Integrase and Maraviroc Intensification in Neurocognitive Dysfunction (InMIND)

A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral Intensification With Maraviroc and Dolutegravir With No Intensification or Intensification With Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Placebo for maraviroc (MVC); Drug: Placebo for dolutegravir (DTG); Drug: Dolutegravir (DTG); Drug: Maraviroc (MVC)

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.

• Study Type: Interventional
• Enrollment (Actual): 191
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Rio De Janeiro, Brazil, 21040-360
    • Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Puerto Rico AIDS Clinical Trials Unit CRS
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2092
      • Wits Helen Joseph Hospital CRS (Wits HJH CRS)
  • Kwa Zulu Natal
    • Durban, Kwa Zulu Natal, South Africa, 4052
      • Durban International Clinical Research Site CRS
  • Western Cape Province
    • Tygerberg, Western Cape Province, South Africa, 7505
      • Famcru Crs
• Thailand
  • Bangkok, Thailand, 10330
    • Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
• United States
  • California
    • Los Angeles, California, United States, 90035
      • UCLA CARE Center CRS
    • San Diego, California, United States, 92103
      • UCSD Antiviral Research Center CRS
    • Torrance, California, United States, 90502
      • Harbor-UCLA CRS
  • District of Columbia
    • Washington, District of Columbia, United States, 20005
      • Whitman-Walker Health CRS
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University CRS
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1010
      • Washington University Therapeutics (WT) CRS
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School Clinical Research Center CRS
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Uptown CRS
    • New York, New York, United States, 10010
      • Weill Cornell Chelsea CRS
    • Rochester, New York, United States, 14642
      • University of Rochester Adult HIV Therapeutic Strategies Network CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Chapel Hill CRS
    • Greensboro, North Carolina, United States, 27401
      • Greensboro CRS
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Cincinnati Clinical Research Site
    • Cleveland, Ohio, United States, 44106
      • Case Clinical Research Site
    • Columbus, Ohio, United States, 43210
      • Ohio State University CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Therapeutics, CRS
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh CRS
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital Clinical Research Site (TMH CRS) CRS
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • Vanderbilt Therapeutics (VT) CRS
  • Texas
    • Dallas, Texas, United States, 75208
      • Trinity Health and Wellness Center CRS
    • Houston, Texas, United States, 77030
      • Houston AIDS Research Team CRS
  • Washington
    • Seattle, Washington, United States, 98104-9929
      • University of Washington AIDS CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Arm A: Placebo MVC and placebo DTG; In addition to their existing ART regimens, participants in Arm A received placebo for MVC and placebo for DTG.	Drug: Placebo for maraviroc (MVC); 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; Drug: Placebo for dolutegravir (DTG); Administered orally as one 50 mg tablet BID OR one 50 mg tablet QD depending upon background ARV regimen
Experimental: Arm B: DTG and placebo MVC; In addition to their existing ART regimens, participants in Arm B received DTG and placebo for MVC.	Drug: Placebo for maraviroc (MVC); 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; Drug: Dolutegravir (DTG); Administered orally as one 50 mg tablet BID OR one 50 mg tablet QD depending upon background ARV regimen
Experimental: Arm C: MVC and DTG; In addition to their existing ART regimens, participants in Arm C received MVC and DTG	Drug: Dolutegravir (DTG); Administered orally as one 50 mg tablet BID OR one 50 mg tablet QD depending upon background ARV regimen; Drug: Maraviroc (MVC); 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Normalized Composite Neurocognitive Test Score at Week 48 From Baseline	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.	Measured at Baseline and Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Related Adverse Events (AEs)	Treatment Related Adverse Events were determined by the study sites indicating a relationship between an adverse event and the study treatment.	Measured from treatment initiation through Week 96
Change in Normalized Composite Neurocognitive Test Score at Weeks 24, 72, and 96 From Baseline	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.	Measured at Baseline and Weeks 24, 72, and 96
Change in Functional Status Scores	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.	Measured at Baseline and Weeks 24, 48, 72, and 96
Number of Participants With Plasma HIV-1 RNA Greater Than or Equal to 50 Copies/mL	The number of participants with Plasma HIV-1 RNA greater than or equal to 50 copies/mL was assessed at each given time point.	Measured at Weeks 24, 48, and 96
CD4+ T-cell Counts	CD4+ T-cell counts were recorded at the given time point	Measured at Weeks 24, 48, and 96
Change in CD4+ T-cell Count	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.	Measured at Baseline and Weeks 24, 48, and 96
CD8+ T-cell Counts	CD8+ T-cell counts were recorded at the given time point	Measured at Weeks 24, 48, and 96
Change in CD8+ T-cell Count	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.	Measured at Baseline and Weeks 24, 48, and 96
Change in Log10 sCD14 in Plasma at Week 48 From Baseline	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.	Measured at Baseline and Week 48
Change in Log10 MIP-1 Beta in Plasma at Week 48 From Baseline	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.	Measured at Baseline and Week 48
Change in Log10 sTNFr-II in Plasma at Week 48 From Baseline	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.	Measured at Baseline and Week 48
Change in Log10 VCAM in Plasma at Week 48 From Baseline	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.	Measured at Baseline and Week 48
Change in Log10 MIP-1 Beta in Cerebrospinal Fluid (CSF) at Week 48 From Baseline	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.	Measured at Baseline and Week 48
Change in Log10 IP-10 in CSF at Week 48 From Baseline	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.	Measured at Baseline and Week 48
Change in Log10 Neopterin in CSF at Week 48 From Baseline	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.	Measured at Baseline and Week 48
Change in Log10 NFL in CSF at Week 48 From Baseline	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.	Measured at Baseline and Week 48

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Cell-associated HIV-1 RNA/DNA/2-long Terminal Repeat Sequences (LTR) Circles and Single Copy Assay (SCA)	This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome due to lack of funding for testing.	Measured at Baseline and Week 48
Changes in T Cell and Monocyte Activation	This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome due to lack of funding for testing.	Measured at Baseline and Week 48
Changes in Residual Viremia	This outcome measure was listed as secondary in the protocol but the intention was as an exploratory outcome due to lack of funding for testing.	Measured at Baseline and Week 48

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Kevin Robertson, PhD, University of North Carolina

Publications and helpful links

Helpful Links

• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• 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

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2016
• Primary Completion (Actual): December 2, 2019
• Study Completion (Actual): January 5, 2021

Study Registration Dates

• First Submitted: August 6, 2015
• First Submitted That Met QC Criteria: August 6, 2015
• First Posted (Estimate): August 11, 2015

Study Record Updates

• Last Update Posted (Actual): April 22, 2022
• Last Update Submitted That Met QC Criteria: April 20, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: HIV-Associated Neurocognitive Disorder
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Maraviroc; Dolutegravir
• Other Study ID Numbers: A5324; 11909 (Registry Identifier: DAIDS-ES)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No