| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with documented diagnosis of T2DM with insufficient glycaemic control and at high risk of CV events prior to informed consent can be enrolled in the study. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with type 2 diabetes with insufficient glycaemic control and at high risk of CV events can be enrolled in the study. |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 primary objective is to demonstrate non-inferiority (by means of
comparing the upper limit of a two-sided 95% confidence interval with
the non-inferiority margin of 1.3) of treatment with linagliptin in
comparison to glimepiride (as monotherapy or as add-on therapy) with
respect to time to first occurrence of any of the adjudicated components of the primary composite endpoint (i.e. cardiovascular [CV] death, nonfatal stroke or non-fatal myocardial infarction [MI] (excluding silent MI) in patients with type 2 diabetes mellitus [T2DM]. If the non-inferiority hypothesis with margin 1.3 has revealed a significant result, then secondly, the primary composite endpoint will be tested hierarchically with a superiority hypothesis. |
|
| E.2.2 | Secondary objectives of the trial |
If the superiority test has revealed a significant result, then thirdly the first key secondary endpoint will be tested hierarchically. If the test of the first key secondary hypothesis has revealed a significant result, then fourthly the second key secondary endpoint will be tested hierarchically.
If the test of the second key secondary hypothesis has revealed a
significant result, then fifthly the third key secondary endpoint will be
tested hierarchically. |
|
| 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 |
| Sub-studies are planned that could further advance our understanding of important issues in the management of patients with T2DM related to oral DPP-IV inhibition. The sub-studies currently planned are three: one addressing glycaemic variability and its importance; one addressing cognitive function and factors associated with its decline; and one addressing long term β-cell function associated with the two different treatment strategies. The sub-studies will be described in separate protocols, which will be reviewed separately by IECs/IRBs and HAs. To date protocols of substudies are not yet available. |
|
| E.3 | Principal inclusion criteria |
Documented diagnosis of T2DM and concurrently 1) insufficient glycaemic control and 2) a high risk of CV events prior to informed consent
1) Insufficient glycaemic control (at Visit 1a) defined as:
a) HbA1c 6.5 - 8.5% (48 - 69 mmol/mol) while patient is treatment naïve (if intolerant or contra-indicated to first line anti-diabetic treatment) or treated with:
- metformin monotherapy, or
- alpha-glucosidase inhibitor monotherapy (e.g. acarbose, voglibose), or
- metformin + alpha-glucosidase inhibitor (e.g. acarbose, voglibose), or
b) HbA1c 6.5 - 7.5% (48 - 58 mmol/mol) while patient is treated with
- sulphonylurea (SU) monotherapy, or
- glinide monotherapy (e.g. repaglinide, nateglinide), or
- metformin + SU (combination maximal up to 5 years), or
- metformin + glinide (combination maximal up to 5 years) or
- alpha-glucosidase inhibitor + SU (combination maximal up to 5 years),
- alpha-glucosidase inhibitor + glinide (combination maximal up to 5 years)
2) High risk of CV events defined as any one (or more) of A), B), C) or D):
A) Previous Vascular Disease:
- Myocardial infarction (> 6 weeks prior to informed consent)
- Documented coronary artery disease or disease (≥50% luminal diameter narrowing of left main coronary artery or ≥50% in at least two major coronary arteries in angiogram)
- Percutaneous Coronary Intervention (PCI) > 6 weeks prior informed consent
- Coronary Artery By-pass Grafting (CABG) > 4 years prior to informed consent or with recurrent angina following surgery
- Ischemic or hemorrhagic stroke (> 3 months prior to informed consent)
- Peripheral occlusive arterial disease (previous limb bypass surgery, stenting or percutaneous transluminal angioplasty; previous limb or foot amputation due to circulatory insufficiency, angiographic or ultrasound detected significant vessel stenosis (>50%) of major limb arteries (common iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery), history of intermittent claudication, with an ankle: arm blood pressure ratio < 0.90 on at least one side).
B) Evidence of vascular related end-organ damage:
- Moderately impaired renal function (as defined by modified diet of renal disease (MDRD) formula) with estimated glomerular filtration rate [eGFRF]) 30-59 mL/min/1.73 m2
- Random spot urinary albumin:creatinine ratio ≥ 30 μg/mg (≥ 3.4 mg/mmol) in two of three unrelated specimens in previous 12 months prior Visit 1a
- Proliferative retinopathy defined as retinal neovascularisation or previous retinal laser coagulation therapy.
C) Age ≥ 70 years (at Visit 1a)
D) At least two of the following CV risk factors:
- Type 2 diabetes mellitus duration > 10 years at Visit 1a.
- Systolic blood pressure (SBP) > 140 mmHg (or on at least one blood pressure lowering treatment at Visit 1a)
- Current daily cigarette smoking
- LDL cholesterol ≥ 135 mg/dL (3.5 mmol/l) (or specific current treatment for this lipid abnormality) at Visit 1a
* Current = Blood pressure or LDL cholesterol measurement < 6 months prior V1a.
3) Body Mass Index (BMI) ≤ 45 kg/m2 at Visit 1b
4) Age ≥ 40 and ≤ 85 years at Visit 1a
5) Signed and dated written informed consent at the latest by the date of Visit 1a, in accordance with GCP and local legislation
6) Stable anti-diabetic background medication (unchanged daily dose) for at least 8 weeks prior V1a and without short term use of insulin. Background medication should be stable during screening/run-in phase to allow randomisation
Treatment compliance in the placebo run-in should be between 80% and 120%
to be eligible for randomisation.
Note: To ensure appropriate representation of patients from the different cardiovascular risk categories (A-D), the trial team will monitor the proportion of patients being recruited into these categories (trial level, and by region and/or country). In consultation with the steering committee, limitation of recruitment of a particular category may be arranged (trial level, or per region and/or country level). This process will be implemented to ensure a proper distribution of CV risk categories worldwide.
|
|
| E.4 | Principal exclusion criteria |
• Type 1 diabetes mellitus
• Any history and/or current treatment with other antidiabetic drugs (e.g. rosiglitazone, pioglitazone, GLP-1 analogue/agonists, DPP-IV inhibitors or any insulin) prior to informed consent. Note 1: This also includes clinical trials where these antidiabetic drugs have been provided to the patient. Note 2: previous short term use of any insulin (up to two consecutive weeks) is allowed (e.g. during hospitalisation) if taken at least 8 weeks prior informed consent.
• Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) within 3 months prior to informed consent
Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3
mmol/L) after an overnight fast during placebo run-in and confirmed by
a second measurement (not on the same day)
• Any previous (or planned within next 12 months) bariatric surgery (open or laparascopic) or intervention (gastric sleeve)
• Current treatment with systemic corticosteroids at time of informed consent or pre-planned initiation of such therapy Note: inhaled use of steroids (e.g. for asthma/COPD) is no exclusion criterion, as this does not cause systemic steroid action
• Change in dose of thyroid hormones within 6 weeks prior informed consent
• Active liver disease or impaired hepatic function, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at visit 1a
• Pre-planned coronary artery re-vascularization (PCI, CABG) within next 6 months after V1a or any previous PCI and/or CABG ≤ 6 weeks prior informed consent
• Known hypersensitivity or allergy to the investigational product or its excipients, or glimepiride (or the SU class).
Known hypersensitivity or allergy to the investigational product or its
excipients, or glimepiride (or the SU class)
• Inappropriateness of glimepiride treatment for renal safety issues or other issues (e.g. allergy) according to local prescribing information
Pre-menopausal women (last menstruation ≤ 1 year prior to informed
consent) who are nursing or pregnant,or are of child-bearing potential
and are not practicing an acceptable method of birth control (acceptable methods of birth control include tubal ligation, transdermal patch, intrauterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if allowed by local authorities), double barrier method and vasectomised partner) or do not plan to continue using acceptable method of birth control throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial.
Congestive heart failure of NYHA class III or IV
• Acute or chronic metabolic acidosis (present condition in patient history)
• Hereditary galactose intolerance
• Alcohol or drug abuse within the 3 months prior to informed consent
that would interfere with trial participation
• Participation in another trial with an investigational drug given within 2 months prior to informed consent
•Patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, has a life expectancy less than 5 years for non-CV causes, or has cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study
• Acute coronary syndrome ≤ 6 weeks prior to informed consent
• Stroke or TIA ≤ 3 months prior to informed consent |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint: time to first occurrence of any of the following
adjudicated components of the primary composite endpoint: CV death
(including fatal stroke and fatal MI), non-fatal stroke or non-fatal MI
(excluding silent MI). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The number of confirmed adjudicated primary endpoint events will be
continuously monitored during the trial. Based on the available number
of events the projected number of expected future events will be
calculated. As soon as the projection reliably suggests that the total
number of patients with a by adjudication confirmed primary endpoint
event will reach 631, the trial team will perform respective actions to
stop the trial. |
|
| E.5.2 | Secondary end point(s) |
First key secondary endpoint: time to first occurrence of any of the
following adjudicated components of the composite endpoint: CV death
(including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI
(excluding silent MI) or hospitalization for unstable angina pectoris.
Second First key secondary endpoint: composite endpoint of (treatment
sustainability defined as the proportion of patients that are on study
treatment at study end, that at Final Visit maintain glycaemic control
(HbA1c ≤ 7.0%) without need for rescue medication (between end of
titration [Visit 6] and Final Visit) and patients without any
moderate/severe hypoglycaemic episodes (between Visit 6 and Final
Visit) and without > 2% weight gain at Final Visit (between Visit 6 and
Final Visit)).
Third Second key secondary endpoint: composite endpoint of (treatment sustainability defined as the proportion of patients that are on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%) without need for rescue medication (between Visit 6 and Final Visit) and patients without > 2% weight gain at Final Visit (between Visit 6 and Final Visit)) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 16 weeks the secondary endpoints will be evaluated (up to an
estimated 432 weeks). |
|
| 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 | Yes |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 200 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Czech Republic |
| Finland |
| France |
| Georgia |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Peru |
| Philippines |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Tunisia |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| An independent Data Monitoring Committee (DMC) will review safety and efficacy data and make recommendations whether to continue the study, continue the study with modifications, or terminate the study. See for further details the trial protocol. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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