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

HIV Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01978743
• Other study ID #: NeuroHIV002
• Status: Active, not recruiting
• Phase: Phase 3
• First received: October 20, 2013
• Last updated: April 20, 2016
• Start date: January 2014
• Est. completion date: June 2016

Study information

• Verified date: April 2016
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 10
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV
• HIV-associated Neurocognitive Disorder
• Neurotoxicity
• Neurotoxicity Syndromes

Intervention

Drug:
• switch efavirenz (EFV) to raltegravir (RAL)

Locations

Country	Name	City	State
United States	Brigham and Women's hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neurometabolites based on MRS	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.	8 weeks	No
Primary	Neural activation networks using fMRI	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.	8 weeks	No
Secondary	Other neurometabolite changes measured by MRS	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.	8 weeks	No
Secondary	Neurocognitive changes	Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen.	8 weeks	No
Secondary	Fasting lipid profile	Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.	8 weeks	Yes
Secondary	Sleep quality	Assess for changes in sleep pattern and quality prior to and after switching off EFV-based regimen through self-administered questionnaires.	8 weeks	No
Secondary	ART regimen preference	Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires.	8 weeks	No
Secondary	Markers of immune activation	Change in markers of immune activation and inflammation associated with change to RAL (ie, sCD14, IL-6, hsCRP, D-dimer, CRP, LPS, sCD163, EndoCab)	8 weeks	No
Secondary	Change in level of EFV and metabolites	Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes	8 weeks	Yes