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| Name | Class |
|---|---|
| Brigham and Women's Hospital | OTHER |
| Gilead Sciences | INDUSTRY |
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In this study we 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, we propose to replace the EFV component with a new integrase inhibitor, elvitegravir (EVG) boosted with cobicistat (COBI), given as the EVG/COBI/FTC/TDF Single Tablet Regimen (STR) to evaluate the EFV-related neural alterations. This is a multidisciplinary study which involves a team of infectious disease experts in the field of HIV, neuroradiologists with expertise in fMRI and MRS techniques to study various central nervous system and psychiatric disorders and a psychiatrist with experience and expertise in research on abnormalities of affective and motivational processing in the context of neuropsychiatric disorders. We 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. We 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 |
|---|---|---|---|
| Drug switching | Other | Single-arm with switch from baseline antiretroviral therapy with Atripla to Stribild for total of 8 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir) | Drug | Switch from Atripla (efavirenz, emtricitabine and tenofovir) to Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)for total of 8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS) | Assess the change in levels of neuro-metabolites measured by MRS from week 0 (before switching to the efavirenz-based therapy) and then at week 8 (after completing 9 weeks of integrase-inhibitor based regimen with Stribild). Two areas of the brain: 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for the levels of brain Cr, GABA and GLU. | week 0 to week 8 |
| Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI) | Assess changes in neural activation correlated with affective disturbances associated with efavirenz-based therapy using fMRI employing an Emotional Word/Go-NoGo task paradigm that probes affective symptomatologies typical with EFV use, specifically 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-switch / Post-switch / 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. | week 0 and week 8 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8 | Use MRS to evaluate a fuller panel of known neurometabolites (in addition to the primary endpoints) between week 0 and week 8 to identify prominent and significant changes associated with EFV use. | week 0 to week 8 |
| Neurocognitive Changes |
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Inclusion Criteria:
Exclusion Criteria:
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| 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 | Drug Switching | Single-arm with switch from baseline antiretroviral therapy with Atripla to Stribild for total of 8 weeks. Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir): Switch from Atripla (efavirenz, emtricitabine and tenofovir) to Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)for total of 8 weeks |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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Treatment switch study
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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:
6. Spielberger state trait anxiety inventory (STAI): the higher the score the greater then anxiety level, range of 20 to 80. |
| week 0 and week 8 |
| Fasting Lipid Profile | Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen. | 8 weeks |
| 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; minimum Score = 0 (better); maximum Score = 21 (worse). | week 0 and week 8 |
| ART Regimen Preference | Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus EVG/COBI/FTC/TDF) through a self-administered questionnaire. | week 0 and week 8 |
| Markers of Immune Activation | Change in markers of immune activation and inflammation associated with change to Stibild: sCD14, IP-10,sCD163, IL-6) | week 0 and week 8 |
| Effect of EFV and Its Metabolites | 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). | week 0 and week 8 |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Drug Switching | Single-arm with switch from baseline antiretroviral therapy with Atripla to Stribild for total of 8 weeks. Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir): Switch from Atripla (efavirenz, emtricitabine and tenofovir) to Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)for total of 8 weeks |
| 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 | Participants | No |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
| ||||||||||||||||||||||
| Baseline measures for Neurometabolites Based on MRS | 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 baseline to the second time point. | Mean | Standard Deviation | arbitrary units |
|
| 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 | Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS) | Assess the change in levels of neuro-metabolites measured by MRS from week 0 (before switching to the efavirenz-based therapy) and then at week 8 (after completing 9 weeks of integrase-inhibitor based regimen with Stribild). Two areas of the brain: 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for the levels of brain Cr, GABA and 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 to week 8 |
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| Primary | Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI) | Assess changes in neural activation correlated with affective disturbances associated with efavirenz-based therapy using fMRI employing an Emotional Word/Go-NoGo task paradigm that probes affective symptomatologies typical with EFV use, specifically 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-switch / Post-switch / 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. | 8 of 10 enrolled patients passed QA testing to be included in the final 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 | Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8 | Use MRS to evaluate a fuller panel of known neurometabolites (in addition to the primary endpoints) between week 0 and week 8 to identify 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 to week 8 |
|
| ||||||||||||||||||||||||||||||||||||
| Secondary | Neurocognitive Changes | Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen. Indexes used to access neurocognitive changes included:
6. Spielberger state trait anxiety inventory (STAI): the higher the score the greater then anxiety level, range of 20 to 80. | Several Indexes were used to access neurocognitive changes: WAIS, HAMD, FRSBE, DASS-21, STAI. Participants were given these tests prior to and after drug switch. | Posted | Mean | Standard Deviation | units on a scale | week 0 and week 8 |
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| Secondary | Fasting Lipid Profile | Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen. | Change in fasting lipid profile was measured: total cholesterol, HDL and LDL levels. | Posted | Mean | Standard Deviation | mg/dl | 8 weeks |
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| 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; minimum Score = 0 (better); maximum Score = 21 (worse). | Posted | Mean | Standard Deviation | units on a scale | week 0 and week 8 |
|
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| Secondary | ART Regimen Preference | Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus EVG/COBI/FTC/TDF) through a self-administered questionnaire. | Patients were surveyed at the end of the study with a single question regarding their ART preference. They are asked to pick one of the 3 answers: 1. prefer Atripla, 2. prefer the new drug (Stribild) or 3. no preference. The number of patients who would like to switch to study drug, Stribild, are indicated by the percentage. | Posted | Count of Participants | Participants | week 0 and week 8 |
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| Secondary | Markers of Immune Activation | Change in markers of immune activation and inflammation associated with change to Stibild: sCD14, IP-10,sCD163, IL-6) | Inflammatory markers were measured pre- and post-drug switch from Atripla to Stibild. | Posted | Mean | Standard Deviation | pg/ML | week 0 and week 8 |
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| Secondary | Effect of EFV and Its Metabolites | 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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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Drug Switching | Single-arm with switch from baseline antiretroviral therapy with Atripla to Stribild for total of 8 weeks. Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir): Switch from Atripla (efavirenz, emtricitabine and tenofovir) to Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)for total of 8 weeks | 0 | 10 | 0 | 10 | 0 | 10 |
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One participant did not have repeat fMRI because the pre-switch fMRI was not done correctly. The patient did not fully understand the tasks to be performed, therefore no repeat follow up fMRI was done without the comparator study.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Nina Lin | Boston Medical Center, Boston University School of Medicine | 617-414-5242 | nina.lin@bmc.org |
| ID | Term |
|---|---|
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012897 | Slow Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D000069545 | Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination |
| C509700 | elvitegravir |
| D000069547 | Cobicistat |
| D000068679 | Emtricitabine |
| D000068698 | Tenofovir |
| ID | Term |
|---|---|
| D002219 | Carbamates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D000225 | Adenine |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
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|
| Posterior cingulate GABA |
|
| Anterior cingulate creatine |
|
| Anterior cingulate glutamate |
|
| Anterior cingulate GABA |
|
| Title | Measurements |
|---|---|
|
| Anterior Cingulate Creatine |
|
| Anterior Cingulate Glutamate |
|
| Anterior Cingulate GABA |
|
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| Units | Counts |
|---|---|
| Participants |
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