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Advanced Neuroimaging Evaluation of CNS Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Nina Lin, MD, Boston University
ClinicalTrials.gov Identifier:
NCT01978743
First received: October 20, 2013
Last updated: July 18, 2017
Last verified: July 2017
October 20, 2013
July 18, 2017
January 2014
September 2016   (Final data collection date for primary outcome measure)
  • Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS) [ Time Frame: week 0 and week 8 ]
    Assess the levels of neuro-metabolites measured by MRS at week 0 before switching to the efavirenz-based therapy. Two areas of the brain: 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for the levels of brain creatine (Cr), gamma-aminobutyric acid (GABA) and glutathione (GLU).
  • Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI) [ Time Frame: week 0 and week 8 ]
    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; anxiety/dysphoria and affective dysregulation, and their association with changes in cognitive function. Four brain regions of interests (ROIs) are specified to show the differential frontal-limbic activation patterns in the task-evoked neural responses to the 3 linear contrasts of Pre-/Post-/ Pre-vs. Post-switch: [Negative Word vs. Neutral Word] x [No-Go Trial Block vs. Go Trial Block]: anterior Frontal Pole (aFP), posterior Cingulate Gyrus (pCG), dorsal anterior Cingulate Gyrus (daCG), Left Hippocampus (LHC). A linear mixed-effects model is utilized to examine the effect sizes of the key Regimen/Condition contrasts, with the Subject factor as the random-effect, and Age incorporated as a co-variate of no interest. A z-score is the Mean with a SD=1 and Measure of Dispersion equal to 1.
  • Neurometabolites based on MRS [ Time Frame: 8 weeks ]
    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 ]
    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.
Complete list of historical versions of study NCT01978743 on ClinicalTrials.gov Archive Site
  • Other Neurometabolite Changes Measured by MRS [ Time Frame: week 0 and week 8 ]
    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 Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI [ Time Frame: week 0 and week 8 ]

    Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen. Indexes used to access neurocognitive changes included:

    1. Wechsler Adult Intelligence Scale (WAIS-R) Digital Symbol Substitution Test: sensitive to brain dmamage, dementia, age and depressive changes. Range of 0-100, the higher the score the better the person's performance
    2. Hamilton Rating Scale for Depression (HAMD): Measure of depression. Score of 0-7 is normal, score of >20 is moderate/severe depression
    3. Depression Anxiety Stress Scale (DASS-21) the lower the score, the less severe depression, anxiety and stress. Scale range of 0-63
    4. Frontal Systems Behavior Scale (FRSBE): Increased score indicates greater behavioral impairment associated with frontal systems, range 37.2 to 186
    5. Spielberger state trait anxiety inventory (STAI): the higher the score the greater then anxiety level, range of 20 to 80.
  • Fasting Lipid Profile [ Time Frame: week 0 and week 8 ]
    Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.
  • Sleep Quality [ Time Frame: week 0 and week 8 ]
    Assess for changes in sleep pattern and quality prior to and after switching off EFV-based regimen through a self-administered Pittsburg Sleep Quality Index (PSQI). Measure consists of 19 items with each weighted on 0-3 scale and the sum produces a total score, which ranges from 0-21. The lower the score the healthier the sleep quality.
  • ART Regimen Preference [ Time Frame: week 0 and week 8 ]
    Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires.
  • Markers of Immune Activation [ Time Frame: week 0 and week 8 ]
    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: week 0 and week 8 ]
    Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes
  • Other Neurometabolite Changes Measured by MRS [ Time Frame: 8 weeks ]
    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 ]
    Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen.
  • Fasting Lipid Profile [ Time Frame: 8 weeks ]
    Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.
  • Sleep Quality [ Time Frame: 8 weeks ]
    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 ]
    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 ]
    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 ]
    Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes
Not Provided
Not Provided
 
Advanced Neuroimaging Evaluation of CNS Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen
Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen
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.

Interventional
Not Provided
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
  • HIV
  • HIV-associated Neurocognitive Disorder
  • Neurotoxicity
Drug: Raltegravir
Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
Other Name: Raltegravir (Isentress) 400mg BID
Experimental: Raltegravir
Switch from Atripla (EFV/FTC/TDF) to raltegravir (RAL) + Truvada (FTC/TDF). Raltegravir will be administered 400mg twice-a-day with Truvada for 8 weeks.
Intervention: Drug: Raltegravir
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
10
January 2017
September 2016   (Final data collection date for primary outcome measure)

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 - 65

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.
Sexes Eligible for Study: All
18 Years to 65 Years   (Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01978743
NeuroHIV002
No
Not Provided
Not Provided
Nina Lin, MD, Boston University
Massachusetts General Hospital
Merck Sharp & Dohme Corp.
Principal Investigator: Nina Lin, MD Massachusetts General Hospital
Massachusetts General Hospital
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP