| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus (T2DM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects diagnosed by a medical professional with T2DM type 2 diabetes mellitus, in accordance with the ADA, and inadequately controlled on Metformin |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 dose response for the effect on glycemic control with a range of doses of PF-04937319 administered once daily over 12 weeks in adults with T2DM on stable doses of metformin. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of a range of doses of PF-04937319 administered once daily over 12 weeks in adults with T2DM on stable doses of metformin.
• To characterize the safety and efficacy of glimepiride (titrated) to a maximum of 6 mg per day [or highest approved dose in individual countries if less than 6 mg] administered over 12 weeks in adults with T2DM on stable doses of metformin.
• To evaluate the dose response for effect on additional parameters of glycemic control with a range of doses of PF-04937319 administered once daily over 12 weeks in adults with T2DM on stable doses of metformin. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Male or female subjects between the ages of 18 (or the minimum country specific age of consent if > 18) and 70 years, inclusive at screening (V1)
• Subjects of childbearing potential must agree to use a highly effective method of contraception. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
• Female subjects may be of childbearing potential but must not be pregnant, breastfeeding, or planning to become pregnant for the duration of their participation in this study and within 28 days following last dose of assigned treatment.
• In female subjects, serum β hCG level, confirmed via a single repeat if deemed necessary, must be within the central laboratory’s reference range for non-pregnant state.
• Female subjects may be deemed of non childbearing potential if one of the following criteria are met, at screening (V1):
• Have undergone hysterectomy or bilateral oophorectomy;
• Have medically confirmed ovarian failure;
• Are medically confirmed to be post menopausal (eg, cessation of regular menses for ≥12 months with no alternative pathological or physiological cause);
• Serum FSH level, confirmed via a single repeat if deemed necessary, within the central laboratory’s reference range for postmenopausal state.
2. Subjects diagnosed, by a medical professional, with T2DM in accordance with the ADA guidelines.
3. Subjects who have been on a stable dose of metformin either alone or in combination with another oral anti-diabetic agent (excluding pioglitazone and rosiglitazone) for their T2DM for at least 6 weeks prior to V1.
4. Subjects on an oral anti diabetic agent other than metformin must be willing to discontinue this medication starting at V2 and for duration of the study (ie, until the follow-up visit – V10).
5. HbA1C at Screen (ie, V1), as assessed by study specific central laboratory using a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay, meeting one of the following criteria based on prior background anti-diabetic agents:
• Metformin monotherapy →7.0 11.0%, inclusive;
• Metformin plus acceptable OAD →6.5 9.5%, inclusive;
• Upper limit was chosen so that subjects would have HbA1C ≤11.0% at randomization following withdrawal of the acceptable OAD based on expected rise in HbA1C post discontinuation.
6. Fasting plasma glucose levels <270 mg/dL (ie, 15.04 mmol/L), at screening, (as assessed by study-specific central laboratory) confirmed by a single repeat, if deemed necessary.
7. BMI of ≥18.5 kg/m2 and ≤45.4 kg/m2, and body weight >50 kg (110 lbs), at screening (V1).
8. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures, as outlined in this protocol.
9. Subjects must be willing and able to perform self test of blood sugars at least once daily, and maintain a diary, for the duration of participation in the study.
10. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study. |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Compliance (based on pill count) of <90% during baseline period, as assessed prior to randomization on Day 1 (V4).
2. Subjects with an arm circumference >50 cm when measured at midpoint of the length of the upper arm.
3. Recent [ie, within six (6) months prior to screening] evidence or medical history of unstable concurrent disease such as: documented evidence or history of clinically significant hematological, endocrine, pulmonary, gastrointestinal (including severe gastroparesis), cardiovascular, hepatic, psychiatric, neurologic, or clinically significant allergic disease (including any drug allergies, but excluding treated and untreated seasonal allergies at time of dosing).
4. Any condition possibly affecting drug absorption (eg, gastrectomy or any area of intestinal resection, active inflammatory bowel disease or pancreatic insufficiency).
5. Diagnosis of Type 1 diabetes mellitus or secondary forms of diabetes.
6. Treatment with thiazolidinediones (TZDs), or subcutaneously administered anti diabetic agents (eg, insulin, exenatide, liraglutide, pramlintide) within 6 weeks prior to V1.
7. Subjects who are non pharmacologically managed for their T2DM (ie, treatment naïve).
8. Treatment with certain class of medications within a pre-specified interval prior to Screening (V1) and for duration of participation in this study:
9. History or evidence of diabetic complications with, clinically significant symptomatic or known, end organ damage such as:
• Proliferative retinopathy and/or macular edema; or
• Diabetic neuropathy complicated by neuropathic ulcers; or
• Creatinine clearance ≤60 mL/min based on Cockcroft Gault equation using serum creatinine measured at screening, confirmed via a single repeat, if deemed necessary [see below]:
• Males → [(140 age in years) x total body weight (in kg)] divided by [72 x serum creatinine (in mg/dL)];
• Females → 0.85 x calculation for males.
• Macroalbuminuria defined as UACR ≥300 µg albumin per mg of creatinine (ie, 33.9 mg/mmol) in spot urine collection, at screening, confirmed via a single repeat, if deemed necessary.
10. History of myocardial infarction, unstable angina, coronary revascularization, stroke, or transient ischemic attack within 6 months prior to screening.
11. History of pancreatitis.
12. Episode(s) of HAE of ‘severe’ intensity prior to screening (V1); either:
• ≥1 in the previous 3 months; or
• ≥2 in the previous 6 months.
13. Participation in any formal weight loss program, or fluctuation of >5% in body weight, or having received medications approved for weight loss within 3 months prior to screening.
14. Subjects with ANY of the following abnormalities in clinical laboratory tests at screening (ie, V1) as assessed by study specific central laboratory confirmed by a single repeat, if deemed necessary:
• C peptide concentration of <0.8 ng/mL (267 pmol/L);
• Fasting serum triglycerides ≥400 mg/dL (ie, 4.52 mmol/L);
• AST/SGOT or ALT/SGPT ≥2x ULN;
• Total bilirubin ≥1.5 x ULN and direct bilirubin > ULN; those with history of Gilbert's syndrome are eligible for this study provided direct bilirubin is ≤ ULN.
15. At screening/V1, 12 lead electrocardiogram (ECG) demonstrating QTc interval >470 msec, following ≥10 minute supine rest, confirmed by a single repeat, if deemed necessary.
16. Persistent severe, uncontrolled hypertension; for example: seated systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥105 mm Hg after ≥5 minute seated rest at V1, confirmed via a single repeat, if deemed necessary, at screening.
17. Current medical history or current clinical evidence of congestive heart failure, NYHA (New York Heart Association) Functional Classification, Classes III IV.
18. A positive urine drug test for illicit drugs, at screening.
19. History of regular alcohol consumption as defined by alcohol intake in a quantity exceeding 7 drinks per week for females or 14 drinks per week for males;
• 1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor.
20. Participation in other studies involving administration of an investigational drug or device within 30 days before screening for the current study and/or during participation in current study.
21. History of sensitivity or intolerance to PF-04937319 or glimepiride.
22. History of sensitivity to heparin or heparin-induced thrombocytopenia (if heparin is used to flush intravenous catheters used during OGTT).
23. Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening.
Please refer to the protocol for the full list of exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The comparison of interest following 12-weeks of dosing with a range of oral doses of PF-04937319 administered once daily is change from baseline in HbA1C (%) – Day 84 minus baseline (ie, Day 1) as compared to placebo.
• HbA1C change from baseline on Days 14, 28, 42, and 56 will also be included and reported in the primary analysis model.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| HbA1C, the primary endpoint will be evaluated at baseline (Day 1 predose), Day 28, 56 and 84, and 1-2 weeks post last dose |
|
| E.5.2 | Secondary end point(s) |
• Safety and tolerability assessment will include: 12 lead ECGs, vital signs, AEs including HAE, SAEs, body weight, and laboratory tests (including lipid profile); HAE endpoints include the following:
• Proportion of subjects with at least one HAE episode over treatment period
• Number of HAE episodes in each subject
• Time to each recurrent HAE episode in each subject
• Safety and efficacy of glimepiride (titrated) will be assessed in a manner similar to that outlined for PF-04937319
• Assessment of effect of PF-04937319 on additional parameters of glycemic control include:
• Change from baseline in fasting plasma glucose (mg/dL) on Days 14, 28, 42, 56, and 84.
• Proportion of subjects achieving HbA1C <7% as well as <6.5% on Day 84. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change in fasting plasma glucose will be evaluated at baseline, Day 14, 28, 42, 56, 84 and 1-2 weeks post last dose
Proportion of subjects achieving HbA1C <7% and <6.5% on Day 84 Safety and tolerability – including 12-lead ECGs, vitals, AEs and SAEs, and clinical laboratory tests will be evaluated over the 84 days of dosing as well as 1-2 weeks post last dose – for both PF-04937319 and glimepiride |
|
| 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 | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 22 |
| 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 |
| Bulgaria |
| Canada |
| Hungary |
| India |
| Philippines |
| Romania |
| Slovakia |
| Taiwan |
| Turkey |
| United States |
|
| 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
|
| end of trial is defined in the protocol as last subject last visit – section 13.2 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| 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 |
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