Integrase and Maraviroc Intensification in Neurocognitive Dysfunction (InMIND)

Phase 4

Completed

Conditions: HIV Infections

Interventions: Drug: Dolutegravir (DTG)
Drug: Placebo for maraviroc (MVC)
Drug: Placebo for dolutegravir (DTG)
Drug: Maraviroc (MVC)

Registration Number: NCT02519777

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief 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.

Detailed Description: HIV-infected people often have cognitive dysfunction (HIV-associated neurocognitive disorder, or HAND), which includes asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD), even if they are on ART and have undetectable viral loads. In this study, researchers evaluated the effectiveness of adding MVC and DTG to the current ART regimen of HIV-infected people with undetectable (\<50 copies/mL) plasma HIV-1 RNA who had neurocognitive impairment and who had been on stable ART for at least 6 months prior to study entry. The purpose of this study was to evaluate if the addition of MVC and DTG to participants' existing ART regimens improved participants' neurocognitive performance.

Participants were randomly assigned to one of three arms. All participants remained on their existing ART regimens; they took their assigned study drugs in addition to their ART regimen. Study visits occurred at entry and Weeks 2, 4, 12, 24, 48, 72, and 96. Visits may have included physical examinations, blood collection, neurocognitive testing, pregnancy testing, and questionnaires. Some participants may have had an optional lumbar puncture procedure at study entry and Week 48. Participants returned for refills of study drugs on Weeks 36, 60, and 84.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 191

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm C: MVC and DTG	Dolutegravir (DTG)	In addition to their existing ART regimens, participants in Arm C received MVC and DTG
Arm A: Placebo MVC and placebo DTG	Placebo for maraviroc (MVC)	In addition to their existing ART regimens, participants in Arm A received placebo for MVC and placebo for DTG.
Arm B: DTG and placebo MVC	Dolutegravir (DTG)	In addition to their existing ART regimens, participants in Arm B received DTG and placebo for MVC.
Arm B: DTG and placebo MVC	Placebo for maraviroc (MVC)	In addition to their existing ART regimens, participants in Arm B received DTG and placebo for MVC.
Arm A: Placebo MVC and placebo DTG	Placebo for dolutegravir (DTG)	In addition to their existing ART regimens, participants in Arm A received placebo for MVC and placebo for DTG.
Arm C: MVC and DTG	Maraviroc (MVC)	In addition to their existing ART regimens, participants in Arm C received MVC and DTG

Primary Outcome Measures

Name	Time	Method
Change in Normalized Composite Neurocognitive Test Score at Week 48 From Baseline	Measured at Baseline and Week 48	The normalized composite neurocognitive test score (total z-score) was defined as the average of the z-scores from the following tests: Domestic (US-based) and International Participants: * Grooved pegboard dominant * Grooved pegboard non-dominant * Hopkins Verbal Learning Test (HVLT-R) Learning trials * HVLT-R Delayed recall * HVLT-R Delayed recognition * Semantic verbal fluency Domestic only: * Stroop color naming * Stroop word reading * Stroop interference trial * Letter fluency * Trail Making A * Trail Making B * WAIS-III Symbol search * Digit Symbol International only: * Timed Gait * Finger Tapping Dominant * Finger Tapping Non-dominant * Color Trail 1 Z-scores were calculated using a demographically appropriate norming process. Higher z-scores correspond with better neurocognitive performance. Change was calculated as the total z-score at Week 48 minus the total z-score at Baseline.

Secondary Outcome Measures

Name	Time	Method
Change in CD8+ T-cell Count	Measured at Baseline and Weeks 24, 48, and 96	Changes in CD8+ T-cell count were calculated as the CD8+ T-cell count at a given time point minus the CD8+ T-cell count at baseline.
Change in Normalized Composite Neurocognitive Test Score at Weeks 24, 72, and 96 From Baseline	Measured at Baseline and Weeks 24, 72, and 96	The normalized composite neurocognitive test score (total z-score) was defined as the average of the z-scores from the following tests: Domestic and International Participants: * Grooved pegboard dominant * Grooved pegboard non-dominant * HVLT-R Learning trials * HVLT-R Delayed recall * HVLT-R Delayed recognition * Semantic verbal fluency Domestic only: * Stroop color naming * Stroop word reading * Stroop interference trial * Letter fluency * Trail Making A * Trail Making B * WAIS-III Symbol search * Digit Symbol International only: * Timed Gait * Finger Tapping Dominant * Finger Tapping Non-dominant * Color Trail 1 * Color Trail 2 Z-scores were calculated using a demographically appropriate norming process. Higher z-scores correspond with better neurocognitive performance. Change was calculated as the total z-score at the given time point minus the total z-score at Baseline.
CD8+ T-cell Counts	Measured at Weeks 24, 48, and 96	CD8+ T-cell counts were recorded at the given time point
Number of Participants With Plasma HIV-1 RNA Greater Than or Equal to 50 Copies/mL	Measured at Weeks 24, 48, and 96	The number of participants with Plasma HIV-1 RNA greater than or equal to 50 copies/mL was assessed at each given time point.
Number of Participants With Treatment Related Adverse Events (AEs)	Measured from treatment initiation through Week 96	Treatment Related Adverse Events were determined by the study sites indicating a relationship between an adverse event and the study treatment.
Change in Functional Status Scores	Measured at Baseline and Weeks 24, 48, 72, and 96	Functional status scores were calculated based on the instrumental activities of daily living (IADLs) forms. IADL scores were calculated as the sum of the eight IADL tasks where the task scores were equal to 1 if a participant did not need assistance with the task and equal to 0 if a participant needed some level of help with the task. The maximum possible functional status score was 8, while the minimum possible functional status score was 0, with higher functional status scores indicating a higher level of functionality.
CD4+ T-cell Counts	Measured at Weeks 24, 48, and 96	CD4+ T-cell counts were recorded at the given time point
Change in CD4+ T-cell Count	Measured at Baseline and Weeks 24, 48, and 96	Changes in CD4+ T-cell count were calculated as the CD4+ T-cell count at a given time point minus the CD4+ T-cell count at Baseline.
Change in Log10 sCD14 in Plasma at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 sCD14 in Plasma were calculated as the Log10 sCD14 in Plasma at Week 48 minus the Log10 sCD14 in Plasma at Baseline.
Change in Log10 VCAM in Plasma at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 VCAM in Plasma were calculated as the Log10 VCAM in Plasma at Week 48 minus the Log10 VCAM in Plasma at Baseline.
Change in Log10 MIP-1 Beta in Plasma at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 MIP-1 Beta in Plasma were calculated as the Log10 MIP-1 Beta in Plasma at Week 48 minus the Log10 MIP-1 Beta in Plasma at Baseline. Results below the lower limit of quantification were set to the lower limit value of 11.
Change in Log10 sTNFr-II in Plasma at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 sTNFr-II in Plasma were calculated as the Log10 sTNFr-II in Plasma at Week 48 minus the Log10 sTNFr-II in Plasma at Baseline.
Change in Log10 MIP-1 Beta in Cerebrospinal Fluid (CSF) at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 MIP-1 Beta in CSF were calculated as the Log10 MIP-1 Beta in CSF at Week 48 minus the Log10 MIP-1 Beta in CSF at Baseline.
Change in Log10 IP-10 in CSF at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 IP-10 in CSF were calculated as the Log10 IP-10 in CSF at Week 48 minus the Log10 IP-10 in CSF at Baseline.
Change in Log10 Neopterin in CSF at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 Neopterin in CSF were calculated as the Log10 Neopterin in CSF at Week 48 minus the Log10 Neopterin in CSF at Baseline.
Change in Log10 NFL in CSF at Week 48 From Baseline	Measured at Baseline and Week 48	Changes in Log10 NFL in CSF were calculated as the Log10 NFL in CSF at Week 48 minus the Log10 NFL in CSF at Baseline.

Trial Locations

Locations (30): UCSD Antiviral Research Center CRS
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San Diego, California, United States
Northwestern University CRS
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Chicago, Illinois, United States
Johns Hopkins University CRS
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Baltimore, Maryland, United States
University of Washington AIDS CRS
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Seattle, Washington, United States
Wits Helen Joseph Hospital CRS (Wits HJH CRS)
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Johannesburg, Gauteng, South Africa
Vanderbilt Therapeutics (VT) CRS
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Nashville, Tennessee, United States
Ohio State University CRS
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Columbus, Ohio, United States
Harbor-UCLA CRS
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Torrance, California, United States
Weill Cornell Uptown CRS
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New York, New York, United States
Chapel Hill CRS
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Chapel Hill, North Carolina, United States
Greensboro CRS
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Greensboro, North Carolina, United States
Case Clinical Research Site
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Cleveland, Ohio, United States
Cincinnati Clinical Research Site
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Cincinnati, Ohio, United States
UCLA CARE Center CRS
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Los Angeles, California, United States
Weill Cornell Chelsea CRS
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New York, New York, United States
Penn Therapeutics, CRS
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Philadelphia, Pennsylvania, United States
University of Rochester Adult HIV Therapeutic Strategies Network CRS
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Rochester, New York, United States
University of Pittsburgh CRS
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Pittsburgh, Pennsylvania, United States
Washington University Therapeutics (WT) CRS
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Saint Louis, Missouri, United States
New Jersey Medical School Clinical Research Center CRS
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Newark, New Jersey, United States
Trinity Health and Wellness Center CRS
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Dallas, Texas, United States
The Miriam Hospital Clinical Research Site (TMH CRS) CRS
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Providence, Rhode Island, United States
Houston AIDS Research Team CRS
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Houston, Texas, United States
Famcru Crs
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Tygerberg, Western Cape Province, South Africa
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
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Rio De Janeiro, Brazil
Puerto Rico AIDS Clinical Trials Unit CRS
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San Juan, Puerto Rico
Durban International Clinical Research Site CRS
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Durban, Kwa Zulu Natal, South Africa
Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
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Bangkok, Thailand
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
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Chiang Mai, Thailand
Whitman-Walker Health CRS
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Washington, District of Columbia, United States