| 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 insulin as compared with insulin 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 insulin as compared with insulin alone
• To evaluate changes in pancreatic function after treatment with SYR-322 in combination with insulin as compared with insulin alone
• To evaluate changes in body weight following treatment with SYR-322 in combination with insulin as compared with insulin alone
• To evaluate the safety of SYR-322 in combination with insulin as compared with insulin 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 insulin as compared with insulin 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 insulin alone (with or without metformin), and who are inadequately controlled. Metformin dose must be stable for at least 8 weeks prior to Randomization.
2. No treatment with antidiabetic agents other than insulin and metformin within the 8 weeks prior to Randomization.
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 ≥8.0% at Screening
6. Using a stable dose of insulin of at least 15 units but not more than 100 units per day for at least 8 weeks prior to Randomization. A dose of insulin that varies by up to 15% of the mean will be considered as stable.
7. 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.
8. Systolic blood pressure ≤159 mm Hg and diastolic pressure ≤99 mm Hg
9. Hemoglobin ≥12 g/dL (≥120 gm/L) for males and ≥10 g/dL (≥100 gm/L) for females
10. Alanine aminotransferase ≤3 x upper limit of normal
11. Serum creatinine ≤2.0 mg/dL (≤177 micromol/L) (Subjects on metformin must have a serum creatinine <1.5 mg/dL (<133 micromol/L) for males and <1.4 mg/dL (<124 micromol/L) for females)
12. Thyroid-stimulating hormone level ≤ the upper limit of the normal range and the subject is clinically euthyroid
13. Neither pregnant (confirmed by laboratory testing in females of childbearing potential) nor lactating
14. 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.
15. Able and willing to monitor their own blood glucose concentrations with a home glucose monitor
16. No major illness or debility that in the investigator’s opinion prohibits the subject from completing the study
17. 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 ≥8.0% 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 <300 mg/dL (<16.65 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 efficacy endpoint will be the change from baseline (Day 1) 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 | 8 |
| 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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