Pharmacokinetics and Safety of SAR441236
Condition: HIV-1-infection
Intervention: SAR441236; Placebo
Intervention description: Administered by intravenous (IV) infusion(s) or subcutaneous (SC) injection(s); Administered by intravenous (IV) infusion(s) or subcutaneous (SC) injection(s)
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 52.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: HIV; pharmacokinetics; pharmacodynamics; broadly neutralizing antibody; antiretroviral; Phase 1

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).
    

Eligibility criteria:

        Note: The following inclusion and exclusion criteria 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

          -  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.

          -  Diagnosis of AIDS-defining illness using the current list on the US Centers for
             Disease Control and Prevention (CDC) website within 1 year prior to entry.

          -  Weight greater than 115 kg within 45 days prior to study entry.

          -  Use of maraviroc, ibalizumab, or enfuvirtide at any time.

        Additional Arms A- and C-specific Exclusion Criterion

          -  Within 6 months prior to study entry, any plasma HIV-1 RNA ≥50 copies/mL on any
             FDA-approved assay with a limit of quantification of <50 copies/mL performed by a US
             laboratory that has a CLIA certification or its equivalent.

        Additional Arm B-specific Exclusion Criterion

          -  Use of any anti-HIV ART, including FDA-approved pre-exposure prophylaxis (PrEP) within
             the preceding 3 months

        Additional Arm C-specific Exclusion Criterion

          -  Presence of abdominal scarring or tattooing that could interfere with assessment of
             injection-site reaction.