HivPhase 4(MARAND-X)NCT03163277
Using Less Neurotoxic Drugs in Patients With HAND (MARAND-X)
A Phase 4 study testing emtricitabine, darunavir/cobicistat, maraviroc in people with Hiv and Neurocognitive Dysfunction, run by Giovanni Di Perri at 1 site in Italy.
Trial summary
Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hiv, Neurocognitive Dysfunction
- What is being tested?
- emtricitabine, darunavir/cobicistat, maraviroc
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 1 siteItaly
- Study dates
- 15 May 2017to 30 Jun 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age above >18 years;
- Confirmed HIV-positivity;
- Diagnosed with HAND according to the Frascati Criteria;
- On combination antiretroviral treatment;
- No evidence of major resistance associated mutations on previous plasma or CSF samples;
- Plasma HIV RNA <50 copies/mL;
- CSF HIV RNA <50 copies/mL;
- R5-tropic virus as detected by a genotype or phenotype based test before starting HAART or genotype-based test performed on HIV DNA in the previous 12 months;
Who cannot join
- the use of drugs having major drug-to-drug interaction with maraviroc (for instance rifampicin);
- the use of efavirenz- or darunavir-containing regimens at baseline;
- confounding comorbidities that may influence or affect the diagnosis of HAND including developmental disability, history of traumatic brain injury or of cerebrovascular accident;
- a previous diagnosis of central nervous system opportunistic, autoimmune, neurodegenerative or neoplastic disease;
- severe untreated depression;
- active alcohol or recreational substance abuse (in the previous 3 months);
- not fluent in Italian or unable to complete the neurocognitive tests.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: MARaviroc-based Treatment Switch in HIV-positive Patients With HAND: Consequences of Reducing Antiretroviral-associated Neurotoxicity
Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND).
Among other hypothesis neurotoxicity of antiretrovirals has been postulated but its impact is unknown.
Our hypothesis is that using drugs with reduced in vitro neurotoxicity may improve cognition in HIV-positive patients withHAND.
76 patients with HAND will be randomized to either continue their treatment or switch to emtricitabine, darunavir/cobicistat, maraviroc. Patients will be re-tested 6 months later.
Read the detailed description
Scientific Rationale for Study / Scientific Study Objectives:
Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND). It should be highlighted that patients presenting no abnormalities in everyday living activities (asymptomatic neurocognitive disorders, ANI) are at higher risk of worse results in performance-based tests, adherence-based measures and they show a significant risk of progressing to more severe forms of impairment. Excluding significantly confounding comorbidities, several factors have been associated with this neurocognitive decline including a low nadir CD4+ T-lymphocyte count, a high HIV DNA, a lower compartmental viral control, a lower concentration/penetration effectiveness score, a lower efficacy in macrophage-derived cells and antiretroviral-generated neuronal toxicity. However several data point out that vascular abnormalities, very common in HIV-positive patients, may deeply influence neurocognitive disorders development and severity: of note, intima media thickness, a well recognized proxy of systemic atherosclerosis, was associated with HAND.
In case of HAND diagnosis, the only recommended approach is to optimize treatment according to plasma and cerebrospinal fluid (CSF) resistance tests; no strategy is currently suggested in case of suppressed plasma and CSF HIV RNA or in case of low level CSF HIV RNA (without evidence of genotypic resistance). It has been postulated that antiretrovirals may have neurotoxic effects through different mechanisms and such effects might become evident once the beneficial effect of HIV RNA suppression vanishes. Available data suggest that, in vitro, the drugs associated with the least neurotoxic effect were emtricitabine, tenofovir, darunavir and maraviroc. Furthermore, several pieces of evidence and a small randomized trial suggest that maraviroc, in HAART-treated subjects may have beneficial effects in terms of improved neurocognitive function, reduced CSF inflammatory biomarkers and improved MRI markers of neuronal integrity.
No study has so far investigated the effect of using drugs with a low neurotoxic profile in HAART-treated patients with HAND.
Primary objective of the study is the variation in neurocognitive tests (global deficit score), 6 months after treatment switch while secondary objectives include the improvement in other biomarkers of neuronal and vascular integrity.
Methods:
Study Design: Randomized, controlled, pilot study. HIV-positive patients that fulfill the inclusion criteria and that sign the informed consent will be enrolled. Patients will be randomized 1:1 (block randomization) to either continue their treatment or to switch to once-daily emtricitabine (200 mg) plus darunavir/cobicistat (800/150 mg) plus maraviroc (300 mg). A lumbar puncture will be performed 6 months after treatment switch.
Number of Patients: 76 (38 per arm)
- Conditions
- Hiv, Neurocognitive Dysfunction
- Being tested
- emtricitabine, darunavir/cobicistat, maraviroc
- Medical subject headings
- Acquired Immunodeficiency Syndrome, Cognition Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
emtricitabine, darunavir/cobicistat, maravirocDrug
Treatment change
| Study group | Role | What they receive |
|---|---|---|
| Standard of care | No intervention | Continue current antiretroviral regimen |
| Reduced Neurotoxicity Arm | Experimental | Emtricitabine plus darunavir/cobicistat plus maraviroc Receives: Drug: emtricitabine, darunavir/cobicistat, maraviroc |
What is being measured
The primary outcome is the main question the study is designed to answer.
6-month variation in global deficit score in NPZ-8 complete neurocognitive tests according to the study arm;
Global deficit score
Measured: 6 months
Secondary outcomes (7)
rs-fMRI
spectroscopic and perfusion markers at MRI as well as the variations in brain connectivity at resting state functional MRI;
Measured: 6 months
EEG-LORETA
electroencephalographic waves using the LORETA software;
Measured: 6 months
CSF HIV RNA
changes in CSF HIV RNA in the two arms
Measured: 6 months
CSF markers
Variation in CSF markers of inflammation or neuronal damage
Measured: 6 months
Blood Brain Barrier Integrity
Variation in CSAR in the two arms
Measured: 6 months
IMT
Variation in carotid intima media thickness in the two arms
Measured: 6 months
TMAO
Variation in trimethylamine-N-oxide in the two arms
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 May 2017
- Study start15 May 2017
- Primary completion30 Jun 2020
- Study completion30 Jun 2020
Why it stopped: Sloww accrual and COVID-19 related problems (impossible to perform LPs)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HivStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Giovanni Di Perri
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Giovanni Di Perri, University of Turin, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03163277
- Sponsor's protocol ID
- MARAND-X
- Acronym
- (MARAND-X)
- Status last verified
- Nov 2020
- First submitted
- 19 May 2017
- Last updated
- 6 Nov 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Stroffolini G, Lazzaro A, Barco A, Pirriatore V, Vai D, Giaccone C, Nigra M, Atzori C, Trunfio M, Bonora S, Di Perri G G, Calcagno A. Changes in Cerebrospinal Fluid, Liver and Intima-media-thickness Biomarkers in Patients with HIV-associated Neurocognitive Disorders Randomized to a Less Neurotoxic Treatment Regimen. J Neuroimmune Pharmacol. 2023 Dec;18(4):551-562. doi: 10.1007/s11481-023-10086-7. Epub 2023 Oct 31.
PubMed 37906406
Study at a glance
From the registry record, last updated by the sponsor on 6 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- MARaviroc-based Treatment Switch in HIV-positive Patients With HAND: Consequences of Reducing Antiretroviral-associated Neurotoxicity
- ClinicalTrials.gov ID
- NCT03163277
- Acronym / sponsor ID
- (MARAND-X) / MARAND-X
- Conditions
- Hiv, Neurocognitive Dysfunction
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Sloww accrual and COVID-19 related problems (impossible to perform LPs)
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Giovanni Di PerriUniversity, hospital or other
- Study start
- 15 May 2017 (actual)
- Primary completion
- 30 Jun 2020 (actual)
- Study completion
- 30 Jun 2020 (actual)
- First posted
- 23 May 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND).
Among other hypothesis neurotoxicity of antiretrovirals has been postulated but its impact is unknown.
Our hypothesis is that using drugs with reduced in vitro neurotoxicity may improve cognition in HIV-positive patients withHAND.
76 patients with HAND will be randomized to either continue their treatment or switch to emtricitabine, darunavir/cobicistat, maraviroc. Patients will be re-tested 6 months later.
Detailed description
Scientific Rationale for Study / Scientific Study Objectives:
Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND). It should be highlighted that patients presenting no abnormalities in everyday living activities (asymptomatic neurocognitive disorders, ANI) are at higher risk of worse results in performance-based tests, adherence-based measures and they show a significant risk of progressing to more severe forms of impairment. Excluding significantly confounding comorbidities, several factors have been associated with this neurocognitive decline including a low nadir CD4+ T-lymphocyte count, a high HIV DNA, a lower compartmental viral control, a lower concentration/penetration effectiveness score, a lower efficacy in macrophage-derived cells and antiretroviral-generated neuronal toxicity. However several data point out that vascular abnormalities, very common in HIV-positive patients, may deeply influence neurocognitive disorders development and severity: of note, intima media thickness, a well recognized proxy of systemic atherosclerosis, was associated with HAND.
In case of HAND diagnosis, the only recommended approach is to optimize treatment according to plasma and cerebrospinal fluid (CSF) resistance tests; no strategy is currently suggested in case of suppressed plasma and CSF HIV RNA or in case of low level CSF HIV RNA (without evidence of genotypic resistance). It has been postulated that antiretrovirals may have neurotoxic effects through different mechanisms and such effects might become evident once the beneficial effect of HIV RNA suppression vanishes. Available data suggest that, in vitro, the drugs associated with the least neurotoxic effect were emtricitabine, tenofovir, darunavir and maraviroc. Furthermore, several pieces of evidence and a small randomized trial suggest that maraviroc, in HAART-treated subjects may have beneficial effects in terms of improved neurocognitive function, reduced CSF inflammatory biomarkers and improved MRI markers of neuronal integrity.
No study has so far investigated the effect of using drugs with a low neurotoxic profile in HAART-treated patients with HAND.
Primary objective of the study is the variation in neurocognitive tests (global deficit score), 6 months after treatment switch while secondary objectives include the improvement in other biomarkers of neuronal and vascular integrity.
Methods:
Study Design: Randomized, controlled, pilot study. HIV-positive patients that fulfill the inclusion criteria and that sign the informed consent will be enrolled. Patients will be randomized 1:1 (block randomization) to either continue their treatment or to switch to once-daily emtricitabine (200 mg) plus darunavir/cobicistat (800/150 mg) plus maraviroc (300 mg). A lumbar puncture will be performed 6 months after treatment switch.
Number of Patients: 76 (38 per arm)
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard of care | No intervention | –Continue current antiretroviral regimen |
| Reduced Neurotoxicity Arm | Experimental | Drug: emtricitabine, darunavir/cobicistat, maravirocEmtricitabine plus darunavir/cobicistat plus maraviroc |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Age above >18 years;
- Confirmed HIV-positivity;
- Diagnosed with HAND according to the Frascati Criteria;
- On combination antiretroviral treatment;
- No evidence of major resistance associated mutations on previous plasma or CSF samples;
Key exclusion criteria (7 listed)
- the use of drugs having major drug-to-drug interaction with maraviroc (for instance rifampicin);
- the use of efavirenz- or darunavir-containing regimens at baseline;
- confounding comorbidities that may influence or affect the diagnosis of HAND including developmental disability, history of traumatic brain injury or of cerebrovascular accident;
- a previous diagnosis of central nervous system opportunistic, autoimmune, neurodegenerative or neoplastic disease;
- severe untreated depression;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| emtricitabine, darunavir/cobicistat, maravirocTreatment change | Drug | Reduced Neurotoxicity Arm |
Primary outcome
6-month variation in global deficit score in NPZ-8 complete neurocognitive tests according to the study arm;
Time frame: 6 months
Global deficit score
7 secondary outcomes
rs-fMRI
Time frame: 6 months
EEG-LORETA
Time frame: 6 months
CSF HIV RNA
Time frame: 6 months
CSF markers
Time frame: 6 months
Blood Brain Barrier Integrity
Time frame: 6 months
IMT
Time frame: 6 months
TMAO
Time frame: 6 months
Results and safety
The study was stopped early (reason given: Sloww accrual and COVID-19 related problems (impossible to perform LPs)). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2020.
- Derived from this study: PubMed 37906406Stroffolini G, Lazzaro A, Barco A, Pirriatore V, Vai D, Giaccone C, Nigra M, Atzori C, Trunfio M, Bonora S, Di Perri G G, Calcagno A. Changes in Cerebrospinal Fluid, Liver and Intima-media-thickness Biomarkers in Patients with HIV-associated Neurocognitive Disorders Randomized to a Less Neurotoxic Treatment Regimen. J Neuroimmune Pharmacol. 2023 Dec;18(4):551-562. doi: 10.1007/s11481-023-10086-7. Epub 2023 Oct 31.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing emtricitabine, darunavir/cobicistat, maraviroc in people with Hiv and Neurocognitive Dysfunction, run by Giovanni Di Perri at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 6 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Sloww accrual and COVID-19 related problems (impossible to perform LPs)). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
6-month variation in global deficit score in NPZ-8 complete neurocognitive tests according to the study arm; (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03163277, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2020.