Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified October 2013 by Massachusetts General Hospital
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Nina Lin, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01978743
First received: October 20, 2013
Last updated: October 31, 2013
Last verified: October 2013
  Purpose

In this study investigators will use a multi-modal imaging approach of MRS and fMRI to comprehensively assess the biological changes in the brain associated with EFV-based regimen (EFV/FTC/TDF), specifically alterations in the brain circuitry, function and local neurochemistry, and their correlation with neuropsychological function. In a cohort of HIV-infected patients who are clinically stable on the commonly use regimen of EFV/emtricitabine (FTC)/truvada (TDF) or Atripla, investigators propose to replace the EFV component with an integrase inhibitor, Raltegravir (RAL), given as the RAL and FTC/TDF to evaluate the EFV-related neural alterations. This is a multidisciplinary study which will be lead by Dr. Nina Lin, in collaboration with the research teams of Dr. Alexander Lin, Director of the Center for Clinical Spectroscopy, and Dr. Emily Stern, Director of the Functional Neuroimaging Laboratory, both members of the Brigham and Women's Department of Radiology at Harvard Medical School, as well as Dr. Jane Epstein, a researcher in Dr. Stern's research group. Dr. Epstein is a staff psychiatrist at Brigham and Women's hospital with extensive experience and expertise in research on abnormalities of affective and motivational processing in the context of neuropsychiatric disorders. Investigators will utilize the established clinical research platform in the Infectious Disease outpatient clinical practice at the Brigham and Women's Hospital, where there is currently have many ongoing HIV-related studies and a large panel of HIV-infected patients motivated to be involved in clinically relevant research. Investigators propose to use advanced neuroimaging to measure biologically changes in the brain associated with long-term EFV use with the following specific aims:

  1. Determine changes in neurometabolites measured by MRS in the brain associated with long-term EFV use
  2. Assess for alterations in neural activity correlated with affective symptoms associated with EFV vs RAL use using fMRI, and their associations with changes in neurometabolites assessed by MRS, and with changes in cognition assessed by Trail Making and Digit Substitution Tests.
  3. Determine changes in emotion, cognition and sleep quality after switching from EFV to RAL, and how they correlate with subject treatment preference.

This clinical study will extend our current understanding of EFV neurotoxicity by further defining the nature of these biological changes. Further elucidation of the neurobiological underpinnings of EFV-induced CNS toxicity will have clinical relevance in improving the quality of life and drug adherence of HIV-infected patients on ART, especially among older patients or those with baseline neuropsychiatric disorders, whom at baseline are more vulnerable to neurocognitive decline from long-term HIV infection.


Condition Intervention Phase
HIV
HIV-associated Neurocognitive Disorder
Neurotoxicity
Drug: switch efavirenz (EFV) to raltegravir (RAL)
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Neurometabolites based on MRS [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess the changes in levels of neuro-metabolites measured by MRS while on the EFV-based therapy and then post-switch to a RAL-based regimen. Two areas of the brain; 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for change in levels of brain Cr, GABA and GLU between week 0 and 8 of switch to RAL-based regimen.

  • Neural activation networks using fMRI [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess changes in neural activation correlated with affective disturbances associated with EFV vs RAL using fMRI employing a paradigm that probes affective symptomatologies typical with EFV use, specifically anxiety/dysphoria and affective dysregulation, and their association with changes in cognitive function.


Secondary Outcome Measures:
  • Other neurometabolite changes measured by MRS [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Use MRS to evaluate a fuller panel of known neurometabolites (in addition to the primary endpoints) to evaluate for prominent and significant changes associated with EFV use.

  • Neurocognitive changes [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen.

  • Fasting lipid profile [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.

  • Sleep quality [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess for changes in sleep pattern and quality prior to and after switching off EFV-based regimen through self-administered questionnaires.

  • ART regimen preference [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires.

  • Markers of immune activation [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Change in markers of immune activation and inflammation associated with change to RAL (ie, sCD14, IL-6, hsCRP, D-dimer, CRP, LPS, sCD163, EndoCab)

  • Change in level of EFV and metabolites [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes


Estimated Enrollment: 10
Study Start Date: January 2014
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: raltegravir
Switch from Atripla (EFV/FTC/TDF) to raltegravir (RAL) + truvada (FTC/TDF). Raltegravir will be administered 400mg twice-a-day.
Drug: switch efavirenz (EFV) to raltegravir (RAL)
Other Name: raltegravir (Isentress) 400mg BID

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Chronic HIV-infected individuals on suppressive regimen with EFV/FTC/TDF, for at least 6 months
  2. Undetectable HIV-1 RNA virus load for at least 6 months
  3. No co-infections with active hepatitis B and C
  4. Presence of at least moderate symptoms on 2 out of 3 subcores on the DASS
  5. No known active HIV-related and non-HIV related CNS infections
  6. Estimated glomerular filtration rate (EGFR) >60 ml/min
  7. Consent to switching to EVG/COBI/FTC/TDF
  8. Ages 18 - 75

Exclusion Criteria:

  1. History of CNS opportunistic infections or active CNS infections
  2. History of severe psychiatric disorder (excluding depression and anxiety)
  3. History of chronic neurological disorders, such as epilepsy or multiple sclerosis
  4. History of or current significant substance abuse or dependence and/or heavy alcohol use (>12 oz/wk)
  5. Any women who may be pregnant (positive urine pregnancy test or unprotected sex in 2 weeks prior to scan) or known to be pregnant
  6. Contraindications to undergoing fMRI, including metallic implants, claustrophobia, and medical conditions or medications that significantly affect cerebral blood flow or function.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01978743

Contacts
Contact: Nina Lin, MD 617-768-8479 nhlin@partners.org
Contact: Daniel Kuritzkes, MD dkuritzkes@partners.org

Locations
United States, Massachusetts
Brigham and Women's hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Sub-Investigator: Emily Stern, MD         
Sub-Investigator: Alexander Lin, PhD         
Sub-Investigator: Jane Epstein, MD         
Sub-Investigator: Daniel Kuritzkes, MD         
Sponsors and Collaborators
Massachusetts General Hospital
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Nina Lin, MD Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Nina Lin, MD, Instructor in Medicine, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01978743     History of Changes
Other Study ID Numbers: NeuroHIV002
Study First Received: October 20, 2013
Last Updated: October 31, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:
HIV
HIV-associated neurocognitive disorder
neurotoxicity

Additional relevant MeSH terms:
Neurotoxicity Syndromes
Chemically-Induced Disorders
Nervous System Diseases
Poisoning
Efavirenz
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014