E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 diabetes mellitus (T2DM) |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 14.1 |
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 |
To compare the impact of including sitagliptin as part of usual care vs. usual care without sitagliptin on CV outcomes as measured by the time to first event in the primary CV composite endpoint of CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. |
|
E.2.2 | Secondary objectives of the trial |
To compare the impact of including sitagliptin as part of usual care vs. usual care without sitagliptin on:
1 The time to first event in a secondary composite CV endpoint of CV-related death, nonfatal MI, and nonfatal stroke.
2 The time to first event for each of the following individual CV endpoints: confirmed CV-related death, MI (fatal + nonfatal), stroke (fatal + nonfatal), and unstable angina requiring hospitalization.
3 All-cause mortality.
4 Hospital admissions for congestive heart failure as reported by the investigator;
5 Change from baseline in HbA1c over time
6 Change in renal function and albuminuria over time
7 In patients not receiving insulin at baseline, time to initiation of long-term insulin therapy. Long term insulin therapy is defined as a continuous period of insulin use of more than 3 months
8 In patients not receiving insulin at baseline, time to addition of first co-interventional agent
9 Medical resource utilization during the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a. Patient has T2DM with HbA1c of ≥ 6.5% (48 mmol/mol) and ≤ 8.0% (64 mmol/mol) (HbA1c must be documented within 3 months prior to study enrollment) while receiving metformin, pioglitazone, or a sulfonylurea as monotherapy or any dual combination of metformin, pioglitazone, or a sulfonylurea continuously without alteration in dose for at least 3 months OR a stable dose of insulin (±20% of the scheduled total daily insulin dose) either alone or in combination with a stable dose of metformin for at least 3 months
b. Patient is able to see a usual care provider at least twice a year
c. Patient is ≥ 50 years of age with preexisting vascular disease, defined as having any one of the following:
c.1 History of a major clinical manifestation of coronary artery disease (i.e., myocardial infarction, surgical or percutaneous [balloon and/or stent] coronary revascularization procedure, or coronary angiography showing at least one stenosis ≥ 50% in a major epicardial artery or branch vessel);
c.2 Ischemic cerebrovascular disease, including:
c.2.1 History of ischemic stroke. Strokes not known to be hemorrhagic will be allowed as part of this criterion;
c.2.2 History of carotid arterial disease as documented by ≥ 50 % stenosis documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or without symptoms of neurologic deficit.
c.3 Atherosclerotic peripheral arterial disease, as documented by objective evidence such as amputation due to vascular disease, current symptoms of intermittent claudication confirmed by an ankle-brachial pressure index or toe brachial pressure index less than 0.9 or history of surgical or percutaneous revascularization procedure.
d. Female patients agree to use an effective method of contraception or must not otherwise be at risk of becoming pregnant.
e. Patient understands the study procedures, alternative treatments available, and the risks involved with the study, and voluntarily agrees to participate by providing written informed consent.
f. Patient agrees to provide permission to obtain all medical records necessary for complete data ascertainment during the follow-up period. |
|
E.4 | Principal exclusion criteria |
a. Patient has a history of type 1 diabetes mellitus or a history of ketoacidosis.
b. Patient has a history of ≥2 episodes of severe hypoglycemia during the 12 months prior to enrollment. Severe hypoglycemia (hypoglycemia requiring assistance) refers to instances in which the patient was sufficiently disoriented or incapacitated as to require help from either another individual or from medical personnel (whether or not this assistance was actually provided).
c. Patient has taken an approved or investigational DPP-4 inhibitor agent (e.g., sitagliptin, alogliptin, saxagliptin, or vildagliptin), or GLP-1 analogue (e.g., exenatide, exenatide LAR, or liraglutide), or a thiazolidinedione other than pioglitazone within the past 3 months.
d. Patient has cirrhosis of the liver, as assessed by medical history.
e. Patient is enrolled in another experimental protocol which involves the use of an investigational drug or device, or an intervention that would interfere with the conduct of the trial.
f. Patient has a planned or anticipated revascularization procedure.
g. Pregnancy or planned pregnancy during the trial period.
h. Patient has medical history that indicates a life expectancy of < 2 years or might limit the individual’s ability to take trial treatments for the duration of the study.
i. Patient has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance which, in the opinion of the investigator or coordinator, might pose a risk to the patient, make participation not in the patient’s best interest, confound the results of the study (e.g., if patient cannot comply with requirements of the study), or interfere with the patient’s participation for the full duration of the study.
j. Patient has an estimated GFR (calculated based on serum creatinine via the MDRD formula) of < 30 mL/min/1.73 m2.
k. Patient has a known allergy or intolerance to sitagliptin.
l. Patient has previously been enrolled in this trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Time to first confirmed CV event in the primary composite CV endpoint: defined as the time from randomization to first confirmed event in the primary composite CV endpoint (CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
CV endpoints are captured at baseline, month 4, month 8, annual visits (month 12, 24, 36, 48, 60, 72), telephone contacts, brief visits (month 18, 30, 42, 54, 66), end of study, and post-study phone contact
|
|
E.5.2 | Secondary end point(s) |
Time to first confirmed CV event in the secondary composite CV endpoint: defined as time from randomization to first confirmed event in the secondary composite CV endpoint (CV-related death, nonfatal MI, or nonfatal stroke).
- Time to first confirmed CV event for individual CV endpoints: defined as time from randomization to each of the components of the primary composite endpoint (CV-related death, MI [fatal + nonfatal], stroke [fatal +nonfatal], and unstable angina requiring hospitalization).
- Time to all-cause mortality: defined as time from randomization to death due to any cause.
- Time to congestive heart failure: defined as time from randomization to hospital admission for congestive heart failure and treatment with intravenous diuretics, inotropes, or vasodilator therapy.
- Change from baseline in urinary albumin to creatinine ratio over time.
- Change from baseline in eGFR over time.
- Change from baseline in HbA1c over time.
- Time to initiation of chronic insulin therapy: defined as continuous use longer than three months in patients not receiving insulin at baseline.
- Time to initiation of first co-interventional agent (i.e., next oral AHA or chronic insulin therapy in patients not receiving insulin at baseline).
- Count of hospitalizations for any reason. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1, 2, 4, 7-9) Endpoints are captured at baseline, month 4, month 8, annual visits (month 12, 24, 36, 48, 60, 72), telephone contacts, brief visits (month 18, 30, 42, 54, 66), end of study, and post-study phone contact
(3) Mortality: Date of death from any cause captured per patient
(5) HbA1c: captured at baseline, month 4, month 8, annual visits (month 12, 24, 36, 48, 60, 72) and end of study
(6) eGFR: captured at baseline, annual visits (month 12, 24, 36, 48, 60, 72), brief visits (month 18, 30, 42, 54, 66), and end of study
|
|
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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 290 |
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 |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
Colombia |
Czech Republic |
Estonia |
European Union |
Finland |
France |
Germany |
Hong Kong |
Hungary |
India |
Italy |
Korea, Republic of |
Latvia |
Lithuania |
Malaysia |
Netherlands |
Norway |
Spain |
Sweden |
Israel |
Poland |
Romania |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Taiwan |
Turkey |
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
|
|
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |