohort of antiretroviral naïve, viremic participants, Cohort 9, may open at a lower dose. Participants in Cohort 9 will receive a single IV dose of SAR441236. All Arm B participants will be followed for 24 weeks.

Participants in Arm B will initiate non-study-provided combination antiretroviral therapy (selected by their primary HIV clinician) on Day 28.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase I, First-in-Human, Ascending Dose Study of SAR441236, a Tri-specific Broadly Neutralizing Antibody, in Participants With HIV
Estimated Study Start Date : October 31, 2018
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Arm A, Cohort 1A: SAR441236
In addition to continuing non-study-provided ART, participants will receive 1 mg/kg of SAR441236, administered as a single intravenous (IV) infusion on Day 0.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm A, Cohort 1B: Placebo for SAR441236
In addition to continuing non-study-provided ART, participants will receive placebo administered as a single IV infusion on Day 0.
Biological: Placebo
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm A, Cohort 2A: SAR441236
In addition to continuing non-study-provided ART, participants will receive 3 mg/kg of SAR441236, administered as a single IV infusion on Day 0.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm A, Cohort 2B: Placebo for SAR441236
In addition to continuing non-study-provided ART, participants will receive placebo administered as a single IV infusion on Day 0.
Biological: Placebo
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm A, Cohort 3A: SAR441236
In addition to continuing non-study-provided ART, participants will receive 10 mg/kg of SAR441236, administered as a single IV infusion on Day 0.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm A, Cohort 3B: Placebo for SAR441236
In addition to continuing non-study-provided ART, participants will receive placebo administered as a single IV infusion on Day 0.
Biological: Placebo
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm A, Cohort 4A: SAR441236
In addition to continuing non-study-provided ART, participants will receive 30 mg/kg of SAR441236, administered as an IV infusion on Day 0 and then every 12 weeks (at weeks 12, 24, and 36) for a total of four doses.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm A, Cohort 4B: Placebo for SAR441236
In addition to continuing non-study-provided ART, participants will receive placebo administered as an IV infusion on Day 0 and then every 12 weeks (at weeks 12, 24, and 36) for a total of four doses.
Biological: Placebo
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm B, Cohort 5: SAR441236
Participants will receive 1 mg/kg of SAR441236, administered as a single IV infusion on Day 0. Antiretroviral treatment will be initiated by Day 28.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm B, Cohort 6: SAR441236
Participants will receive 3 mg/kg of SAR441236, administered as a single IV infusion on Day 0. Antiretroviral treatment will be initiated by Day 28.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm B, Cohort 7: SAR441236
Participants will receive 10 mg/kg of SAR441236, administered as a single IV infusion on Day 0. Antiretroviral treatment will be initiated by Day 28.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm B, Cohort 8: SAR441236
Participants will receive 30 mg/kg of SAR441236, administered as a single IV infusion on Day 0. Antiretroviral treatment will be initiated by Day 28.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.

Experimental: Arm B, Cohort 9: SAR441236
Participants will receive 0.3 mg/kg of SAR441236, administered as a single IV infusion on Day 0. Antiretroviral treatment will be initiated by Day 28.
Biological: SAR441236
Administered by intravenous (IV) infusion

Drug: Antiretroviral treatment
Antiretroviral treatment will be prescribed by participants' primary HIV clinician. It is not provided by the study.




Primary Outcome Measures :
  1. Occurrence of a Grade 3 or higher adverse event (AE) that is related to study treatment (as judged by the core safety team, blinded to treatment arm) any time from study treatment administration through the entire follow-up [ Time Frame: Measured through Week 72 for Cohort 4 ]
    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

  2. Occurrence of a Grade 3 or higher AE that is related to study treatment (as judged by the core safety team, blinded to treatment arm) any time from study treatment administration through the entire follow-up [ Time Frame: Measured through Week 24 for Cohorts 1-3 and Arm B cohorts ]
    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

  3. AUCinf of SAR441236 for Cohorts 1-3 and Arm B cohorts [ Time Frame: Measured through Week 24 ]
    As assessed by pharmacokinetic sampling and analysis

  4. AUC12wk of SAR441236 following each infusion for Cohort 4 [ Time Frame: Measured through Week 48 ]
    As assessed by pharmacokinetic sampling and analysis

  5. Change in plasma HIV-1 RNA (log10 copies/mL) from baseline (defined as the last measurement taken prior to the treatment initiation) to Day 7 of monotherapy for treatment-naïve, viremic participants with HIV (Arm B cohorts) [ Time Frame: Measured through Day 7 ]
    Based on laboratory evaluations


Secondary Outcome Measures :
  1. Change in plasma HIV-1 RNA (copies/mL) from baseline to Days 1, 2, 3, 4, 14, and 28 of monotherapy for treatment-naïve, viremic participants with HIV (Arm B cohorts) [ Time Frame: Measured through Day 28 ]
    Based on laboratory evaluations

  2. Change in plasma HIV-1 RNA (log10 copies/mL) from baseline (defined as the last measurement taken prior to treatment initiation) to Day 14 and Day 28 of monotherapy for Arm B cohorts [ Time Frame: Measured through Day 28 ]
    Based on laboratory evaluations

  3. Maximum reduction of plasma HIV-1 RNA during 28 days of monotherapy for treatment-naïve, viremic participants with HIV (Arm B cohorts) [ Time Frame: Measured through Day 28 ]
    Based on laboratory evaluations

  4. Percentage of participants who developed anti-SAR441236 antibodies [ Time Frame: Measured through Week 24 for Cohorts 1-3 and Arm B cohorts ]
    Based on laboratory evaluations

  5. Percentage of participants who developed anti-SAR441236 antibodies [ Time Frame: Measured through Week 72 for Cohort 4 ]
    Based on laboratory evaluations

  6. Change in CD4+ T cell counts (cells/mm^3) from baseline to week 12 following single dose of SAR441236 for all cohorts [ Time Frame: Measured through Week 12 ]
    Based on laboratory evaluations

  7. Change in CD4+ T cell counts (cells/mm^3) from baseline to week 12 following each infusion for Cohort 4 [ Time Frame: Measured through Week 72 ]
    Based on laboratory evaluations

  8. Maximum concentration of SAR441236 after infusion for Cohorts 1-3 and Arm B cohorts [ Time Frame: Measured through Week 24 ]
    Based on laboratory evaluations

  9. Trough concentration of SAR441236 after infusion for Cohorts 1-3 and Arm B cohorts [ Time Frame: Measured through Week 24 ]
    Based on laboratory evaluations

  10. Half life of SAR441236 after infusion for Cohorts 1-3 and Arm B cohorts [ Time Frame: Measured through Week 24 ]
    Based on laboratory evaluations

  11. Time to half life of SAR441236 after infusion for Cohorts 1-3 and Arm B cohorts [ Time Frame: Measured through Week 24 ]
    Based on laboratory evaluations

  12. Clearance of SAR441236 after infusion for Cohorts 1-3 and Arm B cohorts [ Time Frame: Measured through Week 24 ]
    Based on laboratory evaluations

  13. Distribution volume of SAR441236 after infusion for Cohorts 1-3 and Arm B cohorts [ Time Frame: Measured through Week 24 ]
    Based on laboratory evaluations

  14. Maximum concentration of SAR441236 after each infusion for Cohort 4 [ Time Frame: Measured through Week 72 ]
    Based on laboratory evaluations

  15. Trough concentration of SAR441236 after each infusion for Cohort 4 [ Time Frame: Measured through Week 72 ]
    Based on laboratory evaluations

  16. Half life of SAR441236 after each infusion for Cohort 4 [ Time Frame: Measured through Week 72 ]
    Based on laboratory evaluations

  17. Time to half life of SAR441236 after each infusion for Cohort 4 [ Time Frame: Measured through Week 72 ]
    Based on laboratory evaluations

  18. Clearance of SAR441236 after each infusion for Cohort 4 [ Time Frame: Measured through Week 72 ]
    Based on laboratory evaluations

  19. Distribution volume of SAR441236 after each infusion for Cohort 4 [ Time Frame: Measured through Week 72 ]
    Based on laboratory evaluations

  20. Establish concentration (or dose)-response relationship between SAR441236 exposure and changes in plasma HIV-1 RNA from entry baseline to week 4 (or viral load nadir) [ Time Frame: Measured through Week 4 ]
    Based on laboratory evaluations



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria, Arms A and B

  • 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 or equal to 60 mL/min

      • Refer to the calculator located on the FSTRF website (at www.fstrf.org): Calculated Creatinine Clearance - Cockcroft-Gault Equation (Adult).
    • Aspartate aminotransferase (AST) (SGOT) less than 2.0 x upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) (SGPT) less than 2.0 x ULN
    • Alkaline phosphatase less than 2.0 x ULN
    • Total bilirubin less than 2.5 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.
  • Individuals age greater than or equal to 18 years and less than or equal to 70 years at study entry.
  • Ability and willingness of participant to provide informed consent.

Inclusion Criteria, Arm A only

  • 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 below the limit of quantification by any FDA-approved assay on a licensed kit with a limit of quantification less than or equal to 50 copies/mL of plasma 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 below the limit of quantification by any FDA-approved assay on a licensed kit with a limit of quantification less than or equal to 50 copies/mL of plasma by a US laboratory that has a CLIA certification or its equivalent.

Inclusion Criteria, Arm B only

  • Plasma HIV-1 RNA greater than 5000 and less than 100,000 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 combination ART by or on Day 28 of the study.

Exclusion Criteria, Arms A and B

  • Breastfeeding or plans to become pregnant.
  • Receipt of chimeric, humanized or human long-acting mAbs, whether licensed or investigational, within 12 months prior to entry, or receipt of chimeric, humanized or human regular mAbs, whether licensed or investigational, within 6 months prior to entry, unless reviewed and approved by the study's core team.
  • Known allergy/sensitivity or any hypersensitivity to components of study treatment or its formulation (refer to the product's Investigator's Brochure).
  • Vaccination within 30 days prior to entry or intent to receive an elective vaccination (e.g., hepatitis A vaccine, travel-related) during the course of the study except as noted in the study protocol.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Acute or serious illness requiring systemic treatment and/or hospitalization within 45 days prior to entry.
  • Documented opportunistic infection within 45 days prior to entry.
  • Weight greater than 115 kg within 45 days prior to study entry.

Exclusion Criteria, Arm A

  • Within 12 months prior to study entry, any plasma HIV-1 RNA above the limit of quantification by any FDA-approved assay on a licensed kit with a limit of quantification less than or equal to 50 copies/mL of plasma performed by a US laboratory that has a CLIA certification or its equivalent.
  • Any current or prior use of maraviroc, ibalizumab, or enfuvirtide.

Exclusion Criterion, Arm B

  • Any prior use of ART, including pre-exposure prophylaxis (PrEP) at any time.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03705169


Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: 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

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03705169     History of Changes
Other Study ID Numbers: ACTG A5377
38508 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: October 15, 2018    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
HIV
pharmacokinetics
pharmacodynamics
broadly neutralizing antibody
antiretroviral
Phase 1

Additional relevant MeSH terms:
Antibodies, Blocking
Immunologic Factors
Physiological Effects of Drugs