Trial Outcomes & Findings for A Study of the Neurological Effects of Adding Maraviroc to HAART Regimen in Patients With HIV (HANDmac) (NCT NCT01449006)

Last Updated: 2019-02-27

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

19 participants

Primary outcome timeframe

Baseline, 6-months and 12-months

Results posted on

2019-02-27

Participant Flow

Participants were recruited from St Vincent's Hospital and/or referred from tertiary sexual health centres over the period January 2012 to June 2013.

Two enrolled participants failed screening (1 HCV+, 1 not cognitively impaired)

Participant milestones

Participant milestones
Measure	Standard of Care HAART Regimen Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	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.
Overall Study STARTED	8	9
Overall Study COMPLETED	5	9
Overall Study NOT COMPLETED	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Standard of Care HAART Regimen Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	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.
Overall Study Lost to Follow-up	1	0
Overall Study Withdrawal by Subject	1	0
Overall Study Protocol Violation	1	0

Baseline Characteristics

A Study of the Neurological Effects of Adding Maraviroc to HAART Regimen in Patients With HIV (HANDmac)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard of Care HAART Regimen n=5 Participants Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	Maraviroc n=9 Participants 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.	Total n=14 Participants Total of all reporting groups
Age, Continuous	60 years STANDARD_DEVIATION 9.4 • n=5 Participants	52.2 years STANDARD_DEVIATION 3.7 • n=7 Participants	55 years STANDARD_DEVIATION 7.1 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	9 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	5 participants n=5 Participants	9 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Australia	5 participants n=5 Participants	9 participants n=7 Participants	14 participants n=5 Participants
Education	11.6 years STANDARD_DEVIATION 2.3 • n=5 Participants	12.3 years STANDARD_DEVIATION 2.8 • n=7 Participants	12.1 years STANDARD_DEVIATION 2.6 • n=5 Participants
Premorbid intelligence quotient (IQ)	104.4 units on a scale STANDARD_DEVIATION 18.9 • n=5 Participants	102.2 units on a scale STANDARD_DEVIATION 16.3 • n=7 Participants	103 units on a scale STANDARD_DEVIATION 16.6 • n=5 Participants
Nadir cluster of differentiation 4 (CD4)	310 cells/mm3 n=5 Participants	150 cells/mm3 n=7 Participants	174.5 cells/mm3 n=5 Participants
Current CD4	980 cells/mm3 n=5 Participants	499 cells/mm3 n=7 Participants	625.5 cells/mm3 n=5 Participants
HAND Status Asymptomatic Neurocognitive Impairment (ANI)	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
HAND Status Mild Neurocognitive Disorder (MND)	2 participants n=5 Participants	8 participants n=7 Participants	10 participants n=5 Participants
HAND Status HIV-Associated Dementia (HAD)	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 6-months and 12-months

Population: 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).

Outcome measures

Outcome measures
Measure	Standard of Care HAART Regimen n=5 Participants Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	Maraviroc n=9 Participants 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.
Change in Neurocognitive Functioning Baseline	-0.94 Global Neurocognitive Z-Score Standard Error 0.30	-0.81 Global Neurocognitive Z-Score Standard Error 0.23
Change in Neurocognitive Functioning 6 months	-1.03 Global Neurocognitive Z-Score Standard Error 0.30	-0.51 Global Neurocognitive Z-Score Standard Error 0.23
Change in Neurocognitive Functioning 12 months	-0.93 Global Neurocognitive Z-Score Standard Error 0.30	-0.56 Global Neurocognitive Z-Score Standard Error 0.23

SECONDARY outcome

Timeframe: Baseline and 12-months

Population: 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.

Change in concentration of the CSF neuroinflammatory marker neopterin (measured in nmol/L) from baseline to 12-months.

Outcome measures

Outcome measures
Measure	Standard of Care HAART Regimen n=4 Participants Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	Maraviroc n=7 Participants 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.
Change in CSF Neopterin Concentration Baseline	11.5 nmol/L Standard Error 3.41	12.57 nmol/L Standard Error 2.57
Change in CSF Neopterin Concentration 12-months	13.25 nmol/L Standard Error 3.41	15.71 nmol/L Standard Error 2.57

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard of Care HAART Regimen n=4 Participants Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	Maraviroc n=9 Participants 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.
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia Cr Baseline	3.09 ratio Standard Error 0.16	2.91 ratio Standard Error 0.11
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia Cr 12 Months	3.24 ratio Standard Error 0.16	3.08 ratio Standard Error 0.11
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia Cho Baseline	1.42 ratio Standard Error 0.14	1.45 ratio Standard Error 0.09
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia Cho 12 Months	1.59 ratio Standard Error 0.14	1.55 ratio Standard Error 0.09
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia mIo Baseline	1.10 ratio Standard Error 0.22	1.19 ratio Standard Error 0.15
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia NAA Baseline	3.76 ratio Standard Error 0.16	3.96 ratio Standard Error 0.11
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia NAA 12 Months	3.87 ratio Standard Error 0.16	3.89 ratio Standard Error 0.11
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia mIo 12 Months	0.88 ratio Standard Error 0.22	1.07 ratio Standard Error 0.15

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard of Care HAART Regimen n=4 Participants Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	Maraviroc n=9 Participants 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.
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter NAA Baseline	4.32 ratio Standard Error 0.34	4.16 ratio Standard Error 0.23
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter NAA 12 Months	4.30 ratio Standard Error 0.34	4.16 ratio Standard Error 0.23
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter mIo Baseline	1.11 ratio Standard Error 0.15	1.07 ratio Standard Error 0.10
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter mIo 12 Months	1.15 ratio Standard Error 0.15	1.35 ratio Standard Error 0.10
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter Glx Baseline	2.16 ratio Standard Error 0.23	2.27 ratio Standard Error 0.15
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter Cr Baseline	2.74 ratio Standard Error 0.21	2.93 ratio Standard Error 0.14
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter Cr 12 Months	2.99 ratio Standard Error 0.21	3.05 ratio Standard Error 0.14
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter Cho Baseline	2.19 ratio Standard Error 0.16	2.13 ratio Standard Error 0.11
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter Cho 12 Months	2.19 ratio Standard Error 0.16	2.24 ratio Standard Error 0.11
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter Glx 12 Months	2.05 ratio Standard Error 0.23	2.18 ratio Standard Error 0.15

Adverse Events

Standard of Care HAART Regimen

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Maraviroc

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Standard of Care HAART Regimen n=8 participants at risk Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen.	Maraviroc n=9 participants at risk 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.
Nervous system disorders Cerebrospinal fluid leakage	12.5% 1/8 • Number of events 1 • Baseline to 12-months	11.1% 1/9 • Number of events 1 • Baseline to 12-months
Eye disorders Blurred vision	12.5% 1/8 • Number of events 1 • Baseline to 12-months	0.00% 0/9 • Baseline to 12-months
Renal and urinary disorders Renal calculi	12.5% 1/8 • Number of events 1 • Baseline to 12-months	0.00% 0/9 • Baseline to 12-months
Infections and infestations Upper respiratory infection	0.00% 0/8 • Baseline to 12-months	22.2% 2/9 • Number of events 2 • Baseline to 12-months
Skin and subcutaneous tissue disorders Skin infection	0.00% 0/8 • Baseline to 12-months	22.2% 2/9 • Number of events 2 • Baseline to 12-months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	0.00% 0/8 • Baseline to 12-months	11.1% 1/9 • Number of events 1 • Baseline to 12-months
Injury, poisoning and procedural complications Fall	0.00% 0/8 • Baseline to 12-months	11.1% 1/9 • Number of events 1 • Baseline to 12-months

Additional Information

Prof. Bruce Brew

St Vincent's Hospital, Sydney, Australia

Phone: 61 2 8382 1111

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60