| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Insulin resistance in HIV-positive patients treated with antiretroviral therapy |
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| E.1.1.1 | Medical condition in easily understood language |
| Reduced response to insulin (insulin resistance) in HIV-positive patients treated with antiretroviral therapy |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10022489 |
| E.1.2 | Term | Insulin resistance |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
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| E.2.2 | Secondary objectives of the trial |
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, TNFα, 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 |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Body fat redistribution study included in the main trial protocol (19/08/2014 v6.0):
Objectives:
i) To assess the differences in total body adipose content between baseline (T0) and 24-weeks telmisartan treatment (T+24) in three different dose groups as compared to the control (non-intervention group) using MRI.
ii) To assess the differences in intrahepatic and intramyocellular lipid content between baseline (T0) and 24-weeks telmisartan treatment (T+24) in three different dose groups as compared to the control by 1H Magnetic Resonance Spectroscopy (MRS).
Separate consent will be obtained from patients to participate in the MRI/ MRS sub-study. The patient information sheet given to patients will contain additional information on the sub-study and requirements for MRI/MRS.
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| E.3 | Principal 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.
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| E.4 | Principal 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.
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| E.5 End points |
| E.5.1 | 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). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timepoints of evaluation of the primary endpoint is at 24 weeks. |
|
| E.5.2 | 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-α, 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.
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| E.5.2.1 | 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. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Non-intervention arm will be the comparator |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the trial is defined to be the date on which data for all participants is frozen and data entry privileges are withdrawn from the trial database. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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