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
Department Name: UNLISTED
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.
Organisations
- University of Liverpool (Lead Research Organisation)
- Royal Liverpool University Hospital (Collaboration)
- Brighton and Sussex University Hospitals NHS Trust (Collaboration)
- UNIVERSITY OF THE HIGHLANDS AND ISLANDS (Collaboration)
- Lancaster University (Collaboration)
- NORTH MIDDLESEX UNIVERSITY HOSPITAL NHS TRUST (Collaboration)
- Southmead Hospital (Collaboration)
- The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust (Collaboration)
- Western General Hospital (Collaboration)
- UNIVERSITY HOSPITALS COVENTRY AND WARWICKSHIRE NHS TRUST (Collaboration)
- James Cook University Hospital (Collaboration)
- St James's University Hospital (Jimmy's) (Collaboration)
- Gemini Biosciences Ltd. (Collaboration)
- Mesoscale Diagnostics (Collaboration)
- Healx Ltd (Collaboration)
- Guy's and St Thomas' NHS Foundation Trust (Collaboration)
- Yorclinic (Collaboration)
- Royal Free London NHS Foundation Trust (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
Publications
Pushpakom S
(2020)
TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Pushpakom S
(2019)
Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT.
in NIHR Journals Library
Pushpakom SP
(2018)
Telmisartan reverses antiretroviral-induced adipocyte toxicity and insulin resistance in vitro.
in Diabetes & vascular disease research
Wason J
(2016)
Some recommendations for multi-arm multi-stage trials.
in Statistical methods in medical research
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 | Public |
Country | United Kingdom |
Start | 08/2016 |
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 | 05/2013 |
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 | Examples of clinical trials to repurpose a drug |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | This talk was presented at a conference 'Modern Methods in Life Science and Drug Research' organised by the University of Helsinki, Finland (Sept 16-17, 2019). |
Year(s) Of Engagement Activity | 2019 |
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 | Presentation at a International conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Dr Sudeep Pushpakom was invited to present on the TAILoR trial and the opportunities it presents to drug repurposing (TAILoR clinical trial - An academic translational approach to drug repositioning) at the 9th Annual Drug Repurposing event in September 21-22 in Washington, DC (the event was organised virtually this year). |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.drugrepositioningconference.com/index/agenda |
Description | Presentation at an International drug safety workshop |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Dr Sudeep Pushpakom was invited to present on drug safety research including the TAILoR trial at a drug safety workshop in Xi'an Jiaotong Liverpool University (XJTLU) in September 15-17, 2023 in Suzhou, China. |
Year(s) Of Engagement Activity | 2023 |
Description | Presentation in a meeting with Chinese Pharma |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Dr Sudeep Pushpakom was invited to present on drug safety research including the TAILoR trial at the headquarters of Jiangsu Hengrui Pharmaceuticals Ltd, Shanghai, China on September 20th, 2023. |
Year(s) Of Engagement Activity | 2023 |
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 |