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| ID | Type | Description | Link |
|---|---|---|---|
| COL114560 | Other Grant/Funding Number | VIIV Healthcare |
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Slower than expected recruitment
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| Name | Class |
|---|---|
| ViiV Healthcare | INDUSTRY |
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Patients infected with Human Immunodeficiency Virus (HIV) are at risk of brain related complications despite the use of highly active antiretroviral therapy (HAART). Such complications are termed HIV neurocognitive disorders (HAND) and comprise a spectrum from asymptomatic neurocognitive impairment (ANI), through mild cognitive impairment (MCI) to severe HIV dementia (HAD).
Prior to HAART approximately 30% of patients with advanced HIV disease had cognitive impairment; with HAART the incidence of HAND has decreased but its prevalence increased. The reasons for the ongoing development of cognitive impairment in HAART treated patients are not clear. They might relate to virus induced brain injury prior to starting HAART, the onset of a separate neurological process, toxicity related to HAART, or ongoing viral infection in the brain.
It is clear that the ability of different antiretroviral drugs to penetrate the brain varies but what is not established is whether these differences between drugs lead to different neurological outcomes. The investigators propose to study HIV infected patients stable on HAART for 12 months; subdividing the groups according to the brain penetrance of their drug combination. Patients would undergo neuropsychological assessment and MRI brain scan at the start of the study and after 12 months.
Differences in neuropsychological tests and MRI would be sought between treatment groups to establish whether HAART with better CNS penetration is associated with better outcome and fewer MRI changes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Non Neuro-HAART (low CNS penetrance) | 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. | ||
| Neuro-HAART (high CNS penetrance) | 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. |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in Neurocognitive Functioning | 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. | Change from baseline Neuropsychological testing at 6 and 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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HIV positive participants on HAART who attend outpatient primary care clinics.
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| Name | Affiliation | Role |
|---|---|---|
| Bruce J Brew, MBBS, PhD | St Vincent's Hospital, Sydney | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St Vincent's Hospital | Sydney | New South Wales | 2010 | Australia | ||
| The Alfred Hospital |
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Participants were recruited from St Vincent's Hospital and/or referred from tertiary sexual health centres over the period January 2012 to June 2013.
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| ID | Title | Description |
|---|---|---|
| FG000 | Non Neuro-HAART (Low CNS Penetrance) | 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. |
| FG001 | Neuro-HAART (High CNS Penetrance) | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Data presented reflect baseline demographic and clinical characteristics for participants included in the primary analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | Non Neuro-HAART (Low CNS Penetrance) | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 Neurocognitive Functioning | 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. | 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). | Posted | Least Squares Mean | Standard Error | Global neurocognitive z-score | Change from baseline Neuropsychological testing at 6 and 12 months |
|
Baseline to 12 Months
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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 | Non Neuro-HAART (Low CNS Penetrance) | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Post-lumbar puncture headache | Investigations | Non-systematic Assessment |
Lower than expected participant recruitment rate and early termination led to a small sample size and underpowered statistical analyses
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Bruce Brew | St Vincent's Hospital, Sydney | +61 2 8382 1111 | 4100 | b.brew@unsw.edu.au |
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Cerbrospinal fluid and bloods
| Baseline and 12 months |
| Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | 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. | Baseline and 12 months |
| Cerebrospinal Fluid | 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). | Baseline to 12 Months |
| Prahran |
| Victoria |
| 3181 |
| Australia |
| BG001 | Neuro-HAART (High CNS Penetrance) | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Region of Enrollment | Number | participants |
|
| Education | Mean | Standard Deviation | years |
|
| Premorbid intelligence quotient (IQ) | 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. | Mean | Standard Deviation | units on a scale |
|
| Nadir cluster of differentiation 4 (CD4) | Median | Inter-Quartile Range | cells/mm3 |
|
| Current CD4 | Median | Inter-Quartile Range | cells/mm3 |
|
| HIV-Associated Neurocognitive Disorder (HAND) status | Number | participants |
|
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. |
| OG001 | Neuro-HAART (High CNS Penetrance) | 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. |
|
|
|
| Secondary | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | 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. | 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. | Posted | Least Squares Mean | Standard Error | Ratio | Baseline and 12 months |
|
|
|
|
| Secondary | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | 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. | 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. | Posted | Least Squares Mean | Standard Error | Ratio | Baseline and 12 months |
|
|
|
|
| Secondary | Cerebrospinal Fluid | 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). | 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). | Posted | Mean | Standard Error | ug/L | Baseline to 12 Months |
|
|
|
| 0 |
| 7 |
| 2 |
| 7 |
| EG001 | Neuro-HAART (High CNS Penetrance) | 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. | 0 | 12 | 5 | 12 |
| Laser eye surgery | Surgical and medical procedures | Non-systematic Assessment |
|
| Kidney stones and stent insertion | Renal and urinary disorders | Non-systematic Assessment |
|
| Rash and excema | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Influenza | Infections and infestations | Non-systematic Assessment |
|
| Staphylococcal infection | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Skin biopsy | Investigations | Non-systematic Assessment |
|
| Basal cell carcinoma removal | Surgical and medical procedures | Non-systematic Assessment |
|
| Muscle strain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Vitamin D deficiency | Metabolism and nutrition disorders | Non-systematic Assessment |
|
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| Cr Baseline |
|
| Cr 12 Months |
|
| Cho Baseline |
|
| Cho 12 Months |
|
| mIo Baseline |
|
| mIo 12 Months |
|
| ANOVA |
| 0.44 |
| No |
| Superiority or Other |
| Change in Cho/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects. | ANOVA | 0.86 | No | Superiority or Other |
| Change in mIo/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects. | ANOVA | 0.98 | No | Superiority or Other |
| Cr Baseline |
|
| Cr 12 Months |
|
| Cho Baseline |
|
| Cho 12 Months |
|
| mIo Baseline |
|
| mIo 12 Months |
|
| Glx Baseline |
|
| Glx 12 Months |
|
| ANOVA |
| 0.09 |
| No |
| Superiority or Other |
| Change in Cho/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects. | ANOVA | 0.06 | No | Superiority or Other |
| Change in mIo/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects. | ANOVA | 0.68 | No | Superiority or Other |
| Change in Glx/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm*time interaction as fixed effects. | ANOVA | 0.58 | No | Superiority or Other |
| Raltegravir Baseline |
|
| Raltegravir 12 months |
|
| Darunavir Baseline |
|
| Darunavir 12 months |
|