MARCH Central Nervous System Substudy

Study Overview
=================
Brief Summary
-----------------
This substudy is a prospective, observational, open-label, randomised study within the MARCH study. The purpose of this substudy is to investigate the changes in cerebral function parameters at 5 timepoints over 96 weeks of the three different treatment arms within the MARCH study. The investigators hypothesise that there will be improvements in cerebral function in those patients randomised, as part of the parent study, into the maraviroc arms. the assessments in this CNS substudy will include: Neurocognitive function as assessed by a computerised testing battery called CogState; changes in cerebral metabolites as measured via 1H Magnetic Resonance Spectroscopy (1H-MRS) In those randomised to the maraviroc arms (arms 2 and 3) there is an optional Lumbar puncture at week 48. The cerebrospinal fluid will be used to measure maraviroc levels and an ultrasensitive CSF HIV-1 viral load. These results will be matched with levels in the plasma.

Detailed Description
-----------------
this is detailed above, this is a substudy of MARCH

Official Title
-----------------
Maraviroc Switch Central Nervous System (CNS) Substudy: a Substudy of MARCH, a Randomised, Open-label Study to Evaluate the Efficacy and Safety of Maraviroc (MVC) as a Switch for Either Nucleoside or Nucleotide Analogue Reverse Transcriptase Inhibitors (N(t)RTI) or Boosted Protease Inhibitors (PI/r) in HIV-1 Infected Individuals With Stable, Well-controlled Plasma HIV-RNA While Taking Their First N(t)RTI + PI/r Regimen of Combination Antiretroviral Therapy (cART).

Conditions
-----------------
HIV-1 Infection

Intervention / Treatment
-----------------
* Drug: Arm 1 TNucleotide Analogue Reverse Transcriptase Inhibitors and Boosted Protease Inhibitors
* Drug: Arm 2 Maraviroc and Protease Inhibitors
* Drug: Arm 3 Maraviroc and Nucleotide Analogue Reverse Transcriptase Inhibitors


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of written, informed consent for participation in the substudy Enrolled into the substudy either at or before the week 0 visit of the main study Exclusion Criteria: Pre-existing CNS diseases Recent head injury (past three months) Current history of major depression or psychosis

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| NRTI + PI<br>This is the randomisation of the main study, Arm 1 | Drug: Arm 1 TNucleotide Analogue Reverse Transcriptase Inhibitors and Boosted Protease Inhibitors<br>* NRTI+PI<br>* Other names: fosamprenavir;|
| maraviroc + PI<br>this is the randomisation of the main study, Arm 2 | Drug: Arm 2 Maraviroc and Protease Inhibitors<br>* maraviroc + PI<br>* Other names: fosamprenavir;|
| maraviroc + NRTI<br>this is the randomisation of the main study, Arm 3 | Drug: Arm 3 Maraviroc and Nucleotide Analogue Reverse Transcriptase Inhibitors<br>* maraviroc + NRTI<br>* Other names: abacavir;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess changes in NC function over 96 weeks, measured via a computerised testing battery in HIV-infected subjects stable on antiretroviral therapy randomised to three different treatment approaches | using CogState testing at 5 timepoints, weeks 0, 12, 24, 48, 96 | 96 weeks | 
| To assess changes in cerebral metabolites over 96 weeks, measured via 1H Magnetic Resonance Spectroscopy (1H-MRS), in HIV-infected subjects stable on antiretroviral therapy randomised to three different treatment approaches | Assessment of CNS metabolites via 1H-MRS at week 0, 48, 96 Cerebral metabolites in frontal white and grey voxels, and basal ganglia will be measured Measurable metabolites will include assessment of neuronal markers, N-acetyl-aspartate, and inflammatory markers, myo-Inositols and Choline | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to assess CSF HIV-1 RNA and CSF maraviroc concentration (in the MVC treatment arms) versus plasma HIV -1 RNA and MVC concentration after 48 weeks of therapy | A LP examination at week 48 (optional and only in the MVC treatment arms, and only if there is no contraindication to LP) to assess, with matched plasma samples: CSF MVC concentration CSF HIV-1 RNA CSF biomarkers | 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV-1 infection, neurocognitive function, switch study