Integrase and Maraviroc Intensification in Neurocognitive Dysfunction (InMIND)
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: Placebo for maraviroc (MVC); Placebo for dolutegravir (DTG); Dolutegravir (DTG); Maraviroc (MVC)
Intervention description: Administered orally as one 150 mg tablet BID OR two 300 mg tablet BID OR one 300 mg tablet BID depending upon background ARV regimen; Administered orally as one 50 mg tablet BID OR one 50 mg tablet QD depending upon background ARV regimen; Administered orally as one 50 mg tablet BID OR one 50 mg tablet QD depending upon background ARV regimen; Administered orally as one 150 mg tablet BID OR two 300 mg tablet BID OR one 300 mg tablet BID depending upon background ARV regimen
Intervention MeSH terms: Dolutegravir; Maraviroc
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 191.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV-Associated Neurocognitive Disorder

Summary:

      People infected with HIV often have cognitive dysfunction even if they are on antiretroviral
      therapy (ART) and have undetectable viral loads. The study evaluated if the addition of
      maraviroc (MVC) and dolutegravir (DTG) (which are two antiretroviral [ARV] medications) to
      participants' existing ART regimens improved participants' neurocognitive performance.
    

Eligibility criteria:

        Inclusion Criteria:

          -  HIV-1 infection, documented by:

               -  a licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA)
                  test kit at any time prior to study entry and confirmed by a licensed Western
                  blot or a second antibody test by a method other than the initial rapid HIV
                  and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load. NOTE: The term
                  "licensed" refers to a United States Food and Drug Administration (FDA)-approved
                  kit, which is required for all IND studies, or for sites located in countries
                  other than the United States, a kit that has been certified or licensed by an
                  oversight body within that country and validated internally. Non-US sites are
                  encouraged to use US FDA-approved methods for IND studies. 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 (eg,
                  indirect versus competitive), or a Western blot or a plasma HIV-1 RNA. OR

               -  Documentation of HIV diagnosis in the medical record by a healthcare provider.

          -  On current ART for at least 6 months prior to study entry with no interruption in
             treatment of greater than or equal to 7 consecutive days. Note: The following ART
             changes are allowed:

               -  Tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide fumarate
                  (TAF)/TAF-containing fixed-dose combination regimens

               -  Ritonavir (RTV) to cobicistat (COBI)/COBI-containing fixed-dose combination
                  regimens

          -  No plans to change ART while on study. Note: The following planned ART changes are
             allowed:

               -  TDF to TAF/TAF-containing fixed-dose combination regimens

               -  RTV to COBI/COBI-containing fixed-dose combination regimens

          -  HIV-1 plasma RNA less than 50 copies/mL obtained within 90 days prior to study entry
             by any FDA-approved assay at any United States laboratory that has a Clinical
             Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any
             network-approved non-US laboratory that operates in accordance with Good Clinical
             Laboratory Practices (GCLP) and participates in appropriate external quality assurance
             programs.

          -  No more than one HIV-1 plasma RNA greater than or equal to 50 and less than 200
             copies/mL (only one "blip") in the past 6 months with a subsequent HIV-1 plasma RNA
             less than 50 copies/mL. NOTE: There should be no plasma HIV-1 RNA greater than 200
             copies/mL within the 6 months prior to study entry.

          -  HAND diagnosis (ANI, MND, or HAD) within 60 days prior to study entry. HAND is defined
             as at least mild impairment on neurocognitive testing (more than one standard
             deviation below appropriate normative data in two domains of functioning) and no
             severely confounding factors.

          -  Screening laboratory values obtained within 60 days prior to study entry by any US
             laboratory that has a CLIA certification or its equivalent, or at any network-approved
             non-US laboratory that operates in accordance with GCLP and participates in
             appropriate external quality assurance programs:

               -  Absolute neutrophil count (ANC) greater than or equal to 500/mm^3

               -  Hemoglobin greater than or equal to 7.5 g/dL

               -  Platelet count greater than or equal to 40,000/mm^3

               -  Creatinine less than or equal to 2.0 x upper limit of normal (ULN)

               -  Aspartate transaminase (AST) less than or equal to 5 x ULN

               -  Alanine transaminase (ALT) less than 3 x ULN

               -  Alkaline phosphatase less than or equal to 5 x ULN

               -  Total bilirubin less than 1.5 x ULN. NOTE: If the potential participant is taking
                  an indinavir (IDV)- or atazanavir (ATV)-containing regimen at the time of
                  screening, total bilirubin less than or equal to 5 x ULN is acceptable.

               -  Creatinine clearance (CrCl) greater than or equal to 60 mL/min, either measured
                  or estimated by Cockcroft-Gault equation. NOTE: A calculator for estimating the
                  CrCl can be found at www.fstrf.org/ACTG/ccc.html

          -  Females of reproductive potential (women who have not been post-menopausal for at
             least 24 consecutive months, ie, who have had menses within the preceding 24 months,
             or women who have not undergone surgical sterilization, hysterectomy or bilateral
             salpingectomy or bilateral oophorectomy or tubal ligation) must have a negative serum
             or urine pregnancy test 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, or at any
             network-approved non-US laboratory or clinic that operates in accordance with GCLP and
             participates in appropriate external quality assurance programs within 48 hours prior
             to study entry

          -  Females of reproductive potential must agree not to participate in the conception
             process (ie, active attempt to become pregnant, in vitro fertilization), and if
             participating in sexual activity that could lead to pregnancy, must use at least one
             reliable form of contraception. Female participants must use contraceptives while
             receiving study treatment and for 6 weeks after stopping study treatment. More
             information on this criterion is available in the protocol.

          -  Ability and willingness of participant to complete the neuropsychological tests

          -  Ability and willingness of participant or a legally authorized representative (see
             protocol for more information) to provide informed consent

          -  Ability and willingness to take oral study medications

        Exclusion Criteria:

          -  Current or past medical condition(s) that in the opinion of the investigator prevents
             attribution of the cause of cognitive impairment to HIV. For example:

               -  Major depressive disorder with psychotic features

               -  Traumatic Brain Injury (TBI) with a clear impact on activities of daily living

               -  Developmental delay, intellectual deficit, and/or severe educational disability
                  resulting in some dependence for activities of daily living

               -  Ongoing substance use disorder with significant impact on activities of daily
                  living. Difficult or impossible to determine whether cognitive or functional
                  decline is due to substance use or HIV, or both

               -  Evidence of intoxication or withdrawal during the screening evaluation

               -  Central nervous system (CNS) infections or opportunistic conditions: brain
                  abscess (bacterial, mycobacterial, fungal or Toxoplasma), meningitis with
                  persistent neurologic impairment, primary CNS lymphoma, progressive multifocal
                  leukoencephalopathy (PML), or another structural brain lesion with neurological
                  sequelae

               -  Other CNS conditions: non-opportunistic primary or metastatic brain tumors,
                  uncontrolled seizure disorder, progressive multiple sclerosis, stroke with
                  neurological sequelae, or dementia due to causes other than HIV (eg, Alzheimer's
                  disease)

               -  Constitutional illness (eg, persistent unexplained fever, diarrhea, significant
                  weight loss, disabling weakness) within 30 days of screening

               -  Known untreated B12 deficiency or malnutrition (body mass index [BMI] less than
                  18) at screening

          -  Evidence of current hepatitis C virus infection (HCV) (ie, HCV antibody [Ab] positive
             within 90 days prior to study entry unless also shown to be plasma HCV RNA negative
             within the same time period)

          -  Unstable and advanced liver disease (as defined by the presence of at least one of the
             following: ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or
             gastric varices, or persistent jaundice)

          -  Prior or current use of any CCR5 antagonist (such as MVC and cenicriviroc [CVC]) and
             integrase inhibitor (such as RAL, DTG, and elvitegravir [EVG])

          -  Current use of any medication, including antiretrovirals, prohibited in the study
             (refer to the A5324 protocol-specific web page [PSWP] for the prohibited medications)

          -  Breastfeeding

          -  Presence of an AIDS-defining opportunistic infection within 6 months prior to entry.
             Note: Refer to the A5324 Manual of Operations (MOPS) for the list of AIDS-defining
             opportunistic infections.

          -  Active syphilis or treatment for syphilis within 90 days prior to study entry. NOTE:
             Active syphilis is defined as four-fold increase in serum rapid plasma reagin (RPR) or
             venereal disease research laboratory (VDRL) tests in an individual with past syphilis,
             or newly reactive serum RPR or VDRL with a reactive confirmatory test (enzyme
             immunoassays [EIA] or chemiluminescent assay [CIA], T. pallidum particle agglutination
             [TP-PA], or fluorescent treponemal antibody absorbed [FTA-ABS]).

          -  Known allergy/sensitivity or any hypersensitivity to components of study drugs or
             their formulation