Condition category
Infections and Infestations
Date applied
29/01/2018
Date assigned
12/02/2018
Last edited
12/02/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Non- alcoholic fatty liver disease (NAFLD) is a common liver disease defined by fat in the liver, named as “steatosis”. NAFLD is mainly caused by metabolic disorders including obesity, hypertension, high lipids or diabetes. It is most frequently a benign disease. However, steatosis can induce liver inflammation (swelling) and scarring (fibrosis) defining non-alcoholic steatohepatitis (NASH). NASH is a more severe liver disease and is associated with a higher risk of liver complications including cirrhosis (late stage scarring) and liver cancer. HIV-infected patients are at particularly high risk of NAFLD and NASH due to drug exposure and chronic HIV infection. In non-HIV as well as HIV individuals the diagnosis of NASH requires a liver biopsy (a procedure that takes a small sample of tissue) and its best therapeutic options remain under evaluation. Maraviroc (MVC), a licensed and well-tolerated HIV drug might also have benefits on inflammation and liver fibrosis. Experimental and human studies have shown that MVC can improve liver injuries (steatosis, inflammation and fibrosis) suggesting its potential benefits in patients with NASH. No study as examined the role of MVC in HIV-associated NASH. This study aims to assess the benefits of MVC in addition to the current antiretroviral regimen of patients with HIV mono-infection and NASH.

Who can participate?
Adults aged 18-75 who have HIV and NASH.

What does the study involve?
Participants with liver-biopsy proven NASH are offered 48 weeks treatment with MVC according to standard licensed dosing. They are reviewed two weeks after treatment initiation and then every 3 months, before a liver biopsy at the end of treatment which will be compared to the pre-treatment biopsy. MVC will then be discontinued. If the study reports significant changes in liver injury after MVC treatment, we will be able to run a larger trial. This will open the way for HIV-NASH treatment which is currently not available.

What are the possible benefits and risks of participating?
There are no proven benefits to taking part, although we do hope that the care patients receive as part of this study will reduce harmful inflammation in the liver caused by NASH. The risks include rare but potentially serious complications from the liver biopsy, and common side effects from maraviroc include postural hypotension, nausea, headaches and depression.

Where is the study run from?
This study is being run by St Mary’s Hospital (UK) and takes place in hospitals in the UK.

When is the study starting and how long is it expected to run for?
June 2017 to December 2019

Who is funding the study?
VIIV Healthcare Limited (UK)

Who is the main contact?
Dr James Maurice (Scientific)

Trial website

N/A

Contact information

Type

Scientific

Primary contact

Dr James Maurice

ORCID ID

http://orcid.org/0000-0003-1530-5328

Contact details

Liver and Antiviral Unit
10th Floor QEQM
St Mary’s Hospital
South Wharf Road
London
W21NY
United Kingdom

Additional identifiers

EudraCT number

2017-003172-32

ClinicalTrials.gov number

Protocol/serial number

36017

Study information

Scientific title

Maraviroc Add-on Therapy for Steatohepatitis in HIV

Acronym

The MASH Trial

Study hypothesis

The aim of this study is to conduct a proof of concept trial which investigates whether Maraviroc reduces the inflammatory infiltrate in the liver of patients with HIV-NASH.

Ethics approval

East of England- Cambridge and Hertfordshire Research Ethics Committee, 30/10/2017, ref: 17/EE/0387

Study design

Non-randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

See additional files

Condition

Specialty: Hepatology, Primary sub-specialty: Hepatology; UKCRC code/ Disease: Oral and Gastrointestinal/ Diseases of liver, Infection/ Human immunodeficiency virus [HIV] disease

Intervention

This is an multicentre single arm open label study. All participants have a baseline liver biopsy followed by 48 weeks treatment with Maraviroc in addition to their existing antiretroviral regimen. A second liver biopsy is performed at week 48. Participants are reviewed every 12 weeks throughout the trial, with a final follow-up review at week 52.

Intervention type

Other

Phase

Phase II

Drug names

Primary outcome measure

Change in the number of hepatic immune cells- including CD3+, CD4+, CD8+, T-bet+, CD56, CD68, CD163 and myeloperoxidase positive cells, identified using immunohistochemistry- in the liver biopsies after 48 weeks of treatment with Maraviroc as compared to baseline.

Secondary outcome measures

1. Improvement in biochemical (fasting glucose, lipids and HOMA index) metabolic parameters at 48 weeks as compared to baseline
2. Modification of circulating inflammatory cytokines, adipokines and markers of macrophage activation (high sensitive IL6, sTNFR1/2, sCD14, sCD163, hsCRP, Leptin, Total and High molecular weight adiponectin) at 48 weeks as compared to baseline
3. Number of subjects with a reduction in the NAS score by ≥2 points without worsening of fibrosis at 48 weeks as compared to baseline
4. Number of subjects with a reduction in the degree of liver steatosis, inflammation and/or ballooning at 48 weeks as compared to baseline
5. Number of subjects with a reduction of at least one stage of liver fibrosis in patients with fibrosis at 48 weeks as compared to baseline
6. Number of subjects with a reduction of Fibroscan® values and biochemical markers of fibrosis (APRI, Fib-4, NAFLD Fibrosis Score[5]) from at 48 weeks as compared to baseline
7. Number of subjects with normalization of Fibroscan values at 48 weeks
8. Number of subjects with a reduction in liver transaminases (ALT and AST) levels at 48 weeks as compared to baseline

Overall trial start date

07/06/2017

Overall trial end date

01/12/2019

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. HIV-1 infected individuals (males and females) aged 18-75 years
2. Stable antiretroviral therapy for at least one year on a regimen that is unlikely to change in the next 12 months
3. At least two consecutive undetectable HIV viral loads defined by HIV RNA ≤50 copies/mm3 for at least 6 months prior to the date of inclusion
4. CD4 count ≥ 200 cells/mm3
5. Histological evidence of NASH based on liver histology performed within 12 months prior to visit 1 (Week 0) with a NAFLD activity score (NAS) ≥ 4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte ballooning)[26] and <10% weight loss since the time of liver biopsy (see appendix 2 for criteria for offering liver biopsy)
6. Consent to second liver biopsy after 48 weeks treatment with MVC.
7. Patient able to understand and sign a consent form

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 30; UK Sample Size: 15

Participant exclusion criteria

Liver co-morbidities:
1. Positive HBs antigen (HBsAg)
2. Positive HCV antibody (HCVAb), with the exception of subjects with the presence of HCVAb but negative hepatitis C virus RNA without treatment (i.e. spontaneous clearance following acute infection).
3. Underlying acute or chronic liver disease including non- B non- C viral hepatitis (A & E), autoimmune liver disease, biliary disease, hemochromatosis, Wilson´s disease, alpha-1-antitrypsin deficiency.
4. History of decompensated cirrhosis including ascites, hepatic encephalopathy, or variceal bleeding.
5. Suspicion of drug-related toxicity defined by abnormal LFTs following the recent introduction of a new medication.

Additional co-morbidities:
1. Active, serious infections that require parenteral antibiotic or antifungal therapy within 30 days prior to screening visit.
2. Active AIDS-defining disease other than oesophageal candidiasis.
3. Any active life- threatening disease
4. Active malignancy (except for early dysplastic lesions eg anal dysplasia)
5. Congestive cardiac failure
6. Platelet count < 100x103 cells/mm3 and/or INR > 1.4
7. Severe renal impairment with CrCl< 30mL/min

Lifestyle:
Excessive alcohol consumption during the last 6 months prior inclusion defined by more than 14 units/week for women or 21 units/week for men

Concomitant medications:
1. Patients actively treated with Maraviroc or having received Maraviroc over the last 12 months.
2. Weight reduction through bariatric surgery in the past 5 years or planned during the conduct of the study.
3. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents or immunomodulating agents.
4. Receiving any experimental medications within 30 days prior to screening or anticipated use during the trial.
5. Patients receiving pioglitazone, rosiglitazone, vitamin E 800 IU/day, , and/or ursodeoxycholic acid since these drugs may have confounding effect on efficacy of MVC

Others
1. Females who are pregnant or breastfeeding
2. Allergy to the study drug or its components (including peanut and soya)
3. Participation in any other clinical trial at Screening without approval from the Sponsor

Recruitment start date

02/04/2018

Recruitment end date

01/08/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

St Mary’s Hospital
South Wharf Road
London
W21NY
United Kingdom

Trial participating centre

Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom

Trial participating centre

Chelsea and Westminster Hospital
369 Fulham Road
London
SW10 9NH
United Kingdom

Trial participating centre

Centre for Infectiology
Driesener Strasse 11
Berlin
10439
Germany

Trial participating centre

University Hospital
Sigmund-Freud-Strasse 25
Bonn
53127
Germany

Trial participating centre

Infectiology Centre Hamburg,
Grindelallee 35
Hamburg
20146
Germany

Sponsor information

Organisation

Imperial College of Science, Technology and Medicine

Sponsor details

Imperial College London (Gisela Pereira-Barreto)
London
SW7 2AZ
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

VIIV Healthcare Limited

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Abstracts will be submitted to international conferences on liver diseases (EASL or AASLD) and on HIV infection (CROI). Publication of data will then be submitted to international peer- reviewed journals.

IPD sharing statement:
The datasets generated during and/or analysed during the current study will be stored in a publically available repository.

Intention to publish date

01/12/2020

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes