| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with type II diabetes mellitus (T2DM) who are currently treated with a stable daily dose of metformin alone but experiencing inadequate glycemic control |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 durability (for up to approximately 2 years) of the efficacy of alogliptin plus metformin as compared to glipizide plus metformin as measured by HbA1c change from baseline to Week 52 or 104 in adults with type 2 diabetes mellitus. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate other measures of glycemic control after treatment with alogliptin plus metformin as compared with glipizide plus metformin, including HbA1c change from baseline in other visit and FPG change from baseline in all visits.
• To evaluate clinically meaningful levels of response in HbA1c after treatment with alogliptin plus metformin as compared with glipizide plus metformin.
• To evaluate changes in body weight after treatment with alogliptin plus metformin as compared with glipizide plus metformin.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility is determined according to the following criteria:
1. Male or female subjects, 18 to 80 years of age, inclusive with a historical diagnosis of T2DM
2. The subjects must meet one of the following:
a) The subject has been inadequately controlled on a stable daily dose of ≥1500 mg (or documented MTD) of metformin for at least 2 months prior to Screening. Inadequate glycemic control is defined as an HbA1c concentration between 7.0 and 9.0%, inclusive. These subjects will immediately enter the stabilization period according to Study Schedule A.
b) The subject has been inadequately controlled (as defined by an HbA1c 7.5-10%, inclusive) on metformin <1500 mg without documented MTD. After completing the Pre-screening visit, these subjects will have their metformin dose immediately increased to <1500 mg (or MTD) for an 8-week period according to Study Schedule B. Following this 8-week period, the subject must qualify for entry into the stabilization period by completing the Screening Visit having inadequate glycemic control defined as an HbA1c concentration between 7.0 and 9.0%, inclusive.
3. No treatment with antidiabetic agents other than metformin within 2 months prior to Screening (for Schedule A) / Pre-Screening (for Schedule B) (Exception: if a subject has received other antidiabetic therapy for less than 7 days within the 2 months prior to Screening/Pre-Screening).
4. Body mass index (BMI) ≥23 kg/m2 and ≤45 kg/m2 unless the subject is Asian or of Asian descent, for whom the allowable body mass index will be ≥20 kg/m2 and ≤35 kg/m2, inclusive.
5. Fasting C-peptide concentration ≥0.8 ng/mL (≥0.26 nmol/L).
6. Subjects regularly using other, non-excluded medications, must be on a stable dose for at least the 4 weeks prior to Screening/Pre-screening. However, PRN (as needed) use of prescription or over-the-counter medications is allowed at the discretion of the investigator.
7. A female subject of childbearing potential and males who are sexually active agree to routinely use adequate contraception from Screening throughout the duration of the study.
NOTE: Women NOT of childbearing potential are defined as those who have been surgically sterilized (hysterectomy, bilateral salpingo-oophorectomy, bilateral tubal ligation) or who are postmenopausal (defined as at least 45 years and above and at least 1 year since last regular menses). Acceptable methods of contraception are defined in Section 9.1.13 Contraception and Pregnancy Avoidance Procedure.
8. Subject or the subject’s legally acceptable representative is able and willing to provide written informed consent prior to the initiation of any study procedures.
9. The subject is capable of understanding and complying with protocol requirements, including scheduled clinic appointments.
10. Able and willing to monitor their own blood glucose concentrations with a home glucose monitor and complete subject diaries.
Additional Inclusion Criteria
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 9.0%, 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. FPG <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 but no more than 125% compliant with the open-label medication (metformin) regimen during the stabilization period, as assessed by tablet count.
4. No use of oral or systemically injected glucocorticoids (including intra-articular injection) 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:
1. Systolic blood pressure ≥150 mm Hg and/or diastolic pressure ≥90 mm Hg at Screening Visit.
2. Hemoglobin ≤12 g/dL (≤120 gm/L) for males and ≤10 g/dL (≤100 gm/L) for females at Screening Visit.
3. Alanine aminotransferase >2.5 x upper limit of normal at Screening Visit.
4. Serum creatinine ≥1.5 mg/dL for males and ≥1.4 mg/dL for females or creatinine clearance <60 mL/min, based on calculation by central lab using the Cockcroft-Gault approximation at Screening Visit.
5. Subject plans to become pregnant during the study or is pregnant (confirmed by laboratory testing, ie, serum/urine hCG, in females of childbearing potential) or is lactating.
6. 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, II or CIN III [cervical intraepithelial neoplasia] is allowed.)
7. Subject has a history of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
8. Subject has a history of treatment for diabetic gastric paresis, gastric banding, or gastric bypass surgery.
9. 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 (see Appendix E.)
10. Subject has a history of coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, stroke or transient ischemic attack (TIA) within the 3 months prior to Screening.
11. Subject has a history of any hemoglobinopathy that may affect determination of HbA1c.
12. Subject has a known history of infection with human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
13. Subject has a history of any psychiatric disorder that will affect the subject’s ability to participate in the study.
14. Subject has a history of alcohol or substance abuse within the 2 years prior to Screening.
15. Subject has received any investigational drug within the 30 days prior to Screening or has received an investigational antidiabetic drug within the 3 months prior to Screening.
16. Subject has received any antidiabetic drug in the DPP-IV inhibitors or GLP-1 mimetics classes within 90 days prior to Screening.
17. Subject has any major illness or debility that in the investigator’s opinion prohibits the subject from completing the study.
18. Subject has participated in a previous investigational study of alogliptin that has completed and received alogliptin treatment.
19. The subject is a study site employee, or is an immediate family member (ie, spouse, parent, child, and sibling) of a study site employee who is involved in conduct of this study.
20. The subject has a history of hypersensitivity, allergies, or have had an anaphylactic reaction(s) to any DPP-IV inhibitor drug, metformin or glipizide.
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.
22. Subject has a documented history or concurrent signs of significant thyroid disease (eg, autoimmune thyroid diseases such as Graves disease and Hashimoto thyroiditis or active thyroid nodules). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
HbA1c change from baseline at Week 52 or 104.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline at Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91or early termination visit |
|
| E.5.2 | Secondary end point(s) |
HbA1c change from baseline at Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91.
FPG change from baseline at Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104.
Clinical response endpoints including:
– Incidence of HbA1c ≤6.5% at Weeks 26, 52, 78, and 104.
– Incidence of HbA1c <7.0% at Weeks 26, 52, 78, and 104.
Body weight change from baseline at Weeks 12, 26, 39, 52, 65, 78, 91, and 104. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline at Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | No |
| 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 |
| Austria |
| Germany |
| Hungary |
| Israel |
| Italy |
| Latvia |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Defined within the protocol |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
