Clinical trial NCT02519777: Integrase and Maraviroc Intensification in Neurocognitive Dysfunction (InMIND)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Keywords: HIV-Associated Neurocognitive Disorder
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2015-08-11
Enrollment: 191
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Normalized Composite Neurocognitive Test Score at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
Secondary outcomes:
measure: Number of Participants With Treatment Related Adverse Events (AEs)
timeFrame: Measured from treatment initiation through Week 96
measure: Change in Normalized Composite Neurocognitive Test Score at Weeks 24, 72, and 96 From Baseline
timeFrame: Measured at Baseline and Weeks 24, 72, and 96
measure: Change in Functional Status Scores
timeFrame: Measured at Baseline and Weeks 24, 48, 72, and 96
measure: Number of Participants With Plasma HIV-1 RNA Greater Than or Equal to 50 Copies/mL
timeFrame: Measured at Weeks 24, 48, and 96
measure: CD4+ T-cell Counts
timeFrame: Measured at Weeks 24, 48, and 96
measure: Change in CD4+ T-cell Count
timeFrame: Measured at Baseline and Weeks 24, 48, and 96
measure: CD8+ T-cell Counts
timeFrame: Measured at Weeks 24, 48, and 96
measure: Change in CD8+ T-cell Count
timeFrame: Measured at Baseline and Weeks 24, 48, and 96
measure: Change in Log10 sCD14 in Plasma at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
measure: Change in Log10 MIP-1 Beta in Plasma at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
measure: Change in Log10 sTNFr-II in Plasma at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
measure: Change in Log10 VCAM in Plasma at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
measure: Change in Log10 MIP-1 Beta in Cerebrospinal Fluid (CSF) at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
measure: Change in Log10 IP-10 in CSF at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
measure: Change in Log10 Neopterin in CSF at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
measure: Change in Log10 NFL in CSF at Week 48 From Baseline
timeFrame: Measured at Baseline and Week 48
Other outcomes:
measure: Changes in Cell-associated HIV-1 RNA/DNA/2-long Terminal Repeat Sequences (LTR) Circles and Single Copy Assay (SCA)
timeFrame: Measured at Baseline and Week 48
measure: Changes in T Cell and Monocyte Activation
timeFrame: Measured at Baseline and Week 48
measure: Changes in Residual Viremia
timeFrame: Measured at Baseline and Week 48
Locations:
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: Torrance
country: United States
facility: Harbor-UCLA CRS
state: California
city: Washington
country: United States
facility: Whitman-Walker Health CRS
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Cleveland
country: United States
facility: Case Clinical Research Site
state: Ohio
city: Columbus
country: United States
facility: Ohio State University CRS
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital Clinical Research Site (TMH CRS) CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Dallas
country: United States
facility: Trinity Health and Wellness Center CRS
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Rio De Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
city: Johannesburg
country: South Africa
facility: Wits Helen Joseph Hospital CRS (Wits HJH CRS)
state: Gauteng
city: Durban
country: South Africa
facility: Durban International Clinical Research Site CRS
state: Kwa Zulu Natal
city: Tygerberg
country: South Africa
facility: Famcru Crs
state: Western Cape Province
city: Bangkok
country: Thailand
facility: Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
Study officials:
affiliation: University of North Carolina
name: Kevin Robertson, PhD
role: STUDY_CHAIR
References: