E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes Mellitus (T2DM) |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 Diabetes Mellitus (T2DM) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
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 |
In subjects with T2DM with inadequate glycemic control on metformin and sitagliptin, who initiate and titrate insulin glargine (LANTUS®), to assess the effect of continuing sitagliptin relative to withdrawing sitagliptin on: (1) HbA1c (A1C) after 30 weeks; (2) the event rate of documented symptomatic hypoglycemia with blood glucose < or = 70 mg/dL (< or = 3.9 mmol/L) over 30 weeks; (3) general safety and tolerability over 30 weeks. |
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E.2.2 | Secondary objectives of the trial |
In subjects with T2DM with inadequate glycemic control on metformin and sitagliptin, who initiate and titrate insulin glargine (LANTUS®), to assess the effect of continuing sitagliptin relative to withdrawing sitagliptin on: 1) the incidence of the following over 30 weeks: a) documented symptomatic hypoglycemia with blood glucose (BG) < or =70 mg/dL; b) documented hypoglycemia with BG < or =70 mg/dL; c) documented symptomatic hypoglycemia with BG <56 mg/dL; d) documented hypoglycemia with BG <56 mg/dL; 2) the event rate of the following over 30 weeks: a) documented symptomatic hypoglycemia with BG <56 mg/dL; b) documented hypoglycemia with BG < or =70 mg/dL ; c) documented hypoglycemia with BG <56 mg/dL; 3) the daily dose of insulin after 30 weeks; 4) the proportion of subjects with A1C <7.0% after 30 weeks; 5) the proportion of subjects with A1C <7.0% after 30 weeks without any event of documented hypoglycemia with BG < or =70 mg/dL ; 6) fasting plasma glucose after 30 weeks. |
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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 |
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The
objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is
to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the subject must: (1) have T2DM and be > or = 18 years of age on the day of signing ICF; (2) be on one of the following treatment regimens: (a) stable dose of sitagliptin (100 mg/day) and metformin IR or XR (> or = 1500 mg/day) either co-administered or as a FDC for > or = 12 weeks with A1C between 7.5% and 11.0%, inclusive; (b) stable dose of metformin IR or XR (> or = 1500 mg/day) and another DPP-4 inhibitor (at maximum labeled dose), other than sitagliptin, either co-administered or as a FDC, for > or = 12 weeks with A1C between 7.5% and 11.0%, inclusive; (c) stable dose of sitagliptin (100 mg/day) and metformin IR or XR (> or = 1500 mg/day) either co-administered or as a FDC, and a sulfonylurea for > or = 12 weeks OR stable dose of metformin IR or XR (> or = 1500 mg/day) and a sulfonylurea administered as a FDC and sitagliptin (100 mg/day) with A1C between 7.0% and 10.0%, inclusive; (d) stable dose of metformin IR or XR (> or = 1500 mg/day) and another DPP-4 inhibitor (at maximum labeled dose), other than sitagliptin, either co-administered or as a FDC, and a sulfonylurea for > or = 12 weeks OR stable dose of metformin IR or XR (> or = 1500 mg/day) and a sulfonylurea administered as a FDC and another DPP-4 inhibitor other than sitagliptin with A1C between 7.0% and 10.0%, inclusive; (e) stable dose of metformin IR or XR (> or = 1500 mg/day) and a sulfonylurea either co-administered or as a FDC for > or = 12 weeks with A1C between 7.5% and 11.0% (> or = 58 mmol/mol and < or = 97 mmol/mol), inclusive. (3) At Visit 3, have an A1C of 7.5% to 11.0%. |
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E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject: (1) has been treated with any AHA other than protocol-specified agents (i.e., other than metformin, DPP-4 inhibitor, or sulfonylurea agent) within the prior 12 weeks; (2) has a history of 2 or more episodes of hypoglycemia resulting in seizure, coma, or loss of consciousness, OR subject has had recurrent (> or = 3 times per week) episodes of hypoglycemia over the past 8 weeks; (3) has a history of type 1 diabetes mellitus (T1DM) or ketoacidosis, or has a history of latent autoimmune diabetes of adults (LADA), or subject is assessed by the investigator as possibly having T1DM or LADA confirmed with a C-peptide <0.7 ng/mL (<0.23 nmol/L), or has a history of other specific types of diabetes; (4) has a history of intolerance or hypersensitivity to sitagliptin, insulin, or metformin or any contraindication to sitagliptin, insulin, or metformin based upon the label of the country of the investigational site; (5) is currently participating, or has participated, in a study in which the subject received an investigational compound or used an investigational device within the prior 12 weeks of signing informed consent or is not willing to refrain from participating in another study; (6) is currently on or likely to require treatment with a prohibited medication (see Section 5.5.2 of protocol). Example: is on, or likely to require treatment with more than 14 consecutive days or repeated courses of pharmacologic doses of corticosteroids; (8) is pregnant or breast-feeding; (9) has an exclusionary laboratory value as listed in the protocol; (10) At Visit 4, has a site fasting fingerstick glucose of <130 mg/dL (7.2 mmol/L) or >270 mg/dL (15.0 mmol/L). |
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E.5 End points |
E.5.1 | Primary end point(s) |
(1) Change from baseline in A1C at Week 30; (2) Event rate of documented symptomatic hypoglycemia with blood glucose < or = 70 mg/dL (< or = 3.9 mmol/L) over 30 weeks. |
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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) |
1) Event rate of documented symptomatic hypoglycemia with blood glucose <56 mg/dL (< or = 3.1 mmol/L) over 30 weeks; (2) Incidence of each of the following over 30 weeks: (a) documented symptomatic hypoglycemia with blood glucose < or = 70 mg/dL (< or = 3.9 mmol/L); (b) documented hypoglycemia with blood glucose < or = 70 mg/dL (< or = 3.9 mmol/L); (c) documented symptomatic hypoglycemia with blood glucose <56 mg/dL (< or = 3.1 mmol/L); (d) documented hypoglycemia with blood glucose <56 mg/dL (< or = 3.1 mmol/L); (3) Change from baseline in total daily insulin dose at Week 30; (4) Event rate of each of the following over 30 weeks: (a) documented hypoglycemia with blood glucose < or = 70 mg/dL (< or = 3.9 mmol/L); (b) documented hypoglycemia with blood glucose <56 mg/dL (< or = 3.1 mmol/L); (5) Proportion of subjects at A1C goal <7.0% (<53 mmol/mol) at Week 30; (6) Proportion of subjects at A1C goal <7.0% (<53 mmol/mol) at Week 30 with no documented hypoglycemia with blood glucose < or = 70 mg/dL (< or = 3.9 mmol/L); (7) Change from baseline in FPG at Week 30. |
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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 | Yes |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
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 |
Canada |
Israel |
Korea, Republic of |
Philippines |
Puerto Rico |
United States |
Estonia |
France |
Latvia |
Poland |
Romania |
Spain |
Czechia |
Germany |
Denmark |
Hungary |
Russian Federation |
Turkey |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |