E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hepatic steatosis in adults with chronic HIV-1 infection |
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E.1.1.1 | Medical condition in easily understood language |
HIV-1- infected patients with non-alcoholic fatty liver disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029530 |
E.1.2 | Term | Non-alcoholic fatty liver |
E.1.2 | System Organ Class | 100000004871 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
MAVMET is trying to find out if maraviroc, metformin or a combination of both results in a change in percentage of liver fat as measured by MR PDFF a type of MRI imaging over 48 weeks. |
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E.2.2 | Secondary objectives of the trial |
Secondary outcomes over 48 weeks are as follows:
1) Grade of hepatic steatosis as measured by MR PDFF 2) Liver enzymes: ALT, AST, ALP and GGT 3) Absolute and percentage CD4+ and CD8+ T-cells 4) plasma HIV RNA; 5) SAE 6) Grade 3 and 4 AEs 7) Treatment-limiting toxicity of any grade 8) Quality of life (QoL) as measured by EQ-5D-QL 9) Adherence to trial drugs 10) Use of all potentially hepatotoxic medications, including over-the-counter medication such as paracetamol
There are a number of other exploratory objectives including measuring the levels of inflammation in blood, looking at greater details of the exact changes in immune cells during the trial, and in a subset of people enrolling at Mortimer Market Centre, there is the option to have a brain MRI scan at the beginning of the trial and at the end.
Optional stored blood samples: these will be collected, stored and later tested to help understand how genes affect the amount of fat in liver, for example to measure the e.g. PNP3A g |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed informed consent 2) Age ≥35 years of age 3) Chronic HIV-1-infection for ≥5 years 4) On combination antiretroviral therapy (cART) and with virological suppression (<50 copies/mL) for ≥1 year 5) i)>1 abnormal (above the upper limit) of LFTS (ALT or AST) in the last 2 years with no other explanation (e.g. secondary syphilis) and/or ii) increased waist circumference ≥94 cm (≥90cm if South Asian origin) in men, ≥80cm in women and/or iii) a confirmed diagnosis of NAFLD on liver imaging (CT/MRI/ultrasound), FibroScan and/or iv) liver biopsy confirmed diagnosis of NALFD 6) For females of child bearing potential (CBP) agree to avoid pregnancy for the duration of the study 7) Able to comply with protocol requirements
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E.4 | Principal exclusion criteria |
1. Co-infection with hepatitis B or C 2. Confirmed chronic liver disease from any other cause (e.g. hepatitis C, hepatitis B) 3. Daily intake of alcohol >20g in women and >30g in men 4. Current illicit drug use that in the opinion of the investigator would interfere with patient’s ability to comply with the protocol 5. On metformin or another biguanide agent 6. Currently on maraviroc 7. Any contraindication to the receipt of maraviroc and/or metformin 8. Known B12 deficiency 9. Pregnant or breast feeding 10. Contraindication to MRI scanning 11. Peanut or soya allergy 12. eGFR <60 ml/min/1.73m2 13. ALT ≥10 x ULN 14. History of cardiovascular (ischaemic heart disease) or cerebrovascular disease. 15. Any other condition that in the opinion of the investigator would not make the patient suitable for the trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in percentage of liver fat as measured by MR PDFF between baseline and week 48. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) Grade of hepatic steatosis as measured by MR PDFF 2) Liver enzymes: ALT, AST, ALP and GGT 3) Absolute and percentage CD4+ and CD8+ T-cells 4) Plasma HIV RNA 5) SAE 6) Grade 3 and 4 AEs 7) Treatment-limiting toxicity of any grade 8) Quality of life (QoL) as measured by EQ-5D-QL 9) Adherence to trial drugs 10) Use of all potentially hepatotoxic medications, including over-the-counter medication such as paracetamol.
Exploratory outcomes over 48 weeks All participants 1) Sleep quality and quantity as captured on the sleep questionnaire 2) Fasting HOMA-IR and lipids 3) BMI 4) Anthropometric measures 5) Framingham 10-year cardiovascular risk score 6) Alcohol use 7) NALFD fibrosis score 8) Percentage of liver fat as measured by 1H MRS 9) Liver T1 MRI scan determined change in grade of liver fibrosis 10) Percentage of pancreatic fat as measured by MR PDFF 11) Percentage of total body fat as measured by MR PDFF 12) Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) area as assessed by MR PDFF.
In those consenting to stored blood collection and/or a *participant at Mortimer Market Centre, the change in the following over 48 weeks 1) *Absolute and percentage activated CD4+ and CD8+ T-cells (CD38+HLA-DR+); 2) Plasma levels of ligands for CCR5, changes in LPS and sCD14; leptin and adiponectin; 3) Inflammatory biomarkers (e.g. IL-6, hsCRP; D-dimer); 4) Liver specific inflammatory biomarkers e.g. hyaluronic acid; 5) Ultrasensitive HIV RNA.
Exploratory neuroimaging outcomes*
1) Total volume of white matter hyperintensities of presumed vascular origin on brain MRI 2) Sodium concentration in supratentorial white matter and deep grey matter 3) Fractional anisotropy and mean diffusivity in supratentorial white matter and deep grey matter
*In a subset of patients at Mortimer Market Centre only (maximum enrollment is 32), optional scans over 48 weeks.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial will be defined as when the last patient recruited has attended their week 48 visit, and key data queries have been considered to be resolved. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |