Trial Outcomes & Findings for Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy and Switch to an Elvitegravir-based Regimen (NCT NCT01929759)
NCT ID: NCT01929759
Last Updated: 2017-07-28
Results Overview
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.
COMPLETED
NA
10 participants
week 0 to week 8
2017-07-28
Participant Flow
Participant milestones
| Measure |
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
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|---|---|
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Overall Study
STARTED
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10
|
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Overall Study
COMPLETED
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10
|
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Overall Study
NOT COMPLETED
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0
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy and Switch to an Elvitegravir-based Regimen
Baseline characteristics by cohort
| Measure |
Drug Switching
n=10 Participants
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
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|---|---|
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Age, Categorical
<=18 years
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0 Participants
n=5 Participants
|
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Age, Categorical
Between 18 and 65 years
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10 Participants
n=5 Participants
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Age, Categorical
>=65 years
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0 Participants
n=5 Participants
|
|
Sex: Female, Male
Female
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1 Participants
n=5 Participants
|
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Sex: Female, Male
Male
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9 Participants
n=5 Participants
|
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Region of Enrollment
United States
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10 participants
n=5 Participants
|
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Baseline measures for Neurometabolites Based on MRS
Posterior cingulate creatine
|
19.09 arbitrary units
STANDARD_DEVIATION 2.27 • n=5 Participants
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Baseline measures for Neurometabolites Based on MRS
Posterior cingulate glutamate
|
25.36 arbitrary units
STANDARD_DEVIATION 3.73 • n=5 Participants
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Baseline measures for Neurometabolites Based on MRS
Posterior cingulate GABA
|
4.99 arbitrary units
STANDARD_DEVIATION 1.29 • n=5 Participants
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Baseline measures for Neurometabolites Based on MRS
Anterior cingulate creatine
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14.06 arbitrary units
STANDARD_DEVIATION 2.44 • n=5 Participants
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Baseline measures for Neurometabolites Based on MRS
Anterior cingulate glutamate
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19.16 arbitrary units
STANDARD_DEVIATION 3.11 • n=5 Participants
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Baseline measures for Neurometabolites Based on MRS
Anterior cingulate GABA
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4.21 arbitrary units
STANDARD_DEVIATION 1.18 • n=5 Participants
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PRIMARY outcome
Timeframe: week 0 to week 8Population: 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.
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.
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
|
|---|---|
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Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Posterior Cingulate Creatine
|
19.61 arbitrary units
Standard Deviation 3.44
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Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Posterior Cingulate Glutamate
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24.54 arbitrary units
Standard Deviation 3.69
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Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Posterior Cingulate GABA
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6.71 arbitrary units
Standard Deviation 1.07
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Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Anterior Cingulate Creatine
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12.08 arbitrary units
Standard Deviation 4.63
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Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Anterior Cingulate Glutamate
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16.16 arbitrary units
Standard Deviation 6.00
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Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Anterior Cingulate GABA
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3.67 arbitrary units
Standard Deviation 1.52
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PRIMARY outcome
Timeframe: week 0 and week 8Population: 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.
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.
Outcome measures
| Measure |
Drug Switching
n=8 Participants
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
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|---|---|
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo: aFP
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3.42 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo: pCG
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3.90 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo: daCG
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-2.76 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo:LHC
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-2.96 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo: aFP
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3.39 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo:pCG
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3.61 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo: daCG
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-3.15 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo: LHC
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-2.27 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: aFP
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-3.17 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: pCG
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-2.66 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: daCG
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3.69 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: LHC
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3.47 z-score
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SECONDARY outcome
Timeframe: week 0 to week 8Population: 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.
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.
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
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|---|---|
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Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8
Posterior cingulate glutathione
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5.06 arbitrary units
Standard Deviation 1.17
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Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8
Posterior cingulate aspartate
|
3.69 arbitrary units
Standard Deviation 0.98
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Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8
Anterior cingulate glutathione
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3.17 arbitrary units
Standard Deviation 1.34
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Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8
Anterior cingulate aspartate
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2.57 arbitrary units
Standard Deviation 1.29
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SECONDARY outcome
Timeframe: week 0 and week 8Population: 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.
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 damage, 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 6\. Spielberger state trait anxiety inventory (STAI): the higher the score the greater then anxiety level, range of 20 to 80.
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
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|---|---|
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Neurocognitive Changes
pre-switch WAIS
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49.3 units on a scale
Standard Deviation 11.62
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Neurocognitive Changes
post-switch WAIS
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53.4 units on a scale
Standard Deviation 12.60
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Neurocognitive Changes
pre-switch FRSBE
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77.5 units on a scale
Standard Deviation 10.01
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Neurocognitive Changes
post-switch FRSBE
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70.4 units on a scale
Standard Deviation 13.00
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Neurocognitive Changes
pre-switch HAMD
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5.5 units on a scale
Standard Deviation 3.41
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Neurocognitive Changes
post-switch HAMD
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2.8 units on a scale
Standard Deviation 2.20
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Neurocognitive Changes
pre-switch DASS depression
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7.6 units on a scale
Standard Deviation 8.58
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Neurocognitive Changes
post-switch DASS depression
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3.4 units on a scale
Standard Deviation 4.72
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Neurocognitive Changes
pre-swtich STAI
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28.8 units on a scale
Standard Deviation 5.87
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Neurocognitive Changes
post-switch STAI
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24.2 units on a scale
Standard Deviation 3.19
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SECONDARY outcome
Timeframe: 8 weeksPopulation: Change in fasting lipid profile was measured: total cholesterol, HDL and LDL levels.
Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
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|---|---|
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Fasting Lipid Profile
pre-switch Total cholesterol
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178.8 mg/dl
Standard Deviation 24.24
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Fasting Lipid Profile
post-switch Total cholesterol
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168.5 mg/dl
Standard Deviation 20.84
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Fasting Lipid Profile
pre-switch HDL
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52.6 mg/dl
Standard Deviation 16.49
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Fasting Lipid Profile
post-switch HDL
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52.3 mg/dl
Standard Deviation 19.42
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Fasting Lipid Profile
pre-switch LDL
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106.1 mg/dl
Standard Deviation 22.96
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Fasting Lipid Profile
post-switch LDL
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97.4 mg/dl
Standard Deviation 19.36
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Fasting Lipid Profile
pre-switch triglyceride
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101.3 mg/dl
Standard Deviation 50.39
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Fasting Lipid Profile
post-switch triglyceride
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94.5 mg/dl
Standard Deviation 30.50
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SECONDARY outcome
Timeframe: week 0 and week 8Assess 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).
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
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|---|---|
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Sleep Quality
pre-switch PSQI index
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4.8 units on a scale
Standard Deviation 2.30
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Sleep Quality
post-switch PSQI index
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3.1 units on a scale
Standard Deviation 1.66
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SECONDARY outcome
Timeframe: week 0 and week 8Population: 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.
Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus EVG/COBI/FTC/TDF) through a self-administered questionnaire.
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
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|---|---|
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ART Regimen Preference
Prefers Stribld
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9 Participants
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ART Regimen Preference
Prefers Atripla
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0 Participants
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ART Regimen Preference
No preference
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1 Participants
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SECONDARY outcome
Timeframe: week 0 and week 8Population: Inflammatory markers were measured pre- and post-drug switch from Atripla to Stibild.
Change in markers of immune activation and inflammation associated with change to Stibild: sCD14, IP-10,sCD163, IL-6)
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
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|---|---|
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Markers of Immune Activation
pre-switch sCD14
|
3329000 pg/ML
Standard Deviation 566684
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Markers of Immune Activation
post-switch sCD14
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2879000 pg/ML
Standard Deviation 867793
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Markers of Immune Activation
pre-switch IP-10
|
237.3 pg/ML
Standard Deviation 204.8
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Markers of Immune Activation
post-switch IP-10
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224.2 pg/ML
Standard Deviation 201
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Markers of Immune Activation
pre-switch sCD163
|
732000 pg/ML
Standard Deviation 559000
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Markers of Immune Activation
post-switch sCD163
|
599500 pg/ML
Standard Deviation 319200
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Markers of Immune Activation
pre-switch MCP-1
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102.2 pg/ML
Standard Deviation 68
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Markers of Immune Activation
post-switch MCP-1
|
91.39 pg/ML
Standard Deviation 43.02
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Markers of Immune Activation
pre-switch IL-6
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1.255 pg/ML
Standard Deviation 0.5921
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Markers of Immune Activation
post-switch IL-6
|
1.301 pg/ML
Standard Deviation 0.7115
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Markers of Immune Activation
pre-switch TNFR1
|
833.2 pg/ML
Standard Deviation 222.1
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Markers of Immune Activation
post-switch TNFR1
|
878.1 pg/ML
Standard Deviation 198.8
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SECONDARY outcome
Timeframe: week 0 and week 8Level 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).
Outcome measures
| Measure |
Drug Switching
n=10 Participants
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
|
|---|---|
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Effect of EFV and Its Metabolites
Number with detectable 7-OH and 8-OH (pre-switch)
|
10 participants
|
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Effect of EFV and Its Metabolites
Number with detectable 7-OH and 8-OH (post-switch)
|
0 participants
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Adverse Events
Drug Switching
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Dr. Nina Lin
Boston Medical Center, Boston University School of Medicine
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place