| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
|
| 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 |
| The primary objective of this study is to examine the efficacy of SYR-322 in combination with pioglitazone HCl as compared with SYR-322 alone and pioglitazone HCl alone on glycosylated hemoglobin (HbA1c) change from baseline. |
|
| E.2.2 | Secondary objectives of the trial |
| Key secondary endpoints for this study are fasting plasma glucose, proinsulin, insulin, calculated HOMA beta cell function, calculated HOMA insulin resistance, C-peptide, serum lipids, NMR lipid fractionation, free fatty acid, apolipoproteins (A1, A2, B, C-III), PAI-1, adiponectin, hsCRP, body weight, incidence of marked hyperglycemia, incidence of rescue, and incidence of clinical response. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility is determined based on the following criteria:
1. Males or females, 18-80 years of age, inclusive, with a historical diagnosis of type 2 diabetes.
2. The subject has failed treatment with diet and exercise for at least 2 months prior to Screening.
3. The subject is experiencing inadequate glycemic control as defined as HbA1c concentration between 7.5-11%, inclusive.
4. The subject has received less than 7 days of any antidiabetic therapy within 3 months prior to Screening.
5. The subject is capable of understanding and complying with protocol requirements.
6. The subject or the subject’s legally acceptable representative signs a written, informed consent form prior to the initiation of any study procedures.
7. The subject has a body mass index ≥23 kg/m2 and <45 kg/m2.
8. The subject has a fasting C-peptide ≥0.8 ng/mL (0.26 nmol/L).
9. The subject who has regular use of other, nonexcluded medications must be on a stable dose for at least 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.
10. Female subjects of child-bearing potential (ie, not surgically sterilized and/or postmenopausal) must be practicing adequate contraception (as defined in Section 9.1.11 and the informed consent form) from Screening throughout the duration of the study.
11. The subject is neither pregnant (confirmed by laboratory testing in females of childbearing potential) nor lactating.
12. The subject must be willing and able to monitor their blood concentrations with a home glucose monitor.
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. The subject has a HbA1c concentration between 7.5-11%, inclusive, and a fasting plasma glucose <310 mg/dL (17.5 mmol/L) at the Week -1 visit (of note, if the subject does not qualify for randomization based on these criteria, the assessment may be repeated on a weekly basis, for a maximum of 4 additional weeks).
2. The subject has been at least 75% compliant with the single-blind placebo regimen during the run-in/stabilization period, as assessed by tablet count.
3. The subject has not used oral or systemically injected glucocorticoids or use of weight-loss drugs within 3 months prior to randomization (inhaled corticosteroids are allowed). |
|
| E.4 | Principal exclusion criteria |
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has a systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg.
2. The subject has hemoglobin ≤12 g/dL (120 gm/L) for males and ≤10 g/dL (100 gm/L) for females.
3. The subject has an alanine aminotransferase (ALT) ≥2.5x upper limit of normal.
4. The subject has a serum creatinine >2.0 mg/dL (177 micromol/L).
5. The subject has a thyroid stimulating hormone level > the upper limit of normal range.
6. The subject has a major illness or debility that in the investigator’s opinion prohibits the subject from completing the study.
7. The subject has a urine albumin/creatinine ratio of >1000 ug/mg (>113 mg/mmol) at Screening. If elevated, the subject may be rescreened within 1 week.
8. The subject has a 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).
9. The subject has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
10. The subject has a history of gastroparesis.
11. The subject has 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.
12. The subject has a history of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening.
13. The subject has a history of any hemoglobinopathy that may affect determination of HbA1c.
14. The subject has a history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
15. The subject has a history of a psychiatric disorder that will affect the subject’s ability to participate in the study.
16. The subject has a history of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors.
17. The subject has had any alteration in angiotensin-II receptor inhibitors (dose or drug) within 2 months prior to Randomization, if applicable.
18. The subject has a history of alcohol (defined as regular or daily consumption of more than 4 alcoholic drinks per day) or substance abuse (defined as illicit drug use) within 2 years prior to Screening.
19. The subject has received any investigational drug within 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within 3 months prior to Screening.
20. The subject has previously participated in an investigational study of SYR-322.
21. The subject is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available. |
|
| 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 | Yes |
| 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 | Yes |
| 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 | Information not present in EudraCT |
| 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
| Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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
| |
| 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 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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