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Using Less Neurotoxic Drugs in Patients With HAND (MARAND-X) ((MARAND-X))

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03163277
Recruitment Status : Terminated (Sloww accrual and COVID-19 related problems (impossible to perform LPs))
First Posted : May 23, 2017
Last Update Posted : November 6, 2020
Sponsor:
Information provided by (Responsible Party):
Giovanni Di Perri, University of Turin, Italy

Brief Summary:

Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND).

Among other hypothesis neurotoxicity of antiretrovirals has been postulated but its impact is unknown.

Our hypothesis is that using drugs with reduced in vitro neurotoxicity may improve cognition in HIV-positive patients withHAND.

76 patients with HAND will be randomized to either continue their treatment or switch to emtricitabine, darunavir/cobicistat, maraviroc. Patients will be re-tested 6 months later.


Condition or disease Intervention/treatment Phase
Hiv Neurocognitive Dysfunction Drug: emtricitabine, darunavir/cobicistat, maraviroc Phase 4

Detailed Description:

Scientific Rationale for Study / Scientific Study Objectives:

Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND). It should be highlighted that patients presenting no abnormalities in everyday living activities (asymptomatic neurocognitive disorders, ANI) are at higher risk of worse results in performance-based tests, adherence-based measures and they show a significant risk of progressing to more severe forms of impairment. Excluding significantly confounding comorbidities, several factors have been associated with this neurocognitive decline including a low nadir CD4+ T-lymphocyte count, a high HIV DNA, a lower compartmental viral control, a lower concentration/penetration effectiveness score, a lower efficacy in macrophage-derived cells and antiretroviral-generated neuronal toxicity. However several data point out that vascular abnormalities, very common in HIV-positive patients, may deeply influence neurocognitive disorders development and severity: of note, intima media thickness, a well recognized proxy of systemic atherosclerosis, was associated with HAND.

In case of HAND diagnosis, the only recommended approach is to optimize treatment according to plasma and cerebrospinal fluid (CSF) resistance tests; no strategy is currently suggested in case of suppressed plasma and CSF HIV RNA or in case of low level CSF HIV RNA (without evidence of genotypic resistance). It has been postulated that antiretrovirals may have neurotoxic effects through different mechanisms and such effects might become evident once the beneficial effect of HIV RNA suppression vanishes. Available data suggest that, in vitro, the drugs associated with the least neurotoxic effect were emtricitabine, tenofovir, darunavir and maraviroc. Furthermore, several pieces of evidence and a small randomized trial suggest that maraviroc, in HAART-treated subjects may have beneficial effects in terms of improved neurocognitive function, reduced CSF inflammatory biomarkers and improved MRI markers of neuronal integrity.

No study has so far investigated the effect of using drugs with a low neurotoxic profile in HAART-treated patients with HAND.

Primary objective of the study is the variation in neurocognitive tests (global deficit score), 6 months after treatment switch while secondary objectives include the improvement in other biomarkers of neuronal and vascular integrity.

Methods:

Study Design: Randomized, controlled, pilot study. HIV-positive patients that fulfill the inclusion criteria and that sign the informed consent will be enrolled. Patients will be randomized 1:1 (block randomization) to either continue their treatment or to switch to once-daily emtricitabine (200 mg) plus darunavir/cobicistat (800/150 mg) plus maraviroc (300 mg). A lumbar puncture will be performed 6 months after treatment switch.

Number of Patients: 76 (38 per arm)

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MARaviroc-based Treatment Switch in HIV-positive Patients With HAND: Consequences of Reducing Antiretroviral-associated Neurotoxicity
Actual Study Start Date : May 15, 2017
Actual Primary Completion Date : June 30, 2020
Actual Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
No Intervention: Standard of care
Continue current antiretroviral regimen
Experimental: Reduced Neurotoxicity Arm
Emtricitabine plus darunavir/cobicistat plus maraviroc
Drug: emtricitabine, darunavir/cobicistat, maraviroc
Treatment change




Primary Outcome Measures :
  1. 6-month variation in global deficit score in NPZ-8 complete neurocognitive tests according to the study arm; [ Time Frame: 6 months ]
    Global deficit score


Secondary Outcome Measures :
  1. rs-fMRI [ Time Frame: 6 months ]
    spectroscopic and perfusion markers at MRI as well as the variations in brain connectivity at resting state functional MRI;

  2. EEG-LORETA [ Time Frame: 6 months ]
    electroencephalographic waves using the LORETA software;

  3. CSF HIV RNA [ Time Frame: 6 months ]
    changes in CSF HIV RNA in the two arms

  4. CSF markers [ Time Frame: 6 months ]
    Variation in CSF markers of inflammation or neuronal damage

  5. Blood Brain Barrier Integrity [ Time Frame: 6 months ]
    Variation in CSAR in the two arms

  6. IMT [ Time Frame: 6 months ]
    Variation in carotid intima media thickness in the two arms

  7. TMAO [ Time Frame: 6 months ]
    Variation in trimethylamine-N-oxide in the two arms



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age above >18 years;
  • Confirmed HIV-positivity;
  • Diagnosed with HAND according to the Frascati Criteria;
  • On combination antiretroviral treatment;
  • No evidence of major resistance associated mutations on previous plasma or CSF samples;
  • Plasma HIV RNA <50 copies/mL;
  • CSF HIV RNA <50 copies/mL;
  • R5-tropic virus as detected by a genotype or phenotype based test before starting HAART or genotype-based test performed on HIV DNA in the previous 12 months;

Exclusion Criteria:

  • the use of drugs having major drug-to-drug interaction with maraviroc (for instance rifampicin);
  • the use of efavirenz- or darunavir-containing regimens at baseline;
  • confounding comorbidities that may influence or affect the diagnosis of HAND including developmental disability, history of traumatic brain injury or of cerebrovascular accident;
  • a previous diagnosis of central nervous system opportunistic, autoimmune, neurodegenerative or neoplastic disease;
  • severe untreated depression;
  • active alcohol or recreational substance abuse (in the previous 3 months);
  • not fluent in Italian or unable to complete the neurocognitive tests.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03163277


Locations
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Italy
University of Torino
Torino, Italy
Sponsors and Collaborators
Giovanni Di Perri
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Responsible Party: Giovanni Di Perri, Full Professore of Infectious Diseases, University of Turin, Italy
ClinicalTrials.gov Identifier: NCT03163277    
Other Study ID Numbers: MARAND-X
First Posted: May 23, 2017    Key Record Dates
Last Update Posted: November 6, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cognitive Dysfunction
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Emtricitabine
Maraviroc
Darunavir
Cobicistat
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
HIV Fusion Inhibitors
Viral Fusion Protein Inhibitors
CCR5 Receptor Antagonists
HIV Protease Inhibitors
Protease Inhibitors
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors