TAILoR (TelmisArtan and InsuLin Resistance in HIV): A Dose-Ranging Phase II Randomised Open-Labelled Trial of Telmisartan as a Strategy for the Reduction of Insulin Resistance in HIV-Positive Individuals on Combination Antiretroviral Therapy (cART)

Lead Research Organisation: University of Liverpool

Abstract

HIV is now a chronic disease treatable by combination antiretroviral therapy (cART). This has resulted in a reduction in HIV-related mortality, but has also led to the emergence of serious adverse effects such as HIV lipodystrophy (HIVLD). This condition is characterised by fat loss (from face and limbs) and fat accumulation (abdomen and back of neck), high cholesterol levels, reduced response to insulin (insulin resistance) and sometimes diabetes, and importantly, an increase in the risk of ischaemic heart disease. A key abnormality seems to be insulin resistance, which can also occur in untreated HIV patients. Although more “lipid-friendly” anti-HIV drugs have been introduced, because (a) drugs have to be used in combinations, (b) there is frequent switching of drugs because of other side effects or the occurrence of viral mutations, and (c) we are treating an increasingly older HIV-positive population, almost all patients will develop insulin resistance. There is a need to find new strategies to reduce insulin resistance in HIV-positive individuals treated with cART, which ultimately will reduce the associated cardiovascular risk. We will use telmisartan, a drug that is widely used for the treatment of hypertension. In hypertensive patients, it has been shown to reduce insulin resistance and improve various indicators (biomarkers) of cardiovascular health. In HIVLD, the fat cell (adipocyte) is key to the development of insulin resistance. Anti-HIV drugs interact with fat cells, making them lose their ability to store fat in some instances, and increase the secretion of active molecules called cytokines, which lead to inflammation and insulin resistance. We have shown that telmisartan can prevent HIV drug-induced fat loss in adipocytes, reduction in adiponectin (a marker of cardiac health) and lipin1 (a marker of fat cell formation). The aim of the proposed trial is to investigate whether telmisartan can reduce the insulin resistance observed in HIV-positive individuals on cART. We will compare 3 different doses of telmisartan with the control group (those who do not take telmisartan) to determine the effect on insulin resistance over a period of 48 weeks. We are using a novel adaptive trial design for this study – this has been developed in conjunction with the North West MRC trials methodology hub. Our team consists of experts in HIV medicine, pharmacology and diabetes, scientists and trial statisticians to ensure the successful conduct of this trial, which will be run via an accredited clinical trials unit. We have provided full justification for costs requested. If telmisartan shows a significant beneficial effect on insulin resistance, the next step would be to conduct a larger phase III study to assess its effect on cardiovascular morbidity in HIV-positive individuals treated with cART.

Technical Summary

Research design: A Phase II randomised, open labelled, dose ranging trial of telmisartan in HIV-positive individuals on cART over a period of 48 weeks. An adaptive trial design will be utilised with a single interim analysis performed when half of the planned maximum of 336 patients have been followed up for at least 24 weeks. Study population: Adult HIV-positive individuals receiving antiretroviral therapy containing a boosted protease inhibitor [Lopinavir/ritonavir (LPV/r), Atazanavir/ritonavir (ATV/r), Darunavir/ritonavir (DRV/r), Fosamprenavir/ritonavir (FPV/r)] and/or Efavirenz (EFV), for at least 6 months. Exclusion criteria include known diabetes, low blood pressure, suspected poor compliance, renal disease, use of unboosted ATV and use of ACE-inhibitors. Patient recruitment and interventions: Patients will be recruited from 8 HIV treatment centres and initially randomised (1:1:1:1 allocation ratio) to receive 3 doses of telmisartan (20, 40, and 80mg) or no intervention (controls). In the telmisartan 40 and 80mg arms, dose titration will be undertaken over 4 weeks in order to step-up to the allocated dose, or else the maximum tolerated dose if the target is not achieved. Proposed outcome measures: The primary outcome measure is the change in insulin resistance in the telmisartan-treated group(s) in comparison with the control group as measured by HOMA-IR at 24 weeks. Secondary outcomes include (a) change in visceral fat accumulation; and (b) change in the expression of biomarkers (fasting lipids, adiponectin, lipin1, IL-6, resistin, TNFa and hs-CRP) in telmisartan treated group(s) in comparison to the controls. MRI scans and MR spectroscopy will also be performed at baseline and at 24 weeks in a sub-set of patients. These measurements represent the mechanistic assessment of drug action. Assessments & follow up: Fasting blood glucose and insulin (for calculating HOMA-IR) and lipid assessments will be performed at baseline, 12, 24 and 48 weeks. An independent Data Monitoring and Ethics Committee will monitor study progress and patient safety. Proposed sample size: The maximum total sample size will be 336 patients across all treatment arms and the study will seek to recruit 34 additional patients to account for a 10% drop-out rate. This calculation is based on a one-sided type I error of 5% and a power of 90% of achieving significance if patients on telmisartan have a 65% chance of observing a greater reduction in HOMA-IR score than the controls. Statistical analysis: When 24 week data are available on 168 patients (42 per group), an interim analysis will be conducted. If any active dose can already be seen to be substantially better than control in terms of HOMA-IR, then the trial will be stopped and that dose recommended for further study. Otherwise, recruitment will continue to control and to any active doses that are better than control in terms of HOMA-IR until another 42 patients have been observed in each remaining treatment arm. Project time tables including recruitment rate: Trial duration is 47 months; m1-4, trial set up; m5-30, recruitment; m25, interim analysis; m31-42, follow-up; m43-47, final data cleaning and analysis. The 25 month recruitment period is based on 8 HIV treatment centres each recruiting 3 patients per month with a 4 month staggered start.
 
Description Efficacy and Mechanism Evaluation - Supplementary funding
Amount £21,775 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 12/2016 
End 03/2017
 
Description HEIF funded Connecting Capability Fund (managed by the Business Gateway)
Amount £16,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 03/2018
 
Description KE Voucher (awarded to Sudeep Pushpakom)
Amount £8,300 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 12/2015 
End 07/2016
 
Description MRC Proximity to Discovery award to Sudeep Pushpakom
Amount £10,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 05/2017
 
Description Technology Directorate Voucher Scheme awarded to Dr Sudeep Pushpakom (Metabolomic analysis of insulin resistance in HIV)
Amount £4,468 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 11/2017 
End 12/2018
 
Description University of Liverpool Technology Directorate Voucher (awarded to Sudeep Pushpakom)
Amount £8,500 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 06/2013 
End 12/2013
 
Description Biomarker analysis collaboration with MesoScale Discovery 
Organisation Mesoscale Diagnostics
Country United States 
Sector Public 
PI Contribution I have negotiated this collaboration to undertake analysis of biomarkers using samples from this trial.
Collaborator Contribution The collaborators will provide us with thier expertise in biomarker analysis and work with us in optimising protocols.
Impact No outputs yet.
Start Year 2016
 
Description Collaboration in Drug repositioning 
Organisation Healx Ltd
Country United Kingdom 
Sector Private 
PI Contribution Sudeep Pushpakom entered into a collaboration with this partner.
Collaborator Contribution The collaborator will provide their expertise in computational approaches for drug repositioning which will be undertaken as part of this collaboration.
Impact None yet.
Start Year 2015
 
Description Collaboration with SME to utilise proteomics for drug repurposing 
Organisation Gemini Biosciences Ltd.
Country United Kingdom 
Sector Private 
PI Contribution Sudeep Pushpakom entered into a collaboration with this Drug repurposing SME and the project is currently underway.
Collaborator Contribution The industrial partner will provide part of the costs for undertaking quantitative proteomics and also waive the cost of staff time.
Impact We are in receipt of the results and this is currently being analysed.
Start Year 2016
 
Description Lancaster University 
Organisation Lancaster University
Department Department of Mathematics and Statistics
Country United Kingdom 
Sector Academic/University 
PI Contribution Coordination and conduct of trial, sample storage and analysis
Collaborator Contribution Interim analysis of the data
Impact The collaboration has already contributed to the preparation of TAILoR grant proposal. Further outputs are expected during analysis.
Start Year 2012
 
Description Lipidomics collaboration (UHI) 
Organisation University of the Highlands and Islands
Department Department of Diabetes and Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution I have initiated this collaboration with this partner.
Collaborator Contribution The collaborator has carried out some pilot lipidomic analysis for us in kind. We intend to work with them further over the coming months to generate more results and collaborate with them on grants and publications.
Impact Only output from this collaboration is some pilot data which we are working on.
Start Year 2015
 
Description TAILoR - Royal Liverpool Hospital 
Organisation Royal Liverpool University Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Cosponsoring the trial and patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation Brighton and Sussex University Hospitals NHS Trust
Department Clinical Infectious Diseases Service (CIS)
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation Guy's and St Thomas' NHS Foundation Trust
Department Infectious Diseases
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation James Cook University Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation King's College London
Department Department of Infectious Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation North Middlesex University Hospital NHS Trust
Department Infectious Diseases
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation Royal Free London NHS Foundation Trust
Department Infectious Diseases
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation Southmead Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation St James's University Hospital (Jimmy's)
Department Infectious Diseases
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
Department Infectious Diseases
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation University Hospitals Coventry and Warwickshire NHS Trust
Department Infectious Diseases
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation Western General Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description TAILoR NHS Trusts 
Organisation Yorclinic
Country United Kingdom 
Sector Hospitals 
PI Contribution Coordinating and conducting the trial, sample storage and analysis
Collaborator Contribution Patient recruitment
Impact None yet
Start Year 2012
 
Description Cheltenham Science Festival 7th July 2014 (BPS PERSONALISED MEDICINE ) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Present a broad range of science and scientific issues in an exciting and engaging environment.

To present a broad range of science and scientific issues in an exciting and engaging environment t encourge people to pursue careers in science and bring to life
Year(s) Of Engagement Activity 2014
 
Description European AIDS Clinical Society Meeting, Milan, October 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Sudeep Pushpakom presented the results of the TAILoR clinical trial at the European AIDS Clinical Society Meeting in Milan, 25-27th October, 2017. The presentation was well received and highlighted the need for strategies to reduce important adverse drug effects such as metabolic disease in HIV patients.
Year(s) Of Engagement Activity 2017
 
Description Kuala Lumpar - Visiting Lecturer July 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Series of talks to University of Malayisia Students and other Universities at undergrad, post graduate and academic staff on a rnage of topics aimed at promoting the realms and possibilities of Pharmacogenetics

Promoting the numbe rof opportunities and ideas within Pharamcogenomics
Year(s) Of Engagement Activity 2015
 
Description MRC CDSS Drug Repositioning Workshop (Sudeep Pushpakom) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This was a workshop organised at the University of Liverpool under the Centre for Drug Safety Science attended by scientists, academia, pharma industry and regulatory agency representatives where the current status of drug repositioning was discussed.
Year(s) Of Engagement Activity 2015
 
Description Organisation of a symposium on drug repurposing at an International conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Sudeep Pushpakom organised and chaired a drug repurposing symposium at the British Pharmacological Society annual meeting (December 2018). The meeting was attended by scientists, clinicians, pharma industry, patient groups, undergraduate and postgraduate students and media.
Year(s) Of Engagement Activity 2018
 
Description Personalised Medicine Workshop 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Inited talk at a University workshop on personalised medicine

Well apreciated
Year(s) Of Engagement Activity 2013
 
Description Utrecht Institute for Pharmaceutical Sciences (UIPS) of Utrecht University October 2016 - Keynote speech 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact symposium "Bioinspired therapies UIPS is conducting research from molecule to patient populations, where our division of Pharmacoepidemiology & Clinical Pharmacology is focused on the last stage of drug development.
Year(s) Of Engagement Activity 2016