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)

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.

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.