E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes with Inadequate Glycemic Control on Metformin Alone |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
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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 demonstrate the hemoglobin A1c/glycated hemoglobin (HbA1c)-lowering effects of KRP-104 in patients with type 2 diabetes inadequately controlled on metformin alone. |
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E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of KRP-104 in patients with type 2 diabetes inadequately controlled on metformin alone; • To assess the fasting plasma glucose (FPG)-lowering effects of KRP-104 in patients with type 2 diabetes inadequately controlled on metformin alone; • To compare the HbA1c-lowering effects of KRP-104 at 120 mg, 100 mg, 80 mg, 40 mg, and 20 mg once daily (QD); • To assess the effects of KRP-104 on insulin, other glycemic parameters (homeostasis model index of beta-cell function [HOMA-β] and homeostasis model index of insulin resistance [HOMA-IR]), and body weight in patients with type 2 diabetes inadequately controlled on metformin alone; and • To assess the number and percentage of patients requiring rescue therapy for elevated glucose. |
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E.2.3 | Trial contains a sub-study | No |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
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E.3 | Principal inclusion criteria |
1. Signed written informed consent; 2. Males and females 18 to 75 years of age, inclusive; 3. Females of childbearing potential must agree to use 2 adequate forms of barrier method contraception (eg, latex condom AND intrauterine device or a diaphragm) to avoid pregnancy while in the study; 4. On a stable dose (≥10 weeks at the same dose) of metformin monotherapy (≥1500 mg/day or maximum tolerated dose), have an HbA1c ≥7.0% and ≤10.5%; or On metformin (≤1500 mg/day) and 1 other antidiabetic agent (excluding TZD, insulin, or incretin therapies [DPP-4 inhibitors and GLP-1 analogues]) and have an HbA1c ≥6.8% and ≤10.0%; or Not on antidiabetic therapy (for at least 3 months prior to Visit 1) or have not been on a stable dose of metformin monotherapy for 10 weeks and have an HbA1c ≥8.0% and ≤11.0%. |
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E.4 | Principal exclusion criteria |
1. History of type 1 diabetes mellitus or history of diabetic ketoacidosis or persistent hypoglycemia; 2. History or presence of alcoholism or drug abuse within the 2 years prior to dosing; 3. Typical consumption of ≥10 drinks of alcohol weekly; 4. Presence of any of the following conditions: • Significant renal impairment (glomerular filtration rate <60 mL/min); • Diabetic gastroparesis; • Active liver disease (other than asymptomatic nonalcoholic fatty liver disease), cirrhosis, or symptomatic gallbladder disease; 5. Fasting plasma glucose/blood glucose >240 mg/dL (13.3 mmol/L) at Visit 3 (Week -2) (1 laboratory retest permitted); 6. Body mass index ≤20 kg/m2 and ≥48 kg/m2; 7. Systolic blood pressure <100 mmHg or >160 mmHg and diastolic blood pressure <50 mmHg or >100 mmHg at Visit 3 (Note: medication to control blood pressure is allowed and should be optimized and stabilized prior to Visit 3); 8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 × the upper limit of normal (ULN) (1 laboratory retest permitted); 9. Creatine phosphokinase (CPK) >2 × the ULN (if not explained by muscular trauma or exercise) (1 laboratory retest permitted); 10. Serum creatinine <1.6 mg/dL (141.4 μmol/L); 11. Fasting triglycerides (TG) >600 mg/dL (6.78 mmol/L) at Visit 3 (Week -2) (Note: diet/exercise and lipid-lowering medication to control elevated TG is allowed; medications should be optimized and stabilized prior to Visit 3); 12. Treatment with pioglitazone or rosiglitazone within the previous 10 weeks (Visit 1); treatment with incretin therapy (DPP-4 inhibitors or GLP-1 analogues) within the previous 4 weeks (Visit 1); 13. Treatment with any type of insulin (ie, injected or inhaled) within the previous 3 months; 14. Thyroid hormone therapy that has not been stable for at least 3 months; 15. History or evidence of clinically significant cardiovascular, ECG abnormality, pulmonary, hepatic, renal, hematologic, gastrointestinal (including clinically significant malabsorption), endocrine (other than type 2 diabetes mellitus), immunologic, dermatologic, neurologic (including progressive neuromuscular disorders [eg, multiple sclerosis]), psychiatric, oncologic, or allergic (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) disease that would interfere with the conduct of the study or interpretation of the data. Note: Significant cardiovascular disease includes but is not limited to any of the following within the previous 6 months: acute coronary syndrome such as myocardial infarction or unstable angina, coronary artery interventions such as percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery, congestive heart failure, stroke or peripheral vascular disease such as claudication or non-healing ischemic ulcer; 16. Requires treatment with medications with a narrow therapeutic range (eg, digoxin or other cardiac glucosides, warfarin, warfarin-like (anticoagulants, phenytoin, anti-arrhythmic agents); 17. Requires chronic or repeated treatment with systemic corticosteroids (>14 days) or immunosuppressive/immunomodulating agents (eg, cyclosporine, Enbrel, methotrexate, rituximab); 18. Currently treated with weight-loss medications or had weight loss surgery (eg, gastric bypass); 19. Known hypersensitivity or idiosyncratic reaction to DPP-4 inhibitors or to compounds structurally related to KRP-104; 20. Participation in another clinical trial within 30 days prior to dosing; 21. History or evidence of intravenous illicit drug use, human immunodeficiency virus, hepatitis B, or hepatitis C; 22. Any condition or therapy which, in the opinion of the investigator, might pose a risk to the patient or make participation not in the patient’s best interest; 23. Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study; 24. Female patient who is pregnant, breast feeding, or plans to become pregnant during the study; 25. Medication compliance <80% assessed by tablet count of single-blind placebo run-in (dispensed at Visit 3); or 26. At Visit 4 (randomization), fingerstick glucose >240 mg/dL (13.3 mmol/L) or <60 mg/dL (3.3 mmol/L), change in lipid-lowering medications (fibrates, statins) within the previous 4 weeks, initiation of excluded medications, positive urine pregnancy test, new medical condition or change in status that poses risk to patient or meets previously assessed exclusion criteria. Note: if fingerstick glucose criteria are exclusionary but are believed not to reflect the typical status of the patient based on self-monitoring blood glucose diary values, the current visit can be changed to an unscheduled visit and Visit 4 rescheduled within the allowable visit window. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HbA1c from baseline (Week 0) to Week 24. |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.2.3 | Other | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | Information not present in EudraCT |
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 |
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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 | |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 15 |