E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 Diabetes Mellitus is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
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 |
To assess the impact of MK-3102 25 mg q.w. on time to confirmed CV outcomes as measured by the time to first event in the CV composite endpoint of CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization.
To assess the effect of treatment with MK-3102 25 mg q.w. compared with placebo on A1C at 4 months.
To demonstrate the non-inferiority of MK-3102 (omarigliptin) compared with placebo (against a background of standard of care) on the time to first occurrence in the composite endpoint of cardiovascular death, nonfatal MI or non-fatal stroke. |
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E.2.2 | Secondary objectives of the trial |
To assess the impact of MK-3102 25 mg q.w. on:
a. the key secondary composite CV endpoint of confirmed CV-related death, nonfatal MI, or nonfatal stroke;
b. 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.
c. all-cause mortality;
To assess the effect of treatment with MK-3102 25 mg q.w. compared with placebo on fasting plasma glucose (FPG) at 4 months.
To assess the safety and tolerability of MK-3102 25 mg q.w.
To assess the impact of MK-3102 25 mg q.w. on:
a. The time to first event for each of the following individual CV endpoints: confirmed CV-related death, MI (fatal + nonfatal), and stroke (fatal + nonfatal);
b. All-cause mortality. |
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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 |
An insulin sub-study will be conducted which will include the sub-population of subjects receiving greater or equal to 20 units/day of background insulin (± metformin).
Primary Objective
- After 18 weeks, to assess the effect of MK-3102 25 mg q.w. as compared with placebo on A1C.
- To assess the safety and tolerability of MK-3102 25 mg q.w.
Secondary Objective
- After 18 weeks, to assess the effect of treatment with MK-3102 25 mg q.w. compared with placebo on FPG.
-
After 18 weeks, to assess the proportion of subjects with A1C <7.0% (53 mmol/mol) on MK-3102 25 mg q.w. as compared with placebo. |
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E.3 | Principal inclusion criteria |
1. Having T2DM and is ≥40 years of age.
2. Subject is on one of the following diabetes treatment regimens that is stable for at least 12 weeks (except for pioglitazone for at least 16 weeks) and is within the associated A1C range for that treatment regimen:
- An A1C ≥6.5 and ≤10.0% (≥48 mmol/mol and ≤86 mmol/mol) on
diet and exercise alone (not on an AHA for ≥12 weeks)
OR
monotherapy with metformin (MF); pioglitazone (PIO); an alpha-glucosidase inhibitor (AGI); or an SGLT2 inhibitor (SGLT2i)
OR
dual combination therapy with MF, PIO, AGI or SGLT2i
OR
- An A1C ≥7.0% and ≤10.0% (≥53 mmol/mol and ≤86 mmol/mol) on
monotherapy with a sulfonylurea or meglitinide
OR
dual combination therapy with a sulfonylurea or a meglitinide and MF, PIO, AGI, or SGLT2i
OR
- An A1C ≥7.0% and ≤10.0% (≥53 mmol/mol and ≤86 mmol/mol) on one of the following insulin regimens (with or without metformin)
basal insulin (e.g., insulin glargine, insulin detemir, NPH insulin, degludec)
prandial insulin (e.g., regular, aspart, lispro, glulisine)
basal/prandial insulin regimen consisting of multiple dose insulin injections of basal and prandial insulin or the use of pre-mixed insulin (e.g., Novolog 70/30®, Novolin 70/30®, Humalog 75/25®, or Humulin 70/30®)
Note: A stable insulin regimen is defined as no change in the insulin regimen (i.e. type[s] of insulin) and ≤10% change in the total daily dose of insulin. For example, if the total daily dose of insulin is 50 U/day, doses of 45-55 U/day would be considered as stable.
3. Having following preexisting vascular disease:
(a) 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);
(b)Ischemic cerebrovascular disease, including:
- History of ischemic stroke
- 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) Atherosclerotic peripheral arterial disease, as documented by objective - amputation due to vascular disease, current symptoms of intermittent claudication confirmed by an ankle-brachial pressure index of less than 0.9 or a toe-brachial pressure index less than 0.7 or history of surgical or percutaneous revascularization procedure.
4.Meets one of the following criteria:
a. Subject is a male
b. Subject is a female not of reproductive potential defined as one who has either:
(1) reached natural menopause (defined as ≥12 months of spontaneous amenorrhea in women >45 years of age, or ≥6 months of spontaneous amenorrhea with serum follicular stimulating hormone [FSH] levels in the postmenopausal range as determined by the laboratory), or
(2)had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to screening
c. Subject is a female of reproductive potential and:
1. agrees to remain abstinent from heterosexual activity (if this form of birth control is accepted by local regulatory agencies and ethics review committees as the sole method of birth control) or
2. agrees to use (or have their partner use) acceptable contraception to prevent pregnancy within the projected duration of the trial and for 21 days after the last dose of blinded study medication. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:
•Use of one of the following double-barrier methods:diaphragm with spermicide and a condom; cervical cap and a condom; or a contraceptive sponge and condom.
•Use of hormonal contraception (any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following:diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or intrauterine device (IUD).
•Use of an IUD with one of the following: condom; diaphragm with spermicide; contraceptive sponge, vasectomy; or hormonal contraception (see above).
• Vasectomy with one of the following:diphragm with spermicide; cervical cap; contraceptive sponge; condom; IUD; or hormonal contraception (see above).
5. Understanding the trial procedures, alternative treatments available, providing the providing written informed consent, consent for Future Biomedical Research can be provided (not obligatory). |
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E.4 | Principal exclusion criteria |
1. History of type 1 diabetes mellitus or a history of ketoacidosis or possibly having type 1 diabetes
2. Beeing treated with rosiglitazone, a DPP-4 inhibitor or a GLP-1 receptor agonist within the prior 12 weeks of Visit 1/Screening or previously treated with MK-3102.
3. Having a history of hypersensitivity to a DPP-4 inhibitor
4. Participation in trial with investigational compound prior 12 weeks of signing the informed consent or is not willing to refrain from participating in another trial.
5. Subject is on a weight loss program and is not in the maintenance phase; has been on a weight loss medication in the past 6 months; or has undergone bariatric surgery within 12 months prior to signing the informed consent.
6. Surgical procedure within 4 weeks prior to signing informed consent or has planned major surgery during the trial.
7. Treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids
8. Treatement for hyperthyroidism or thyroid replacement therapy and has not been on a stable dose for at least 6 weeks.
9. Medical history of active liver disease
10. Human immunodeficiency virus (HIV) as assessed by medical history.
11. Worsening signs or symptoms of coronary heart disease or congestive heart failure within the past 3 months.
12. Poorly-controlled hypertension
13. History of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
14. Clinically important hematological disorder
15. Exclusionary laboratory values
16. Positive urine pregnancy test.
17.Subject is pregnant or breast-feeding, or is expecting to conceive during the trial, including 21 days following the last dose of blinded study medication. OR is expecting to undergo hormonal therapy in preparation to donate eggs during the period of the trial, including 21 days following the last dose of blinded study medication.
18. Subject is,at the time of signing informed consent,a user of recreational or illicit drugs or has had a recent history of drug abuse.
19. Subject routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per
week, or engages in binge drinking.
20. History or current evidence of condition, therapy, lab abnormality or other circumstance that
•makes participation not in the subject’s best interest
•might interfere with subject´s participation for the full duration of the trial, or
•might confound the result of the trial.
21.Subject has donated blood products or has had phlebotomy of >300 mL within 8 weeks of signing informed consent, or intends to donate blood products within the projected duration of the trial OR received, or anticipated to receive blood products within 12 weeks of signing informed consent or within the projected duration of the trial.
22. Subject is unlikely to adhere to the trial procedures, keep appointments.
23.Symptomatic hyperglycemia that, in the investigator's opinion, requires immediate initiation, adjustment, or addition of AHA therapy or has a FPG consistently (i.e., measurement repeated and confirmed within 7 days) >260 mg/dL (14.4 mmol/L).
24.Clinically significant ECG abnormality which in the opinion of the investigator exposes the subject to risk by enrolling in the trial.
25.Poorly controlled hypertension defined as systolic blood pressure of ≥160 mm Hg or diastolic blood pressure of ≥90 mm Hg.
26.Subject is on lipid-lowering medication or thyroid replacement therapy, and has not been on a stable therapy for the 4 weeks (lipid-lowering medication), or 6 weeks (thyroid replacement therapy) prior to Visit 3/Day 1 or P2V1/Day 1 (for Cohort 2). In this case the current visit can be changed to an Unscheduled Visit, and the subject should be rescheduled for a Visit 3/Day 1 or P2V1/Day 1 (for Cohort 2).
27.Subject has a positive urine pregnancy test.
28.Subject has a site fasting-fingerstick glucose (FFSG) <126 mg/dL (7.0 mmol/L) or >260 mg/dL (14.4 mmol/L).
29.Subject has developed a new medical condition, suffered a change in status of an established medical condition, developed a laboratory or ECG abnormality, or required a new treatment or medication during the pre-randomization period which meets any previously described trial exclusion criteria or which, in the opinion of the investigator, exposes the subject to risk by enrolling in the trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in A1C and FPG
The primary composite CV endpoint, MACE plus, is comprised of CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
A key secondary endpoint, MACE, is comprised of CV-related death, nonfatal MI, and nonfatal stroke. |
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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 | 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 | 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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 165 |
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 |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
Colombia |
Croatia |
Czech Republic |
Denmark |
Finland |
France |
Georgia |
Germany |
Hong Kong |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Lebanon |
Lithuania |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Philippines |
Poland |
Romania |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
Sweden |
Taiwan |
Ukraine |
United Kingdom |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |