| 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 | Information not present in EudraCT |
| 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):
• 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). Metformin dose should have been stable for at least 8 weeks prior to randomization.
• No treatment with antidiabetic agents other than insulin and metformin within the 8 weeks prior to Randomization.
• Body mass index ≥23 kg/m2 and ≤45 kg/m2
• Fasting C-peptide concentration ≥0.8 ng/mL. (If this screening criterion is not met, the subject still qualifies if C-peptide ≥1.5 ng/mL after a challenge test. See Appendix E.)
• HbA1c concentration ≥8.0% at Screening
• Using a stable dose of insulin of at least 15 units but not more than 100 units per day for at least the last 8 weeks prior to Randomization. A dose of insulin that varies by up to 15% of the mean will be considered as stable.
• 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.
• Systolic blood pressure ≤180 mm Hg and diastolic pressure ≤110 mm Hg
• Hemoglobin ≥12 g/dL for males and ≥10 g/dL for females
• Alanine aminotransferase ≤3 x upper limit of normal
• Serum creatinine ≤2.0 mg/dL
• Thyroid-stimulating hormone level ≤ the upper limit of the normal range and the subject is clinically euthyroid
• Neither pregnant (confirmed by laboratory testing in females of childbearing potential) nor lactating
• 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; doublebarrier 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.
• Able and willing to monitor their own blood glucose concentrations with a home glucose monitor
• No major illness or debility that in the investigator’s opinion prohibits the subject from completing the study
• Able and willing to provide written informed consent
Additional Inclusion Criteria for Randomization:
In order to be eligible for randomization, each of the following additional criteria must
be satisfied with a “YES” answer:
• 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.)
• Have been at least 75% compliant with the single-blind placebo regimen during the run-in/stabilization period, as assessed by tablet count
• 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:
• Urine albumin/creatinine ratio of >1000 μg/mg at Screening. If elevated, the subject may be rescreened within 1 week.
• 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.)
• History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening
• History of treated diabetic gastric paresis
• 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).
• History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening
• History of any hemoglobinopathy that may affect determination of HbA1c
• History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus
• History of a psychiatric disorder that will affect the subject’s ability to participate in the study
• History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors
• History of alcohol or substance abuse within the 2 years prior to Screening
• 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
• 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 | Information not present in EudraCT |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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