| 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 | 8.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
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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 |
Primary Objective for the Main Phase
To evaluate the efficacy of GW823093 (15 mg, 30 mg, and 45 mg) versus placebo on the change from baseline in glycosylated hemoglobin (HbA1c) after 26 weeks of dosing in subjects with T2DM
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives Main Phase
To evaluate the effect of GW823093, versus placebo, on glycemic parameters (HbA1c and fasting plasma glucose [FPG]), fasting insulin, C-peptide, serum lipid profile, body weight, body mass index (BMI), and waist circumference during 26 weeks of dosing in subjects with T2DM.
To investigate the safety and tolerability of GW823093 versus placebo during 26 weeks of dosing in subjects with T2DM.
Extension Phase
To evaluate the effect of GW823093 on safety and tolerability during an additional 26 weeks of dosing in subjects with T2DM.
To investigate glycemic parameters (HbA1c and FPG), fasting insulin, serum lipid profile, body weight, BMI, and waist circumference during an additional 26 weeks of dosing in subjects with T2DM. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects will be entered into this study only if they meet all of the following criteria:
1.Subjects with T2DM as defined by the criteria of the American Diabetes Association and recognized by World Health Organization (WHO) Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [American Diabetes Association, 2004a] for at least 2 months preceding screening.
2.Concurrent T2DM therapy:
·DIET AND EXERCISE ONLY (TREATMENT NAÏVE): Must be diet and exercise treated; must not have taken anti-diabetic medication for at least 3 months prior to the Pre-screening Visit (Visit 1)
OR
·MONOTHERAPY: Not taking more than 1 oral anti-diabetic agent, and willing to stop treatment at Screening (Visit 2)
·Previous diabetes monotherapy will be limited to: sulfonylureas, glitinides, biguanides, or a-glucosidase inhibitors, such as acarbose. A thiazolidinedione is only acceptable if it has been stopped 3 or more months prior to screening. Monotherapy with a fixed-dose combination drug is not allowed. Subjects must not have been taking any oral anti-diabetic combination therapy (including with a fixed dose combination drug) for at least 3 months prior to the screen visit.
3.Glycemic parameters:
·HbA1c level at Pre-screening (Visit 1)
·For subjects treated with oral monotherapy: ≥7.0% and £8.5%;
·For subjects treated with diet and exercise only: ≥7.5% and £10.0%.
·Fasting glucose level at the Screening Visit (Visit 2) £260 mg/dL (14.4 mmol/L)
4.Men and women who are 18 to 75 years of age inclusive at the time of Screening (Visit 2).
5.BMI ≥20 and ≤40 kg/m2.
6.If female, is eligible to enter and participate in this study:
·If of non-childbearing potential (i.e., physiologically incapable of becoming pregnant [tubal ligation), including any female who is post-menopausal [>1 year without menstrual period]); or,
·If of child-bearing potential, has a negative serum pregnancy test at Screening (Visit 2) and Baseline (Week 0, Visit 5) and:
Has a male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for that female subject, or
If she uses double-barrier methods of contraception; condoms (with spermicide) and intrauterine device (IUD) are acceptable, or
If she uses hormonal contraceptives (oral, depots, patches, etc.) with double-barrier methods of contraception as outlined above, or
If she abstains from sexual intercourse, or
If she is with a same-sex partner and does not participate in bisexual activities where there is any risk of pregnancy.
7.Informed Consent: a signed and dated written consent obtained from the subject before any study-related procedures are performed |
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| E.4 | Principal exclusion criteria |
bjects will be entered into this study only if they meet none of the following criteria:
1.Metabolic disease including but not limited to:
·Diagnosis of type 1 diabetes mellitus or ketoacidosis or
·Uncorrected thyroid dysfunction. (Note: subjects with hypothyroidism on a stable dose of thyroid replacement therapy for at least 3 months prior to Screening [Visit 2], and who have a screening thyroid-stimulating hormone [TSH] within the limits of normal may participate).
·Previous use of insulin:
-Within 3 months prior to screening;
-For >2 weeks when used for acute illness in the last 12 months prior to Screening (Visit 2) or
-Used for more than 1 year when associated with gestational diabetes mellitus;
2.History of clinically significant cardiovascular disease, including:
·Documented myocardial infarction, stroke, or transient ischemic attack in the past year;
·Coronary revascularization including percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery in the previous year;
·Unstable angina;
·Clinically significant arrhythmia or valvular heart disease;
·Congestive heart failure classified as New York Heart Association (NYHA) Class III or IV heart failure, NYHA Functional Classification)];
·Blood pressure >150/100 mmHg or heart rate >100 beats/minute at Screening. Subjects using antihypertensives must be on stable doses during the 3 months prior to Screening;
·A QTc interval (Bazett’s) ≥440 msec in males and ≥450 msec in females at Screening (Visit 2); or
·Other clinically significant ECG abnormalities which, in the opinion of the Investigator, may affect the interpretation of safety and/or efficacy data, or which otherwise contraindicates participation in a clinical trial with a new chemical entity.
3.Is currently lactating, pregnant, or actively trying to become pregnant.
4.Has a significant renal impairment as defined by serum creatinine >2 mg/dL (>176 mmol/L).
5.History of significant co-morbid diseases active within the last 6 months (e.g., gastrointestinal disease, malignancy).
6.History of pancreatitis.
7.Subjects with an ALT/AST >2.5 x the upper limit of the normal (ULN) reference range or total bilirubin >1.5 x ULN, other than Gilbert’s syndrome.
8.History of alcohol or substance abuse within the past year, as determined by the Investigator or a positive urine drug screen at Screening (Visit 2) or during treatment:
·Unwilling to refrain from the use of excessive alcohol or illicit drugs and adhere to other protocol-stated restrictions while participating in the study;
·History of alcohol abuse defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint of beer or 1 measure of spirits or 1 glass of wine; or
·The Investigator should exercise his/her medical judgment to determine if a urine drug screen is indicated.
9.Is currently taking prohibited concomitant medications listed in Appendix 1.
10.Known allergy to any of the capsule excipients, or history of drug or other allergy, which, in the opinion of the responsible study physician, contradicts participation.
11.Received treatment with an investigational drug or participated in any other clinical trial during the previous 3 months.
12.Clinically significant anemia (i.e., hemoglobin <12.0 g/dL [<120.0 g/L] for males and <11.0 g/dL [<110.0 g/L for females]) or hemoglobinopathies (e.g., sickle cell anemia or thalessemia).
13.In the opinion of the Investigator has a risk of non-compliance with study procedures, or cannot read, understand, or complete study-related materials, particularly the informed consent.
14.Has any concurrent condition or any clinically significant abnormality identified on the screening physical examination, laboratory tests, ECG, including pulmonary, neurological or inflammatory diseases, which, in the opinion of the Investigator, may affect the interpretation of efficacy and safety data, or which otherwise, contraindicates participation in a clinical trial with a new chemical entity. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Main Phase Endpoints
Primary efficacy
The primary efficacy endpoint for the Main Phase is change from baseline (Week 0) in HbA1c at Week 26.
Secondary efficacy
The secondary efficacy endpoints for the Main Phase are:
• Change from baseline (Week 0) in HbA1c at Weeks 4, 8, 12, 16, and 20.
• Change from baseline (Week 0) in FPG at Weeks 4, 8, 12, 16, 20, and 26.
• Proportion of subjects who achieve various HbA1c (≤6.0%, ≤6.5%, and <7%) and FPG (≤110 mg/dL [6.1 mmol/L]), <126 mg/dL [7.0 mmol/L], and (<140 mg/dL [7.8 mmol/L]) targets, and/or achieve a clinically meaningful decrease in HbA1c (≥0.7%) and FPG (≥30 mg/dL [1.7 mmol/L]) at Week 26.
• Change from baseline (Week 0) in fasting insulin, and homeostasis model assessment of insulin sensitivity (HOMA-S) and β cell function (HOMA-β) at Weeks 12 and 26.
• Change from baseline (Week 0) in C-peptide, fasting lipids (triglycerides, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-c], and high-density lipoprotein cholesterol [HDL-c]), body weight, waist circumference, and BMI) at Weeks 12 and 26.
• Time to rescue with metformin (Protocol reference Section 4.3.2, Subject Withdrawal).
Extension Phase Endpoints
The endpoints for the Extension Phase are:
• Incidence of adverse events.
• Change from baseline (Week 0) in HbA1c at Weeks 32, 40, 46, and 52.
• Change from baseline (Week 0) in FPG at Weeks 32, 40, 46, and 52.
• Change from baseline (Week 0) in C-peptide and fasting insulin at Week 52.
• Change from baseline (Week 0) in fasting lipids (triglycerides, TC, LDL-c, and HDL-c) at Week 52.
• Changes in hematology, clinical chemistry, and urinalysis laboratory parameters.
• Incidence and severity of hypoglycemia.
• Change from baseline (Week 0) in vital signs: cuff systolic and diastolic blood pressure and radial heart rate at Weeks 32, 40, 46, and 52.
• Change from baseline (Week 0) in 12-lead ECG (PR, QRS, and QTc intervals) at Weeks 40 and 52.
• Change from baseline (Week 0) in BMI, body weight and waist circumference at Week 52.
Novel Biomarkers Endpoints (Main and Extension Phases)
Novel candidate biomarkers and subsequently discovered biomarkers of the biological response associated with T2DM or medically related conditions and/or the action of denagliptin may be identified by application of:
• Measurement of a subset of proteins in plasma samples
• Proteome analysis of plasma samples
Safety
The safety endpoints for the Main Phase are:
• Incidence of adverse events.
• Changes in hematology, clinical chemistry, and urinalysis laboratory parameters.
• Incidence and severity of hypoglycemia.
• Change from baseline (Week 0) in vital signs (cuff systolic and diastolic blood pressure and radial heart rate) at Weeks 4, 8, 12, 16, 20, and 26.
• Change from baseline (Week 0) in 12-lead electrocardiogram (ECG) (PR, QRS, and QTc intervals) at Weeks 4, 12, 20, and 26. |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | No |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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