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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Raltegravir | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Raltegravir | Drug | Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS) | 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). | week 0 and week 8 |
| Neural Activation Networks Using Functional Magnetic Resonance Imaging (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; 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. | week 0 and week 8 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | week 0 and week 8 |
| Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nina Lin, MD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's hospital | Boston | Massachusetts | 02115 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Raltegravir | All participants are switched from Atripla (EFV/FTC/TDF) to raltegravir (RAL) + truvada (FTC/TDF). Raltegravir will be administered 400mg twice-a-day. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Raltegravir | All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS) | 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). | The arbitrary units are expressed as the output from MRS software. While similar to concentration (mM) due to assumptions in the software, it is best expressed as arbitrary units for comparison from week 0 to week 8. | Posted | Mean | Standard Deviation | arbitrary units | week 0 and week 8 |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Raltegravir | All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Nina Lin | Boston University School of Medicine | 617-414-5242 | nina.lin@bmc.org |
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| ID | Term |
|---|---|
| D020258 | Neurotoxicity Syndromes |
| ID | Term |
|---|---|
| D009422 | Nervous System Diseases |
| D011041 | Poisoning |
| D064419 | Chemically-Induced Disorders |
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| ID | Term |
|---|---|
| D000068898 | Raltegravir Potassium |
| C494814 | BID protein, human |
| ID | Term |
|---|---|
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen. Indexes used to access neurocognitive changes included:
|
| week 0 and week 8 |
| Fasting Lipid Profile | Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen. | week 0 and week 8 |
| Sleep Quality | 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. | week 0 and week 8 |
| ART Regimen Preference | Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires. | week 0 and week 8 |
| 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) | week 0 and week 8 |
| Change in Level of EFV and Metabolites | Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes | week 0 and week 8 |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Primary | Neural Activation Networks Using Functional Magnetic Resonance Imaging (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; 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. | 8 of 10 enrolled patients passed QA testing to qualify for final fMRI data analyses. The 3 linear contrasts of Pre-switch/Post-switch/Pre- vs. Post-switch: [Neg vs.Neu] x [No-Go vs. Go] are reported as z-score (standardized effect size measures with SD=1). Z-score is obtained for each subject, group Z-score is obtained via a mixed-effects model. | Posted | Number | z-score | week 0 and week 8 |
|
|
|
| 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. | The arbitrary units are expressed as the output from MRS software. While similar to concentration (mM) due to assumptions in the software, it is best expressed as arbitrary units for comparison from week 0 to week 8. | Posted | Mean | Standard Deviation | arbitrary units | week 0 and week 8 |
|
|
|
| Secondary | Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI | Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen. Indexes used to access neurocognitive changes included:
| Posted | Mean | Standard Deviation | units on a scale | week 0 and week 8 |
|
|
|
| Secondary | Fasting Lipid Profile | Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen. | Change in lipid panel pre- and post-switch to RAL-based regimen | Posted | Mean | Standard Deviation | mg/dL | week 0 and week 8 |
|
|
|
| Secondary | Sleep Quality | 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. | Posted | Mean | Standard Deviation | units on a scale | week 0 and week 8 |
|
|
|
| Secondary | ART Regimen Preference | Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires. | Each participant was asked a single self-administered question on their ART preference and asked to chose one of the 3 answers; 1. prefer to take Atripla, 2. prefer RAL-based regimen (that they received in study) or 3. no preference. | Posted | Number | participants | week 0 and week 8 |
|
|
|
| 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) | Posted | Mean | Standard Deviation | pg/ml | week 0 and week 8 |
|
|
|
| Secondary | Change in Level of EFV and Metabolites | Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes | Level of EFV (efavirenz) in Atripla and its two known metabolites known to cause cerebral side effects, 7-hydroxy (OH) EFV and 8-OH EFV, were measured in the plasma prior to switch off Atripla and after 8 weeks of RAL-based regimen (no EFV). | Posted | Number | participants | week 0 and week 8 |
|
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|
| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
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| Title | Measurements |
|---|---|
|
| PreVsPostXNegVsNeuXNoGoVsGo:LHC |
|
| Pre: NegVsNeuXNoGoVsGo: aFP |
|
| Pre: NegVsNeuXNoGoVsGo:pCG |
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| Pre: NegVsNeuXNoGoVsGo: daCG |
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| Pre: NegVsNeuXNoGoVsGo: LHC |
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| Post: NegVsNeuXNoGoVsGo: aFP |
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| Post: NegVsNeuXNoGoVsGo: pCG |
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| Post: NegVsNeuXNoGoVsGo: daCG |
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| Post: NegVsNeuXNoGoVsGo: LHC |
|
|
| Post-switch Posterior Cingulate Aspartate |
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| Pre-switch Anterior Cingulate Glutathione |
|
| Post-switch Anterior Cingulate Glutathione |
|
| Pre-switch Anterior Cingulate Aspartate |
|
| Post-switch Anterior Cingulate Aspartate |
|
| Title | Measurements |
|---|---|
|
| post-switch FRSBE |
|
| pre-switch HAMD |
|
| post-switch HAMD |
|
| pre-switch DASS depression |
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| post-switch DASS depression |
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| pre-switch STAI |
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| post-switch STAI |
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|
| post-switch HDL |
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| pre-switch LDL |
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| post-switch LDL |
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| pre-switch triglyceride |
|
| post-switch triglyceride |
|
| Title | Measurements |
|---|---|
|
|
| post-switch IP-10 |
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| pre-switch sCD163 |
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| post-switch sCD163 |
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| pre-switch MCP-1 |
|
| post-switch MCP-1 |
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| pre-switch IL-6 |
|
| post-switch IL-6 |
|
| pre-switch TNFR1 |
|
| post-switch TNFR1 |
|