| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| 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 |
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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 assess the effect of co-administration of sitagliptin and metformin compared to placebo on the incretin effect (based on the comparison of the insulin secretory response to oral glucose load and an "isoglycemic" intravenous glucose load) |
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| E.2.2 | Secondary objectives of the trial |
To assess the effect of sitagliptin compared with placebo on the incretin effect (based on the comparison of the insulin secretory response to oral glucose load and an "isoglycemic" intravenous glucose load).
To assess the effect of co-administration of sitagliptin and metformin compared with sitagliptin alone and metformin alone on the incretin effect (based on the comparison of the insulin secretory response to oral glucose load and an "isoglycemic" intravenous glucose load). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Visit 1 (Screening):
a. Patient has type 2 diabetes mellitus (T2DM) (according to ADA criteria). Note: an OGTT may be performed to confirm diagnosis of T2DM
b. Patient is ≥ 30 and ≤ 75 years of age on the day of signing informed consent.
c. Patient has a BMI that is ≥ 25 and ≤ 35 kg/m2.
d. Patient is currently not on an OHA medication and has a Screening/Visit 1 HbA1c ≥ 6.5% and ≤ 9% or is on OHA monotherapy with metformin or a sulfonylurea and has a Screening/Visit 1 HbA1c ≥ 6% and ≤ 8.5%
e. Patient is a male, or a female who is unlikely to conceive, as indicated by at least 1 “yes” answer to the following questions:
1) Patient is a male.
2) Patient is a surgically sterilized female.
3) Patient is a postmenopausal female ≥ 45 years of age with > 2 years since last menses.
4) Patient is a non-sterilized, premenopausal female and agrees to abstain from heterosexual activity or to use an adequate method of contraception to prevent pregnancy. Note: Acceptable methods of birth control are: hormonal contraceptive, intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, or vasectomy.
f. Patient understands the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent.
g. Agreement to maintain prior diet and exercise habits during the full course of the study.
h. Ability to comply with all study requirements.
At Visit 3
i. Patient has an FPG of ≥ 110 mg/dL (6.1 mmol/L) and ≤220 mg/dL (12.2 mmol/L).
Note: If the Visit 3 FPG does not meet this criterion AND is not consistent with the patient's recent fasting SBGM values, a single repeat measurement may be performed at the discretion of the investigator. If repeat value meets FPG inclusion criterion, patient may continue in the study.
At Visit 4
j. Patient is ≥ 80% compliant with study medication during the single-blind placebo run-in (as determined by tablet count).
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| E.4 | Principal exclusion criteria |
At Visit 1
a. Patient has a history of type 1 diabetes mellitus or a history of ketoacidosis
b. Patient is assessed by the investigator as possibly having type I diabetes confirmed with a C-peptide ≤ 0.7 ng/mL (0.23 nmol/L). Note: Only patients assessed by the investigator as possibly having type I diabetes should have C-peptide measured at Visit 1.
c. Patient has been taking oral anti-hyperglycemic agent (OHA) within the prior 12 weeks, except metformin or a sulfonylurea.
d. Patient has required insulin therapy within the past 12 weeks. Note: patients who received a brief period of insulin treatment (e.g., several days during a hospitalization) and who are no longer requiring insulin treatment may participate.
Patients Requiring Specific Treatments
e. Patient is on a weight loss program and is not in the maintenance phase, or patient started weight loss medication (e.g., orlistat, sibutramine, or rimonabant) within the prior 8 weeks.
f. Patient is on or likely to require treatment with ≥ 2 consecutive days or repeated courses of pharmacologic doses of corticosteroids, or requires steroid replacement therapy (i.e., in patients with adrenal insufficiency)
Exception: Topical or inhaled corticosteroids are permitted in the study.
g. Patient is being treated with immunosuppressive or immunomodulating agents (e.g., cyclosporine, metotrexate).
h. Patient is currently participating or has participated in a study with an investigational compound or device within 12 weeks or 5 half-lives of signing informed consent.
i. Patient has undergone a surgical procedure within 4 weeks prior to signing informed consent. Exception: Patient with a history of minor surgery (i.e. using local anesthesia, like for removal of basal cell carcinoma, cataract, etc) within 4 weeks of signing informed consent and is fully recovered may participate.
j. Patient has a history of intolerance or hypersensitivity to a DPP- 4- inhibitor or metformin or has any contraindication to DPP-4 inhibitors or metformin based upon label of the country of the investigational site.
Concomitant Disease of Organs and Systems
k. Patient has laboratory values as listed below:
Parameter Values
Creatinine Clearance < 70 mL/min
ALT† > 2 times ULN
AST† > 2 times ULN
TSH Outside of normal range
TG > 600 mg/dL (> 4.5 mmol/L)
MDRD estimated creatinine clearance
† Patients whose serum ALT or AST exceeds this limit may be retested one time if the investigator does not believe the value reflects the patient’s status.
l. Patient has evidence of a significant cardiovascular disorder within 6 months of signing informed consent (e.g. acute coronary syndrome [e.g. MI or unstable angina], new or worsening angina; coronary artery intervention [e.g., CABG or PTCA]; stroke or transient ischemic neurological disorder).
m. Patient has congestive heart failure that requires pharmacological treatment
n. Patient has a systolic blood pressure of ≥ 160 mmHg or diastolic blood pressure of ≥ 95 mmHg. Note: Investigators are encouraged to maximize blood pressure control according to current guidelines. Patient may have blood pressure medication adjusted and be enrolled if repeat blood pressure measurement no longer meets exclusion criterion at Visit 3/Week -2.
o. Patient has a history of malignancy. Exceptions: (1) Patients with adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix may participate; (2) Patients with other malignancies which have been successfully treated for ≥ 5 years prior to screening, where in the judgment of both the investigator and treating physician, appropriate follow-up has revealed no evidence of recurrence from the time of treatment through the time of screening; and (3) Patients, who, in the opinion of the investigator, are highly unlikely to sustain a recurrence during the duration of the study. However, patients with a history of bladder carcinoma, leukemia, lymphoma, myeloproliferative or myelodysplastic diseases, malignant melanoma, renal cell carcinoma are ineligible for the study regardless of the time since treatment, and in such cases, no exceptions will apply.
p. Patient is pregnant or breast-feeding or expecting to conceive within the projected duration of the study.
q. Patient is expecting to donate eggs within the projected duration of the study.
r. Patient has HIV (as assessed by medical history)
s. Patient has a medical history of active liver disease including chronic active hepatitis B or C or symptomatic gallbladder disease including biliary cirrhosis.
t. Patient is being treated for hyperthyroidism.
u. Patient has any other condition or therapy which, in the opinion of the investigator might pose a risk to the patient or make participation not in the patient’s best interest.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The effect of co-administration of sitagliptin and metformin compared to placebo on the incretin effect (based on the comparison of the insulin secretory response to oral glucose load and an ‘isoglycemic’ intravenous glucose load). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Information not present in EudraCT |
| E.6.5 | Efficacy | Information not present in EudraCT |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| 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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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