| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II Diabetes Mellitus |
|
| 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 | 10012614 |
| E.1.2 | Term | Diabetes mellitus NOS |
|
| 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 evaluate the efficacy of the addition of SYR-322 (25 mg) versus the titration of pioglitazone HCl from 30 mg to 45 mg on glycemic control (HbA1c) at Week 26 and Week 52. Efficacy at Week 26 will be assessed via an interim analysis that will be conducted once all ongoing subjects have completed the Week 26 visit. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to determine the effect of treatment with SYR-322 versus titration of pioglitazone HCl on the change from Baseline (Day 1) HbA1c at all visits except Week 26 and Week 52, fasting plasma glucose, proinsulin, insulin, C-peptide, serum lipids, NMR lipid fractionation, free fatty acids, apolipoprotein A-I, A-II, B, C-III, PAI-1, hsCRP, adiponectin, body weight, homeostatic model assessment (HOMA) insulin resistance, HOMA beta-cell function, incidence of marked hyperglycemia (fasting plasma glucose ≥200 mg/dL [11.10 mmol/L]), incidence of rescue, QOL and pharmacoeconomic assessments and to evaluate the safety of SYR-322 versus titration of pioglitazone HCl on AEs, clinical laboratory parameters, electrocardiogram (ECG) readings, physical examinations, and hypoglycemic events. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility is determined based on the following criteria at both the Pre-Screening (if applicable) and Screening visits:
1. Male or female subjects, 18 to 80 years of age, with a historical diagnosis of type 2 diabetes mellitus.
2. The subjects must meet one of the following:
A. The subject has been inadequately controlled on a stable dose of ≥1500 mg (or MTD) of metformin and 30 mg of pioglitazone HCl for at least 2 months prior to Screening. Inadequate glycemic control is defined as an HbA1c concentration between 7.0 and 10.0%, inclusive. These subjects will immediately enter stabilization according to Study Schedule A.
B. The subject has been inadequately controlled (as defined by an HbA1c
≥7.5%) on a combination therapy including metformin and another oral antidiabetic agent (ie, sulfonylureas, rosiglitazone maleate, or pioglitazone HCl 15 mg, etc.). Subjects receiving a combination therapy which includes a DPP-4 inhibitor should be excluded. After completing the Pre-Screening visit, these subjects will discontinue this previous combination therapy and will be switched to a stable dose of ≥1500 mg (or MTD) of metformin and 30 mg of pioglitazone HCl for a 12-week period according to Study Schedule B. Following this 12-week period, the subject must qualify for entry into the stabilization period by completing the Screening visit
including having inadequate glycemic control defined as an HbA1c concentration between 7.0 and 10.0%, inclusive.
3. No treatment with antidiabetic agents other than metformin and pioglitazone HCl within 2 months prior to Screening (Exception: if a subject has received other antidiabetic therapy for less than 7 days within the 2 months prior to Screening).
4. Body mass index ≥23 kg/m2 and ≤45 kg/m2.
5. Fasting plasma C-peptide concentration ≥0.8 ng/mL (0.26 nmol/L).
6. Regular use of non-excluded medications is allowed; however, the subject must be on a stable dose for at least the 4 weeks prior to Screening. However, PRN use of prescription or over-the-counter medications is allowed at the discretion of the investigator.
7. Systolic blood pressure <160 mmHg and diastolic pressure <100 mmHg.
8. Hemoglobin ≥12 g/dL (120 gm/L) for males and ≥10 g/dL (100 gm/L) for females.
9. Alanine aminotransferase ≤2.5 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 normal range and the subject is clinically euthyroid.
12. If female, must be neither pregnant (confirmed by laboratory testing in female subjects of childbearing potential) nor lactating.
13. A female subject of childbearing potential who is sexually active agrees to use adequate contraception (a defined in the informed consent form and Section 9.1.12) from screening and throughout the duration of 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 2 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 2 additional weeks.)
3. At least 75% compliant with the open-label medication (metformin and pioglitazone HCl) regimen during the 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 and topical 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 at both Pre-Screening and Screening visits (if applicable):
1. Urine albumin/creatinine ratio of >1000 µg/mg (113 mg/mmol). 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 bladder cancer.
4. History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
5. Subjects with unexplained microscopic hematuria of > +1, confirmed by repeat testing.
6. History of treated diabetic gastroparesis.
7. History of gastric bypass surgery.
8. New York Heart Association Class I-IV heart failure regardless of therapy.
9. History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening.
10. History of any hemoglobinopathy that may affect determination of HbA1c.
11. History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
12. History of a psychiatric disorder that will affect the subject’s ability to participate in the study.
13. History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors.
14. History of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) or substance abuse (defined as illicit drug use) within the 2 years prior to Screening.
15. 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.
16. Prior treatment in an investigational study of SYR-322.
17. Hypersensitive to pioglitazone HCl, metformin, SYR-322 or other excipients.
18. The subject is a study site employee, or is an immediate family member (ie, spouse, parent, child, sibling) of a study site employee, involved in conduct of this study.
19. The subject has donated more than 400 mL of blood within the 90 days prior to Screening and Pre-Screening, if applicable. |
|
| 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 and Week 52. |
|
| 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 | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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