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Efficacy of Neuro-HAART in Patients With HIV (HANDobs)

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ClinicalTrials.gov Identifier: NCT01434654
Recruitment Status : Terminated (Slower than expected recruitment)
First Posted : September 15, 2011
Results First Posted : May 20, 2016
Last Update Posted : August 9, 2016
Sponsor:
Collaborator:
ViiV Healthcare
Information provided by (Responsible Party):
Bruce Brew, St Vincent's Hospital, Sydney

Study Type Observational
Study Design Observational Model: Cohort;   Time Perspective: Prospective
Condition HIV
Enrollment 19
Recruitment Details Participants were recruited from St Vincent's Hospital and/or referred from tertiary sexual health centres over the period January 2012 to June 2013.
Pre-assignment Details  
Arm/Group Title Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Hide Arm/Group Description Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen. Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Period Title: Overall Study
Started 7 12
Completed 5 12
Not Completed 2 0
Reason Not Completed
Withdrawal by Subject             1             0
Lost to Follow-up             1             0
Arm/Group Title Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance) Total
Hide Arm/Group Description Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen. Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen. Total of all reporting groups
Overall Number of Baseline Participants 5 12 17
Hide Baseline Analysis Population Description
Data presented reflect baseline demographic and clinical characteristics for participants included in the primary analysis.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 5 participants 12 participants 17 participants
50.2  (7.8) 55.4  (8.6) 53.9  (8.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 12 participants 17 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
5
 100.0%
12
 100.0%
17
 100.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 5 participants 12 participants 17 participants
Caucasian 4 11 15
Asian 1 1 2
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Australia Number Analyzed 5 participants 12 participants 17 participants
5 12 17
Education  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 5 participants 12 participants 17 participants
14.4  (3.4) 12.2  (2.7) 12.8  (2.7)
Premorbid intelligence quotient (IQ)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 5 participants 12 participants 17 participants
104.2  (18.7) 102.5  (12.6) 103.0  (14.1)
[1]
Measure Description: Full-scale IQ based on National Adult Reading Test (NART) error score. NART is a test of reading ability that has been extensively validated for use as a proxy measure of pre-morbid intellectual functioning. Full-Scale IQ score is expressed as a Standard Score with Mean=100 and Standard Deviation=15. Possible values range from 69-131. Higher scores indicate better performance.
Nadir cluster of differentiation 4 (CD4)  
Median (Inter-Quartile Range)
Unit of measure:  Cells/mm3
Number Analyzed 5 participants 12 participants 17 participants
400
(300.25 to 499.75)
115
(42.5 to 207.5)
200
(70 to 330)
Current CD4  
Median (Inter-Quartile Range)
Unit of measure:  Cells/mm3
Number Analyzed 5 participants 12 participants 17 participants
943
(752.5 to 1133.5)
583
(386.25 to 979.75)
684
(403.25 to 964.75)
HIV-Associated Neurocognitive Disorder (HAND) status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 5 participants 12 participants 17 participants
Normal/Unimpaired 1 2 3
Asymptomatic Neurocognitive Impairment (ANI) 2 7 9
Mild Neurocognitive Disorder (MND) 1 3 4
HIV-Associated Dementia (HAD) 1 0 1
1.Primary Outcome
Title Change in Neurocognitive Functioning
Hide Description Change in overall neurocognitive performance, defined as a global neurocognitive z-score, after a 12-month period of observation, between HIV positive patients taking antiretroviral regimens categorized as being either of high or low CNS penetration. To derive this score, 1) raw scores obtained from a 5-domain brief neurocognitive battery were converted to age-corrected z-scores (M=0, Standard Deviation=1) and 2) the set of individual subtest z-scores were averaged to generate a single composite (global) z-score for each subject. Lower (negative) scores therefore indicate greater levels of cognitive impairment.
Time Frame Change from baseline Neuropsychological testing at 6 and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Modified intent-to-treat analysis. All enrolled participants were included aside n=2 low CNS penetrance with baseline data only (1 lost to follow-up, 1 withdrew before 6-months).
Arm/Group Title Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Hide Arm/Group Description:
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are allocated to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are allocated to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Overall Number of Participants Analyzed 5 12
Least Squares Mean (Standard Error)
Unit of Measure: Global neurocognitive z-score
Baseline -0.26  (0.27) -0.80  (0.17)
6 months -0.09  (0.27) -0.63  (0.17)
12 months -0.07  (0.27) -0.61  (0.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments The primary outcome was analysed using a mixed-effect regression model with arm and time as fixed linear effects, arm*time interaction as a non-linear fixed effect and participant as a random effect to account for participant attrition.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.99
Comments P-value for arm*time interaction fixed effect.
Method Mixed Models Analysis
Comments 49 datapoints included from baseline, 6 months, and 12 months visits (low CNS penetrance n=14; high CNS penetrance n=35)
2.Secondary Outcome
Title Change in MRS Cerebral Metabolite Ratios in Basal Ganglia
Hide Description Change in major cerebral metabolites in the basal ganglia, as measured by 1H-Magnetic Resonance Spectroscopy (MRS), after a 12 month period of observation. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short echo time (TE). jMRUI/AMARES algorithm was used to process spectra. Metabolite ratios were calculated for the following metabolites: N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mIo), in relation to internal water (H20) as standard.
Time Frame Baseline and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
n=1 participant in high CNS penetrance arm did not return for 12-months follow-up visit. Their baseline data were therefore excluded from analysis.
Arm/Group Title Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Hide Arm/Group Description:
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are allocated to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are allocated to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Overall Number of Participants Analyzed 5 11
Least Squares Mean (Standard Error)
Unit of Measure: Ratio
NAA Baseline 4.14  (0.20) 4.00  (0.13)
NAA 12 months 3.96  (0.20) 3.99  (0.13)
Cr Baseline 3.18  (0.18) 3.03  (0.12)
Cr 12 Months 3.20  (0.18) 3.27  (0.12)
Cho Baseline 1.81  (0.16) 1.79  (0.11)
Cho 12 Months 1.78  (0.16) 1.72  (0.11)
mIo Baseline 1.22  (0.21) 1.27  (0.14)
mIo 12 Months 1.12  (0.21) 1.18  (0.14)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in NAA/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.58
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in Cr/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.44
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in Cho/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.86
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in mIo/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.98
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
3.Secondary Outcome
Title Change in MRS Cerebral Metabolite Ratios in Frontal White Matter
Hide Description Change in major cerebral metabolites in the frontal white matter, as measured by 1H-Magnetic Resonance Spectroscopy (MRS), between baseline and 12-months. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short TE. jMRUI/AMARES algorithm was used to process spectra. Metabolite ratios were calculated for the following metabolites: N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mIo), glutamate/glutamine complex (Glx), in relation to internal H20 as standard.
Time Frame Baseline and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
n=1 participant in high CNS penetrance arm did not return for 12-months follow-up visit. Their baseline data were therefore excluded from analysis.
Arm/Group Title Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Hide Arm/Group Description:
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Overall Number of Participants Analyzed 5 11
Least Squares Mean (Standard Error)
Unit of Measure: Ratio
NAA Baseline 4.39  (0.22) 4.38  (0.15)
NAA 12 Months 4.74  (0.22) 4.32  (0.15)
Cr Baseline 2.77  (0.19) 3.09  (0.12)
Cr 12 Months 3.29  (0.19) 3.16  (0.12)
Cho Baseline 2.25  (0.13) 2.33  (0.09)
Cho 12 Months 2.50  (0.13) 2.31  (0.08)
mIo Baseline 1.06  (0.09) 1.05  (0.06)
mIo 12 Months 1.19  (0.09) 1.23  (0.06)
Glx Baseline 2.26  (0.16) 2.13  (0.11)
Glx 12 Months 2.13  (0.19) 1.96  (0.11)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in NAA/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.16
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in Cr/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.09
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in Cho/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.06
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in mIo/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.68
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Non Neuro-HAART (Low CNS Penetrance), Neuro-HAART (High CNS Penetrance)
Comments Change in Glx/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.58
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
4.Secondary Outcome
Title Cerebrospinal Fluid
Hide Description To measure plateaux CSF ARV concentrations. This will identify the proportion of patients achieving levels of specific ARVs capable of inhibiting 95% of in vitro viral replication (IC95).
Time Frame Baseline to 12 Months
Hide Outcome Measure Data
Hide Analysis Population Description
Data presented for n=5 participants with detectable CSF ARV concentrations who had lumbar puncture at Baseline and 12 months. The pre-specified analysis was not conducted as nevirapine, raltegravir, and darunavir were the only ARVs detected in CSF, and of these, only nevirapine was detected above the minimum threshold (set at >50 ug/L).
Arm/Group Title Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Hide Arm/Group Description:
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
Overall Number of Participants Analyzed 1 4
Mean (Standard Error)
Unit of Measure: ug/L
Nevirapine Baseline NA [1]   (NA) 1161.5  (101.5)
Nevirapine 12 months NA [2]   (NA) 1445  (234)
Raltegravir Baseline 38 [3]   (NA) 39 [3]   (NA)
Raltegravir 12 months 32 [4]   (NA) NA [5]   (NA)
Darunavir Baseline 46 [6]   (NA) 39 [6]   (NA)
Darunavir 12 months NA [7]   (NA) 50 [8]   (NA)
[1]
No participants in this study arm had detectable nevirapine CSF concentrations at baseline. Therefore no data available to report.
[2]
No participants in this study arm had detectable nevirapine CSF concentrations at 12 months. Therefore no data available to report.
[3]
n=1 participant in this study arm had detectable raltegravir CSF concentrations at baseline. Therefore SE not applicable.
[4]
n=1 participant in this study arm had detectable raltegravir CSF concentrations at 12 months. Therefore SE not applicable.
[5]
No participants in this study arm had detectable raltegravir CSF concentrations at 12 months. Therefore no data available to report.
[6]
n=1 participant in this study arm had detectable darunavir CSF concentrations at baseline. Therefore SE not applicable.
[7]
No participants in this study arm had detectable darunavir CSF concentrations at 12 months. Therefore no data available to report.
[8]
n=1 participant in this study arm had detectable darunavir CSF concentrations at 12 months. Therefore SE not applicable.
Time Frame Baseline to 12 Months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Hide Arm/Group Description Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen. Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen.
All-Cause Mortality
Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/7 (0.00%)      0/12 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Non Neuro-HAART (Low CNS Penetrance) Neuro-HAART (High CNS Penetrance)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/7 (28.57%)      5/12 (41.67%)    
Infections and infestations     
Influenza *  1/7 (14.29%)  1 1/12 (8.33%)  1
Investigations     
Post-lumbar puncture headache *  1/7 (14.29%)  1 1/12 (8.33%)  1
Skin biopsy *  0/7 (0.00%)  0 1/12 (8.33%)  1
Metabolism and nutrition disorders     
Vitamin D deficiency *  1/7 (14.29%)  1 0/12 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscle strain *  0/7 (0.00%)  0 1/12 (8.33%)  1
Renal and urinary disorders     
Kidney stones and stent insertion *  1/7 (14.29%)  1 0/12 (0.00%)  0
Skin and subcutaneous tissue disorders     
Rash and excema *  0/7 (0.00%)  0 1/12 (8.33%)  1
Staphylococcal infection *  0/7 (0.00%)  0 1/12 (8.33%)  1
Surgical and medical procedures     
Laser eye surgery *  1/7 (14.29%)  1 0/12 (0.00%)  0
Basal cell carcinoma removal *  0/7 (0.00%)  0 1/12 (8.33%)  1
*
Indicates events were collected by non-systematic assessment
Lower than expected participant recruitment rate and early termination led to a small sample size and underpowered statistical analyses
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: Prof. Bruce Brew
Organization: St Vincent's Hospital, Sydney
Phone: +61 2 8382 1111 ext 4100
Responsible Party: Bruce Brew, St Vincent's Hospital, Sydney
ClinicalTrials.gov Identifier: NCT01434654     History of Changes
Other Study ID Numbers: 09/192
COL114560 ( Other Grant/Funding Number: VIIV Healthcare )
First Submitted: September 12, 2011
First Posted: September 15, 2011
Results First Submitted: February 9, 2016
Results First Posted: May 20, 2016
Last Update Posted: August 9, 2016