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

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ClinicalTrials.gov Identifier: NCT01978743
Recruitment Status : Completed
First Posted : November 7, 2013
Results First Posted : July 26, 2017
Last Update Posted : July 26, 2017
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Nina Lin, MD, Boston University

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Conditions HIV
HIV-associated Neurocognitive Disorder
Neurotoxicity
Intervention Drug: Raltegravir
Enrollment 10

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Raltegravir
Hide Arm/Group Description

All participants are switched from Atripla (EFV/FTC/TDF) to raltegravir (RAL) + truvada (FTC/TDF).

Raltegravir will be administered 400mg twice-a-day.

Period Title: Overall Study
Started 10
Completed 10
Not Completed 0
Arm/Group Title Raltegravir
Hide Arm/Group Description All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
Overall Number of Baseline Participants 10
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
<=18 years
0
   0.0%
Between 18 and 65 years
10
 100.0%
>=65 years
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Female
4
  40.0%
Male
6
  60.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 10 participants
10
1.Primary Outcome
Title Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Hide Description 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).
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Raltegravir
Hide Arm/Group Description:

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.

Drug switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks

Overall Number of Participants Analyzed 10
Mean (Standard Deviation)
Unit of Measure: arbitrary units
Pre-switch Posterior Cingulate Creatine 19.38  (1.82)
Post-switch Posterior Cingulate Creatine 18.94  (4.01)
Pre-switch Posterior Cingulate Glutamate 27.83  (5.06)
Post-switch Posterior Cingulate Glutamate 24.95  (4.54)
Pre-switch Posterior Cingulate GABA 5.27  (0.74)
Post-switch Posterior Cingulate GABA 5.32  (1.85)
Pre-switch Anterior Cingulate Creatine 14.86  (2.18)
Post-switch Anterior Cingulate Creatine 14.34  (2.92)
Pre-switch Anterior Cingulate Glutamate 19.09  (3.83)
Post-switch Anterior Cingulate Glutamate 22.25  (6.21)
Pre-switch Anterior Cingulate GABA 4.73  (1.55)
Post-switch Anterior Cingulate GABA 3.14  (2.12)
2.Primary Outcome
Title Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Hide Description 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.
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Raltegravir
Hide Arm/Group Description:

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.

Drug switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks

Overall Number of Participants Analyzed 8
Measure Type: Number
Unit of Measure: z-score
PreVsPostXNegVsNeuXNoGoVsGo: aFP 3.19
PreVsPostXNegVsNeuXNoGoVsGo: pCG 3.00
PreVsPostXNegVsNeuXNoGoVsGo: daCG -2.53
PreVsPostXNegVsNeuXNoGoVsGo:LHC -3.64
Pre: NegVsNeuXNoGoVsGo: aFP 4.01
Pre: NegVsNeuXNoGoVsGo:pCG 3.61
Pre: NegVsNeuXNoGoVsGo: daCG -2.94
Pre: NegVsNeuXNoGoVsGo: LHC -3.07
Post: NegVsNeuXNoGoVsGo: aFP -3.03
Post: NegVsNeuXNoGoVsGo: pCG -3.13
Post: NegVsNeuXNoGoVsGo: daCG 3.65
Post: NegVsNeuXNoGoVsGo: LHC 2.88
3.Secondary Outcome
Title Other Neurometabolite Changes Measured by MRS
Hide Description 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.
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Raltegravir
Hide Arm/Group Description:

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.

Drug switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks

Overall Number of Participants Analyzed 10
Mean (Standard Deviation)
Unit of Measure: arbitrary units
Pre-switch Posterior Cingulate Glutathione 5.11  (1.18)
Post-switch Posterior Cingulate Glutathione 4.70  (1.51)
Pre-switch Posterior Cingulate Aspartate 4.32  (0.95)
Post-switch Posterior Cingulate Aspartate 3.31  (0.97)
Pre-switch Anterior Cingulate Glutathione 4.25  (1.01)
Post-switch Anterior Cingulate Glutathione 3.18  (1.08)
Pre-switch Anterior Cingulate Aspartate 3.15  (1.28)
Post-switch Anterior Cingulate Aspartate 2.18  (1.61)
4.Secondary Outcome
Title Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
Hide Description

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.
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Raltegravir
Hide Arm/Group Description:

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.

Drug switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks

Overall Number of Participants Analyzed 10
Mean (Standard Deviation)
Unit of Measure: units on a scale
pre-switch WAIS 48.1  (12.53838551)
post-switch WAIS 53.5  (12.00231459)
pre-switch FRSBE 79.2  (13.07074766)
post-switch FRSBE 72.4  (9.834180754)
pre-switch HAMD 4.7  (3.860051813)
post-switch HAMD 2.7  (3.020301677)
pre-switch DASS depression 6.4  (9.834180754)
post-switch DASS depression 3.4  (3.777124126)
pre-switch STAI 29.4  (5.481281278)
post-switch STAI 27.2  (6.528569692)
5.Secondary Outcome
Title Fasting Lipid Profile
Hide Description Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Change in lipid panel pre- and post-switch to RAL-based regimen
Arm/Group Title Raltegravir
Hide Arm/Group Description:
All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
Overall Number of Participants Analyzed 10
Mean (Standard Deviation)
Unit of Measure: mg/dL
pre-switch total cholesterol 200.9  (37.02)
post-switch total cholesterol 176.7  (26.20)
pre-switch HDL 58.8  (9.69)
post-switch HDL 53.1  (13.42)
pre-switch LDL 118.8  (31.56)
post-switch LDL 103.5  (24.08)
pre-switch triglyceride 116.4  (69.62)
post-switch triglyceride 100.6  (54.52)
6.Secondary Outcome
Title Sleep Quality
Hide Description 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.
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Raltegravir
Hide Arm/Group Description:
All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
Overall Number of Participants Analyzed 10
Mean (Standard Deviation)
Unit of Measure: units on a scale
pre-switch PSQI index 5.3  (3.06)
post-switch PSQI index 3.8  (1.99)
7.Secondary Outcome
Title ART Regimen Preference
Hide Description Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires.
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Raltegravir
Hide Arm/Group Description:
All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
Overall Number of Participants Analyzed 10
Measure Type: Number
Unit of Measure: participants
Prefer Raltegravir-based ART 7
Prefer Atripla (EFV-based ART) 0
No preference 3
8.Secondary Outcome
Title Markers of Immune Activation
Hide Description Change in markers of immune activation and inflammation associated with change to RAL (ie, sCD14, IL-6, hsCRP, D-dimer, CRP, LPS, sCD163, EndoCab)
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Raltegravir
Hide Arm/Group Description:
All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
Overall Number of Participants Analyzed 10
Mean (Standard Deviation)
Unit of Measure: pg/ml
pre-switch sCD14 3652333.6  (771769.196)
post-switch sCD14 3135828.52  (791445.1417)
pre-switch IP-10 195.84  (74.57)
post-switch IP-10 202.85  (55.58)
pre-switch sCD163 672844  (281620)
post-switch sCD163 733536  (378.958)
pre-switch MCP-1 95.578  (34.14)
post-switch MCP-1 92.794  (56.25)
pre-switch IL-6 1.49  (0.68)
post-switch IL-6 1.69  (0.89)
pre-switch TNFR1 771.18  (145.46)
post-switch TNFR1 829.12  (130.66)
9.Secondary Outcome
Title Change in Level of EFV and Metabolites
Hide Description Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes
Time Frame week 0 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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).
Arm/Group Title Raltegravir
Hide Arm/Group Description:
All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
Overall Number of Participants Analyzed 10
Measure Type: Number
Unit of Measure: participants
pre-switch detectable 7-OH and 8-OH EFV metablites 9
post-switch detectable 7-OH and 8-OH EFVmetaboites 1
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Raltegravir
Hide Arm/Group Description All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
All-Cause Mortality
Raltegravir
Affected / at Risk (%)
Total   0/10 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Raltegravir
Affected / at Risk (%)
Total   0/10 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Raltegravir
Affected / at Risk (%)
Total   0/10 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Nina Lin
Organization: Boston University School of Medicine
Phone: 617-414-5242
Responsible Party: Nina Lin, MD, Boston University
ClinicalTrials.gov Identifier: NCT01978743     History of Changes
Other Study ID Numbers: NeuroHIV002
First Submitted: October 20, 2013
First Posted: November 7, 2013
Results First Submitted: June 8, 2017
Results First Posted: July 26, 2017
Last Update Posted: July 26, 2017