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| ID | Type | Description | Link |
|---|---|---|---|
| 114560 | Other Grant/Funding Number | VIIV Healthcare Australia |
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| Name | Class |
|---|---|
| ViiV Healthcare | INDUSTRY |
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HIV related cognitive impairment still occurs despite highly active antiretroviral therapy (HAART). HIV disease affects the brain in 20-40% of patients with advancing HIV disease; leading to varying degrees of cognitive impairment, recently termed HIV associated neurocognitive disorders (HAND). HAND may occur in patients who are virally suppressed in both blood and CSF.
Patients with HIV Associated Neurocognitive Disorders (HAND) who are virally suppressed in both their blood and cerebrospinal fluid (CSF), whilst on a highly active antiretroviral therapy (HAART) regimen may have significant cognitive improvement with HAART intensification with the medication Maraviroc; compared to those who remain on their existing regimen.
This study will be a prospective, interventional, randomised and unblinded controlled clinical trial. The aim of this study will be to determine whether HAART intensification with the medication Maraviroc, leads to significant improvement in HIV associated neurocognitive disorders (HAND).
Patients with the recent progression (within 6 months) of HAND (validated by neuropsychological assessment) on HAART, who are virally suppressed (<50 copies per ml) in blood and CSF will be randomised to have their existing HAART regimen intensified with Maraviroc, or not. The control arm will remain on their medication regimen as prescribed. The target is to enrol 70 patients into the control group, and 70 patients into the Maraviroc intensification group.
Patients will undergo baseline neuropsychological testing, MRI, blood tests, and cerebrospinal fluid (CSF) tests (via a lumbar puncture). The methods used to determine the effectiveness of adding Maraviroc, will include further neuropsychological assessment at 6 months, and neuropsychological assessment, MRI and CSF assessment again at 12 months.
Neuropsychological testing completed at 6 and 12 months will be completed by a "blind assessor", in that they will have no knowledge of which arm (treatment or control) the participant is enrolled in.
An evaluation (neuropsychological testing) will be performed should the patient deteriorate during the course of the study, as recognised by the patient's managing physician.
At the end of the study protocol (12 months) the patient's HAART therapy will be managed by their primary physician.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of care HAART regimen | No Intervention | Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen. | |
| Maraviroc | Experimental | Participants randomised to this arm will remain on their usual prescribed HAART regimen, with the addition of Maraviroc. Maraviroc will be prescribed according to the Product Information Sheet, with consideration given to background therapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Maraviroc | Drug | Maraviroc oral tablet. Dosage: 150 mg twice daily, 300 mg twice daily, or 600 mg twice daily. Dosing will be dependent on the participant's background HAART therapy, and will be in accordance with the product information sheet. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Neurocognitive Functioning | Change in overall neurocognitive performance, defined as a global neurocognitive z-score, over the study time-period (baseline, 6-months, 12-months). To derive this score, 1) raw scores obtained from a 5-domain brief neurocognitive battery were converted to age-corrected z-scores (M=0, SD=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. | Baseline, 6-months and 12-months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in CSF Neopterin Concentration | Change in concentration of the CSF neuroinflammatory marker neopterin (measured in nmol/L) from baseline to 12-months. | Baseline and 12-months |
| Change in MRS Cerebral Metabolite Ratios in Basal Ganglia |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bruce J Brew, MBBS, PhD | St Vincent's Hospital - Sydney, Australia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St. Vincent's Hospital | Sydney | New South Wales | 2010 | Australia | ||
| The Alfred Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26825032 | Result | Gates TM, Cysique LA, Siefried KJ, Chaganti J, Moffat KJ, Brew BJ. Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder. AIDS. 2016 Feb 20;30(4):591-600. doi: 10.1097/QAD.0000000000000951. |
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Two enrolled participants failed screening (1 HCV+, 1 not cognitively impaired)
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 | Standard of Care HAART Regimen | Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen. |
| FG001 | Maraviroc | Participants randomised to this arm will remain on their usual prescribed HAART regimen, with the addition of Maraviroc. Maraviroc will be prescribed according to the Product Information Sheet, with consideration given to background therapy. Maraviroc: Maraviroc oral tablet. Dosage: 150 mg twice daily, 300 mg twice daily, or 600 mg twice daily. Dosing will be dependent on the participant's background HAART therapy, and will be in accordance with the product information sheet. |
| 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 | Standard of Care HAART Regimen | Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen. |
| BG001 | Maraviroc | Participants randomised to this arm will remain on their usual prescribed HAART regimen, with the addition of Maraviroc. Maraviroc will be prescribed according to the Product Information Sheet, with consideration given to background therapy. Maraviroc: Maraviroc oral tablet. Dosage: 150 mg twice daily, 300 mg twice daily, or 600 mg twice daily. Dosing will be dependent on the participant's background HAART therapy, and will be in accordance with the product information sheet. |
| 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, over the study time-period (baseline, 6-months, 12-months). To derive this score, 1) raw scores obtained from a 5-domain brief neurocognitive battery were converted to age-corrected z-scores (M=0, SD=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 randomized participants were included except for n=2 controls with baseline data only (1 lost to follow-up, 1 withdrew before 6-months) and n=1 control where a protocol violation was noted (randomized without conclusive evidence of neurocognitive impairment - see participant flow section). | Posted | Least Squares Mean | Standard Error | Global Neurocognitive Z-Score | Baseline, 6-months 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 | Standard of Care HAART Regimen | Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cerebrospinal fluid leakage | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment |
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Bruce Brew | St Vincent's Hospital, Sydney, Australia | 61 2 8382 1111 | 4100 | bruce.brew@svha.org.au |
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| ID | Term |
|---|---|
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D000077592 | Maraviroc |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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|
Change in major cerebral metabolites in the basal ganglia, 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 echot 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.
| 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 H2O as standard. | Baseline and 12 months |
| Melbourne |
| Victoria |
| 3181 |
| Australia |
| Protocol Violation |
|
| 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. 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 |
|
| HAND Status | Number | participants |
|
Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen. |
| OG001 | Maraviroc | Participants randomised to this arm will remain on their usual prescribed HAART regimen, with the addition of Maraviroc. Maraviroc will be prescribed according to the Product Information Sheet, with consideration given to background therapy. Maraviroc: Maraviroc oral tablet. Dosage: 150 mg twice daily, 300 mg twice daily, or 600 mg twice daily. Dosing will be dependent on the participant's background HAART therapy, and will be in accordance with the product information sheet. |
|
|
|
| Secondary | Change in CSF Neopterin Concentration | Change in concentration of the CSF neuroinflammatory marker neopterin (measured in nmol/L) from baseline to 12-months. | The analysis included all randomized participants who were included in the primary analysis aside from n=1 control and n=2 maraviroc who did not provide a CSF sample at 12-months. | Posted | Least Squares Mean | Standard Error | nmol/L | Baseline and 12-months |
|
|
|
|
| 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), between baseline and 12-months. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short echot 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. | The analysis included all randomized participants who were included in the primary analysis aside from n=1 control who did not attend MRI appointment at 12-months. | 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 H2O as standard. | The analysis included all randomized participants who were included in the primary analysis aside from n=1 control who did not attend MRI appointment at 12-months. | Posted | Least Squares Mean | Standard Error | ratio | Baseline and 12 months |
|
|
|
|
| 0 |
| 8 |
| 2 |
| 8 |
| EG001 | Maraviroc | Participants randomised to this arm will remain on their usual prescribed HAART regimen, with the addition of Maraviroc. Maraviroc will be prescribed according to the Product Information Sheet, with consideration given to background therapy. Maraviroc: Maraviroc oral tablet. Dosage: 150 mg twice daily, 300 mg twice daily, or 600 mg twice daily. Dosing will be dependent on the participant's background HAART therapy, and will be in accordance with the product information sheet. | 0 | 9 | 5 | 9 |
| Blurred vision | Eye disorders | CTCAE (4.0) | Non-systematic Assessment |
|
| Renal calculi | Renal and urinary disorders | CTCAE (4.0) | Non-systematic Assessment |
|
| Upper respiratory infection | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment |
|
| Skin infection | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Non-systematic Assessment |
|
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (4.0) | Non-systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | CTCAE (4.0) | Non-systematic Assessment |
|
Not provided
| 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 |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Cr Baseline |
|
| Cr 12 Months |
|
| Cho Baseline |
|
| Cho 12 Months |
|
| mIo Baseline |
|
| mIo 12 Months |
|
| ANOVA |
| 0.94 |
| 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 | 0.80 | 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 | 0.72 | Superiority or Other |
| Cr Baseline |
|
| Cr 12 Months |
|
| Cho Baseline |
|
| Cho 12 Months |
|
| mIo Baseline |
|
| mIo 12 Months |
|
| Glx Baseline |
|
| Glx 12 Months |
|
| ANOVA |
| 0.66 |
| 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 | 0.56 | 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 | 0.29 | 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 | 0.95 | Superiority or Other |