| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Non diabetic hyperglycaemia:
Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG) or both |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065542 |
| E.1.2 | Term | Prediabetes |
| E.1.2 | System Organ Class | 100000004861 |
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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 |
| To assess the effect of treatment with linagliptin, metformin or the combination of linagliptin with metformin, plus lifestyle intervention (diet and physical activity), compared to lifestyle intervention alone, for at least 3 years, and up to 5 years, on different microvascular parameters (retinal, renal and neurological), as defined by the primary and secondary endpoints, in adults with non diabetic hyperglycaemia (IGT, IFG or IFG plus IGT). |
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| E.2.2 | Secondary objectives of the trial |
1- To identify among people with hyperglycaemia who are most likely to develop early diabetic complication
2- To determine the extent to which the compliance to the interventions affect the rate on early diabetic complications prevention
3- To evaluate the effect of the different treatment regimes applied in this study on quality of life and neuropsychological functions
4- To assess the efficacy of treatment with linagliptin, metformin and the combination of sitagliptin with metformin plus lifestyle intervention in comparison to lifestyle intervention alone with regard to surrogate parameters of vascular function and structure, and novel biomarkers of microvascular damage in adults with hyperglycaemia (IGT, IFG or IFG plus IGT)
5- To determine the safety of linagliptin or metformin and the combination of sitagliptin with metformin plus lifestyle intervention in people with non diabetic hyperglycaemia with regard to severe adverse effects and clinically important events
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Men and women
• Age 45 -74 years
• Impaired Fasting Glucose (IFG): FPG 6.1 to 6.9mmol/l and 2-h PG <7.8mmol/L; or Impaired Glucose Tolerance (IGT): FPG <7.0mmol/L and 2h PG >_7.8 and <11.1 mmol/L; or both conditions;
• Informed consent given
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| E.4 | Principal exclusion criteria |
• Type 1 diabetes.
• Known* or unknown T2D (including screen detected T2D) with or without pharmacological treatment.
• Use of a GLP-1 receptor agonist (exenatide or other) or pramlintide or any dipeptidyl peptidase 4 (DPP-4) inhibitor or metformin within the 3 months prior to enrolment.
• Use of insulin or long-acting insulin analogue within 3 months prior to enrolment.
• Any previous cardiovascular or cerebrovascular clinically documented event or revascularization procedure*.
• Clinical evidence of macro-vascular complications (overt clinical cardiovascular disease) at enrolment, including angina (stable or unstable) and evidence of previous myocardial infarction in baseline EKG.
• Current renal replacement therapy.
• A previous diagnosis of liver cirrhosis or chronic hepatitis*, or an elevation of liver enzymes (AST and or ALT) >3 tiems normal ranges.
• Previous diagnosis of Chronic heart failure (NYHA class III or higher).
• A prior solid organ transplant or awaiting solid organ transplant.
• Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Subjects with intraepithelial squamous cell carcinoma of the skin (Bowen’s disease) treated with topical 5-fluorouracil (5FU) and subjects with basal cell skin cancer are allowed to enter the trial.
• Any acute condition or exacerbation of chronic condition that would in the Investigator's opinion interfere with the initial trial visit schedule and procedures.
• Known or suspected hypersensitivity to trial products or related products.
• Known use of non prescribed narcotics or illicit drugs.
• Simultaneous participation in any other clinical trial of an investigational agent.
• Females of childbearing potential who are pregnant (all fertile women will be tested for before randomization), breast-feeding or intend to become pregnant.
• Presence of cataract that impedes the retinal evaluation of both eyes.
• Other previously diagnosed retinal diseases.
• Any diseases that would prevent the measurement of primary endpoints
• Dementia, mental disorder or evident cognitive impairment unable to give informed consent.
• End-stage or metastatic cancer.
• Institutionalization.
• Renal function impairment: GFR <60 ml/min/1.73m2.
• Contraindication to any of the study drugs (metformin or linagliptin). This includes: ALT > 3 times the upper limit of normal, history of cirrhosis or hepatitis, suspected renal artery stenosis, recent gastrointestinal bleeding (within the last year), pregnant, breastfeeding or a female of child-bearing potential not on reliable contraception and also any circumstance where ongoing medication might lead to potential adverse drug interaction with components of the trial medications.
• Any other reason, medical condition, ongoing medication or significant disability that would prevent the participant complying with trial consent, treatment and follow-up procedures or potentially jeopardise her/his medical care.
* Previous diagnosis should be documented after medical record review.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is a combined continuous variable, "the microvascular complication índex" (MCI), composed by the linear combination of the Early Treatment Diabetic Retinopathy Study Scale (ETDRS) score, the level of urinary albumin to creatinine ratio, and sudomotor test (SUDOSCAN) score, measured during the 36th and 60th month visits. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 36 and 60 months after randomization |
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| E.5.2 | Secondary end point(s) |
• Retinopathy score at last visit defined as 2 steps progression on the ETDRS scale between baseline and visits at months 36th and 60th .
• One standard deviation (SD) increase on the level of urinary albumin to creatinine ratio between baseline and visits at months 36th and 60th
• One SD decrease Changes in the level of hands and feet conductance in SUDOSCAN between baseline and visits at months 36th and 60th.
• Change in microvascular endothelial function (MEF) measured by the EndoPAT method (in a subset).
• Change in the Non-Alcoholic Fatty Liver (NAFL) Index (in a subset).
• Change in biomarkers of microvascular damage, endothelial function, per-oxidation, inflammation, and metabolomics (in a subset).
• Change in the insulin secretion and β-cell function.
• Change in self-perceived Quality of Life (QoL).
• Change in symptoms of peripheral neuropathy
• Change in neuropsychological parameters: cognitive function, anxiety and depressive symptoms and indices.
• Changes in Obstructive Sleep Apnoea (OSA) indices as measured by Somnomedics (in a subset).
• Changes in ambulatory blood pressure monitoring (in a subset)
• Change in the mean common carotid intimae-media thickness (CIMT) (in a subset).
• Incidence of major cardiovascular events, defined as an expanded composite of total coronary events, total stroke events, revascularization procedures (coronary artery bypass graft, percutaneous coronary angioplasty, and peripheral revascularization), hospitalization for heart failure, transient ischaemic attack, and cardiovascular or cerebrovascular death
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Bulgaria |
| Germany |
| Greece |
| Italy |
| Lithuania |
| Poland |
| Serbia |
| Spain |
| Switzerland |
| Turkey |
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| 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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| Last Visit Last Object (LVLS) |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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