| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| 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 |
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| 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 of PF-04991532 administered twice daily over 12 weeks on HbA1c in adults with T2DM on stable doses of metformin. |
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| E.2.2 | Secondary objectives of the trial |
• To characterize the dose responses of PF-04991532 administered twice daily and sitagliptin 100 mg administered once daily on fasting plasma glucose over 12 weeks in adults with T2DM on stable doses of metformin.
• To evaluate the dose responses of PF-04991532 administered twice daily and sitagliptin 100 mg administered once daily over 12 weeks on body weight in adults with T2DM on stable doses of metformin.
• To evaluate the safety and tolerability of a range of oral doses of PF-04991532 administered twice daily and sitagliptin 100 mg administered once daily, over 12 weeks in adults with T2DM on stable doses of metformin. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Males and/or females of non-childbearing potential between the ages of 18 (or 21 based on country-specific age of consent) and 70 years, inclusive, at screening.
2. Subjects who have been on a stable dose of metformin either alone or in combination with an acceptable OAD agent (other than metformin) for their T2DM for at least 6 weeks prior to V1.
• Subjects on an acceptable OAD medication (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).
3. HbA1c at Screen (as assessed by study-specific central laboratory) meeting one of the following criteria based on prior background OAD agent:
• Metformin monotherapy → 7.0 - 11.0%, inclusive
• Metformin + acceptable OAD agent→ 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 medication based on expected rise in HbA1c post discontinuation.
4. BMI of ≥22.5 kg/m2 and ≤45.5 kg/m2, at screening.
5. 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.
6. Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures, including the ability to perform self tests of blood sugar at least once daily and have the capacity to store the study drug at 2-8 degrees C for the duration 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. Diagnosis of Type 1 diabetes mellitus or secondary forms of diabetes;
2. Fasting plasma glucose levels >270 mg/dL (ie, 14.98 mmol/L), at V1 (as assessed by study-specific central laboratory) confirmed by a single repeat, if deemed necessary;
3. 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.
4. Recent (ie, within 6 months prior to screening) evidence or medical history of unstable concurrent disease such as clinically significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or clinically significant allergic disease (including any drug allergies, but excluding treated and untreated seasonal allergies at the time of dosing);
5. History of myocardial infarction, unstable angina, coronary revascularization, stroke or transient ischemic attack within 6 months of screening;
6. Past medical history of pancreatitis;
7. Persistent, severe, uncontrolled hypertension; for example: sitting systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥105 mm Hg after at least 5-minutes seated rest at screening, confirmed via 1 repeat if deemed necessary;
8. At screening, 12-lead electrocardiogram (ECG) demonstrating QTc interval >470 msec, confirmed by a single repeat, if deemed necessary;
9. Subjects with any of the following findings in clinical laboratory tests at screening as assessed by study specific central laboratory confirmed by a single repeat, if deemed necessary:
• C peptide concentration of <0.8 ng/mL (265 pmol/L);
• Fasting serum triglycerides ≥400 mg/dL (ie, 4.52 mmol/L);
• AST/SGOT or ALT/SGPT ≥2x ULN;
• Total bilirubin ≥1.5x ULN and direct bilirubin >ULN;
• Those with history of Gilbert's syndrome are eligible for this study provided direct bilirubin is ≤ULN.
10. The following therapeutic agents are prohibited for the duration of the study. These medications are not to be used from the time of the start of the placebo baseline period (V3) to the completion of the dosing period (V9).
• Chronic oral or parenteral corticosteroids (eg, prednisone, dexamethasone, methylprednisolone or hydrocortisone) at any dose. Intercurrent steroid treatment may be administered if treatment does not exceed one week. Note that inhaled and topical corticosteroids are permitted;
• Orlistat, sibutramine, rimonabant, or other medications approved for weight loss;
• Anti-psychotic medication including olanzapine, risperidone;
• Drugs known to inhibit organic anion transport proteins (OATPs), including gemfibrozil, rifampin, cyclosporine, clarithromycin, and protease inhibitors (eg, lopinavir, ritonavir, indinavir).
11. The following diabetic agents are prohibited for the duration of the study. These medications are not to be used within 6 weeks prior to V1 to the completion of the study (V9).
• Insulin;
• Thiazolidinediones (eg, pioglitazone, rosiglitzone);
• GLP-1 analogues (eg, exenatide, liraglutide, pramlintide);
• Bromocriptine;
• Any other anti-hyperglycemic therapy with the exception of the protocol approved agents (includes the drugs that subjects are allowed to wash-off from).
12. Any condition possibly affecting drug absorption (eg, severe gastroparesis, gastrectomy or any area of intestinal resection, active inflammatory bowel disease or pancreatic insufficiency);
13. A positive urine drug test for illicit drugs, at screening;
14. 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.
15. Compliance (based on pill count of remaining placebo run-in study medication) of <90% during baseline period, as assessed prior to randomization on V4 (Day 1); |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in HbA1c (%) at Week 12 (Day 84) as compared to placebo. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Change from baseline in fasting plasma glucose (mg/dL) at Weeks 1, 2, 4, 8 and 12.
• Change from baseline in HbA1c at Weeks 1, 2, 4, and 8.
• Proportion of subjects achieving HbA1c <7%, as well as the proportion achieving <6.5% at Week 12.
• Change from baseline in body weight at Weeks 1, 2, 4, 8 and 12.
• Proportion of subjects at Week 12 with body weight gain from baseline ≥1%.
• Proportion of subjects at Week 12 with body weight loss from baseline ≥1%.
• Proportion of subjects at Week 12 with body weight gain from baseline ≥2%.
• Proportion of subjects at Week 12 with body weight loss from baseline ≥2%.
• Assessment of clinical laboratory tests, 12 lead ECGs, vital signs, adverse events (AEs), as well as serious AEs (SAEs) and including episodes of hypoglycemic adverse events (HAEs).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints are defined within the Secondary end points |
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| 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 | 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) | 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 | 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.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Hungary |
| India |
| Mexico |
| Poland |
| Serbia |
| Slovakia |
| Taiwan |
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| 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
|
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| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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