| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II diabetes mellitus. |
|
| 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 |
| • To evaluate the efficacy of SYR-322 administered in combination with metformin as compared with metformin alone on glycosylated hemoglobin (HbA1c) change from baseline |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate other measures of glycemic control after treatment with SYR-322 in combination with metformin as compared with metformin alone
• To evaluate changes in pancreatic function after treatment with SYR-322 in combination with metformin as compared with metformin alone
• To evaluate changes in body weight following treatment with SYR-322 in combination with metformin as compared with metformin alone
• To evaluate the safety of SYR-322 in combination with metformin as compared with metformin alone
• To evaluate plasma concentrations of SYR-322 using a sparse sampling approach
• To evaluate clinically meaningful levels of response in HbA1c after treatment with SYR-322 in combination with metformin as compared with metformin alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible for this study, each of the following criteria must be satisfied with a “YES” answer (unless not applicable):
1. Males or females, 18 to 80 years of age, inclusive, with a historical diagnosis of type 2 diabetes mellitus who are currently treated with metformin alone but who are experiencing inadequate glycemic control. The subject should have received the metformin monotherapy for at least the 3 months prior to Screening; and the subject must have a stable dose ≥1500 mg metformin for at least 8 weeks prior to randomization. Subjects with a maximum tolerated dose that is documented to be less than 1500 mg of metformin may also be enrolled if this dose has been stable for 8 weeks prior to randomization.
2. No treatment with antidiabetic agents other than metformin within the 3 months prior to Screening. (Exception: if a subject has received other antidiabetic therapy for less than 7 days within the 3 months prior to Screening.)
3. Body mass index (BMI) ≥23 kg/m2 and ≤45 kg/m2
4. Fasting C-peptide concentration ≥0.8 ng/mL (≥0.26 nmol/L). (If this screening criterion is not met, the subject still qualifies if C-peptide ≥1.5 ng/mL (≥0.50 nmol/L) after a challenge test. See Appendix E.)
5. HbA1c concentration between 7.0% and 10.0%, inclusive
6. If regular use of other, nonexcluded medications, must be on a stable dose for at least the 4 weeks prior to Screening. However, PRN (as needed) use of prescription or over-the-counter medications is allowed at the discretion of the investigator.
7. Systolic blood pressure ≤159 mm Hg and diastolic pressure ≤99 mm Hg
8. Hemoglobin ≥12 g/dL (≥120 gm/L) for males and ≥10 g/dL (≥100 gm/L) for females
9. Alanine aminotransferase ≤3 x upper limit of normal
10. Serum creatinine <1.5 mg/dL (< 133 micromol/L) for males and <1.4 mg/dL (< 124 micromol/L) for females
11. Thyroid-stimulating hormone level ≤ the upper limit of the normal range and the subject is clinically euthyroid
12. Neither pregnant (confirmed by laboratory testing in females of childbearing potential) nor lactating
13. Female subjects of childbearing potential (ie, not surgically sterile and/or not postmenopausal) must be practicing adequate contraception. Methods of adequate contraception include the following: intrauterine device; double-barrier device such as a diaphragm or condom plus spermicide; or a hormonal contraceptive (including injectable, implantable, or oral). Adequate contraception must be practiced for the duration of participation in the study.
14. Able and willing to monitor their own blood glucose concentrations with a home glucose monitor
15. No major illness or debility that in the investigator’s opinion prohibits the subject from completing the study
16. Able and willing to provide written informed consent
Additional Inclusion Criteria Prior to Randomization
In order to be eligible for randomization, each of the following additional criteria must be satisfied with a “YES” answer:
1. HbA1c concentration between 7.0% and 10.0%, inclusive at the Week -1 visit. (Of note, if the subject does not qualify for randomization based on this criterion, the assessment may be repeated on a weekly basis, for a maximum of 4 additional weeks.)
2. Fasting plasma glucose <275 mg/dL (<15.27 mmol/L) at Week –1 visit. (Of note, if the subject does not qualify for randomization based on this criterion, the assessment may be repeated on a weekly basis, for a maximum of 4 additional weeks).
3. Have been at least 75% compliant with the single-blind placebo regimen during the run-in/stabilization period, as assessed by tablet count
4. No use of oral or systemically injected glucocorticoids or use of weight-loss drugs is allowed within the 3 months prior to randomization. (Inhaled corticosteroids are allowed.) |
|
| E.4 | Principal exclusion criteria |
In order to be eligible for this study, each of the following criteria must be satisfied with a “NO” answer:
1. Urine albumin/creatinine ratio of >1000 μg/mg (>113 mg/mol) at Screening. If elevated, the subject may be rescreened within 1 week.
2. History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 5 years prior to Screening. (A history of treated CIN I or CIN II [cervical intraepithelial neoplasia] is allowed.)
3. History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening
4. History of diabetic ketoacidosis and diabetic coma
5. History of treated diabetic gastric paresis
6. The glomerular filtration rate (GFR) of <60 mL/min
7. New York Heart Association Class III or IV heart failure regardless of therapy. Currently treated subjects who are stable at Class I or II are candidates for the study (see Appendix F).
8. History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening
9. History of any hemoglobinopathy that may affect determination of HbA1c
10. History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus
11. History of a psychiatric disorder that will affect the subject’s ability to participate in the study
12. History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors
13. History of alcohol or substance abuse within the 2 years prior to Screening
14. Receipt of any investigational drug within the 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within the 3 months prior to Screening
15. Prior treatment in an investigational study of SYR-322 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be change from baseline in HbA1c at Week 26. |
|
| 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 | Yes |
| 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) | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
|
| 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
|
| Last visit of the last subject. |
|
| 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 | 3 |
| 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 |
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