Title: 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)
Funder: Department of Health (England)

Abstract: 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.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION;METABOLIC AND ENDOCRINE