Insulin resistance in HIV-positive patients treated with antiretroviral therapy MedDRA version: 17.0 Level: PT Classification code 10022489 Term: Insulin resistance System Organ Class: 10027433 - Metabolism and nutrition disorders
Conditions
Interventions
Trade Name: Micardis 20mg tablets
Product Name: Telmisartan
Pharmaceutical Form: Tablet
INN or Proposed INN: Telmisartan
CAS Number: 144
Sponsors
University of Liverpool
Royal Liverpool and Broadgreen Hospitals NHS Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients who fulfil the following criteria will be included in the trial: . Adult (age 18 or above) HIV-positive individuals receiving antiretroviral therapy containing • a boosted protease inhibitor (lopinavir/ritonavir, atazanavir/ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir) • and/or efavirenz, rilpivirine, or etravirine for at least 6 months. The backbone can be based on N(t)RTI, raltegravir or maraviroc. Patients on protease inhibitor monotherapy will be included if they meet other criteria. Patients on nevirapine- or dolutegravir regimens, without concomitant boosted PIs, should not be included. Additionally, patients on Elvitegravir which is administered in combination with cobicistat (as Stribild) should not be recruited. 2. Ability to give informed consent. 3. Willingness to comply with all study requirements. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 310 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 60
Exclusion criteria
Exclusion criteria: 1. Pre-existing diagnosis of type 1 or 2 diabetes (Fasting glucose > 7.2mmol/L or HbA1c = 6.5% [48 mmol/mol] or abnormal OGTT or random plasma glucose = 11mmol/l) 2. Patients who consistently show low blood pressure (pre-existing hypotension; A reading below a threshold of 100/60 mm Hg on three separate occassions 3. Patients with renal disease (eGFR<60 in the 6 months preceding randomisation) 4. Patients with known untreated renal artery stenosis 5. Patients with cholestasis, biliary obstructive disorders or severe hepatic impairment 6. Patients with evidence of active, chronic hepatitis C infection (a previously cleared infection is not an exclusion) 7. Patients who are on unboosted atazanavir 8. Patients who are on/ have been on hormone therapy (eg. growth hormone), anabolics (eg. testosterone) and insulin sensitisers (eg. Metformin) within 6 months preceding randomisation. Patients who are on hormonal contraception are eligible. 9. Patients who are already on/ have been on other ARBs, ACE inhibitors, or direct renin inhibitors e.g. aliskiren within 4 weeks preceding randomisation. 10. Those with suspected poor compliance 11. Pregnant or lactating women 12. Women of childbearing age unless using reliable contraception (e.g. coil, barrier method, hormonal contraception) that does not interact with their antiretroviral therapy 13. Co-enrolment in other drug trials 14. Patients who have participated in a trial of an IMP likely to influence insulin sensitivity, plasma insulin, glucose levels or plasma lipid levels within 6 months preceding randomisation. 15. For the sub-cohort of patients undergoing MRI/MRS, normal MR exclusion criteria will apply.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Reduction in insulin resistance (as measured by HOMA-IR) in telmisartan treated arm(s) after 24 weeks of treatment in comparison with control (non-intervention arm). ; Main Objective: The trial will assess whether telmisartan can reduce insulin resistance (reduced response to insulin) in HIV-positive individuals being treated with combination antiretroviral therapy (cART). Primary objective: To determine the effect of telmisartan on insulin resistance in HIV-positive individuals on combination antiretroviral therapy using HOMA-IR (Homeostatic Model Assessment - Insulin Resistance) as a measurable, validated surrogate marker of insulin resistance. ; Secondary Objective: 1) To define the optimal dose of telmisartan that can significantly reduce insulin resistance; this dose will then be taken forward into phase III studies in the future. 2) To measure HOMA-IR values at the baseline and at 12, 24 and 48 weeks to provide data on time to, and sustainability of, reduction in HOMA-IR. 3) To evaluate the tolerability of telmisartan in this patient group. 4) To evaluate whether telmisartan favourably modulates the plasma concentrations of both beneficial (adiponectin and lipin1) and adverse (IL-6, resistin, TNFa, hs-CRP) biomarkers, which may help in further stratifying telmisartan therapy in the future. 5) To determine whether telmisartan improves general lipid homeostasis and reduces visceral fat accumulation in HIV-positive individuals on combination antiretroviral therapy over a 24-week period. 6) To determine whether liver and limb triglyceride content, markers of hepatic steatosis and insulin resistance respectively, are reduced by te ;Timepoint(s) of evaluation of this end point: The timepoints of evaluation of the primary endpoint is at 24 weeks. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Change in lipid profile at T+12, T+24 and T+48 weeks (increase in HDL-c, reduction in total cholesterol, triglycerides and LDL-c) between telmisartan treated arm(s) and the control arm. 2. Change in body fat redistribution as measured by MRI/MRS at T+24 weeks between telmisartan treated arm(s) and control arm (reduction in visceral fat, change in intrahepatic fat, change in lower leg muscle fat) 3. Change in plasma concentrations of biomarkers (adiponectin, lipin1, IL-6, TNF-a, Resistin and hs-CRP) at T+12, T+24 and T+48 weeks between telmisartan treated arm(s) and the control arm. 4. Change in insulin resistance, measured longitudinally, in telmisartan treated arm(s) in comparison with the control arm. 5. Difference in expected and unexpected adverse events between different telmisartan treated dose arm(s) and the control arm. ; Timepoint(s) of evaluation of this end point: 1) Change in lipid profile: The timepoints of evaluation are at weeks 12, 24 and 48. 2) Change in body fat redistribution: The timepoints of evaluation is at week 24. 3) Change in plasma concentrations of biomarkers: The timepoints of evaluation are at weeks 12, 24 and 48. 4) Longitudinal change in insulin resistance: The timepoints of evaluation are at weeks, 12 and 48. 5) Difference in expected and unexpected adverse events: at weeks 12, 24 and 48. | — |
Countries
United Kingdom
Contacts
Public ContactClinical Research Governance Manage
University of Liverpool
Outcome results
None listed