| 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 |
| The primary objective of this study is to test the hypothesis that, for adult patients with T2DM treated with or without metformin, administration of LY2599506 significantly decreases the HbA1c from baseline to endpoint at 12 weeks as compared to glyburide. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of LY2599506 in patients with T2DM.
• To evaluate the effects of LY2599506 and glyburide on frequency and severity of hypoglycemia.
• To evaluate the effects of LY2599506 and glyburide on fasting and post-prandial glucose.
• To evaluate the effects of LY2599506 and glyburide on insulin sensitivity, glucose clearance, and β-cell function.
• To evaluate the popPK and pharmacodynamics of LY2599506 on HbA1c, fasting glucose, fasting insulin, OGTT, glucose AUC, and OGTT insulin AUC endpoints.
• To evaluate the effects of LY2599506 and glyburide on fasting lipids and lipoproteins.
• To evaluate the frequency, extent of dose adjustment, and distribution of doses during 12 weeks of treatment for LY2599506 and glyburide.
• To evaluate the effects of LY2599506 and glyburide on patient-reported outcomes
• To evaluate the effects of LY2599506 and glyburide on change in body weight from baseline to endpoint.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Protocol Sample Storage Addendum I2Q-MC-GMAJ(1) 4 Sept 2009:
"A 12-Week, Phase 2, Randomized, Double-Blind, Active-Controlled Study of LY2599506 Given as Monotherapy or in Combination with Metformin in Patients with Type 2 Diabetes Mellitus". The primary objective is to collect and store samples of blood, plasma, and serum for research into genetics and biomarkers associated with type 2 diabetes mellitus and/or treatment with LY2599506.
2. Protocol PK/PD profiling Addendum I2Q-MC-GMAJ(2) 4 Sept 2009.
"A 12-Week, Phase 2, Randomized, Double-Blind, Active-Controlled Study of LY2599506 Given as Monotherapy or in Combination with Metformin in Patients with Type 2 Diabetes Mellitus". The objectives are
• To evaluate the PKs of LY2599506 after multiple doses.
• To contrast the within- and between-patient variability in 24 hour glycemic control achieved by LY2599506 and glyburide.
• To explore PK/PD relationships for effects on glucose and insulin involved in glucose homeostasis.
• To evaluate effects of LY2599506 and associated glycemia on QT interval.
• To explore the validity of CGMS data compared to conventional laboratory measured glucose assessments in response to both test meal and oral glucose tolerance test (OGTT) challenges.
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| E.3 | Principal inclusion criteria |
[1] Have type 2 diabetes mellitus prior to entering the trial based on the disease diagnostic criteria (WHO) classification.
[2] Are currently being treated with diet and exercise therapy consistent with the local standards of medical care, in the opinion of the Investigator.
[3] Patients may be treated with:
Diet and exercise alone OR Diet and exercise in combination with a stable dose of metformin for at least 3 months before Visit 1 OR Diet and exercise in combination with a stable dose of sulfonylurea for at least 3 months before Visit 1 OR Diet and exercise in combination with stable doses of metformin and sulfonylurea for at least 3 months before Visit 1 and have had diabetes for at least 6 years.
[4] Have an HbA1c value between 7% and 10%, inclusive at Visit 1.
[5] Are men or women between the ages of 18 to 70 years, inclusive.
[6] Are women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. Male patients will be advised to use a reliable method of birth control during the study and until 3 months after the last dose of study medication if their partner is of child-bearing potential. These requirements do not apply if the patient or his partner has been surgically sterilized.
[7] Have a body mass index between 20 and 40 kg/m2, inclusive at Visit 1.
[8] Have stable weight during the 3 months prior to Visit 1 (weight change not to exceed 5 kg over this period by patient self-report).
[9] Are well motivated, capable, and willing to (in the opinion of the Investigator):
• perform SMBG;
• complete study diary/ies, as required for this protocol;
• be receptive to diabetes education, including continuing their prestudy diet and activity levels, and follow simple dietary advice as appropriate.
[10] Have given written informed consent to participate in this study in accordance with local regulations and the ERB governing the study site.
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| E.4 | Principal exclusion criteria |
[11] Use of insulin or any antidiabetic agent other than metformin or sulfonylurea during the 3 months prior to Visit 1.
[12] Have a gastrointestinal disease that significantly impacts gastric empting or motility (for example, severe gastroparesis or pyloric stenosis) , in the opinion of the Investigator, or have undergone gastric bypass or gastric banding surgery.
[13] Have had more than 1 episode of severe hypoglycemia within 6 months prior to entry into the study, or are currently diagnosed as having hypoglycemia unawareness.
[14] Have had 2 or more emergency room visits or hospitalizations due to poor glucose control in the past 6 months.
[15] Are currently taking or have taken within the last 2 months medications which affect body weight.
[16] Have cardiac autonomic neuropathy (for example, resting tachycardia or orthostatic hypotension), based on clinical signs, symptoms, or appropriate diagnostic testing.
17] Have cardiac disease with functional status that is NYHA Class II, III, or IV or a history of myocardial infarction, unstable angina, or decompensated congestive heart failure in the past 6 months.
[18] Have poorly controlled hypertension (that is, mean systolic blood pressure >160 mm/Hg or mean diastolic blood pressure >100 mm/Hg) confirmed by 2 separate blood pressure measurements at Visit 1, history of malignant hypertension, evidence of renal artery stenosis and/or evidence of labile blood pressure including symptomatic postural hypotension. Doses of antihypertensive medications must be stable for 30 days before randomization.
[19] Have a QTcB (Bazett’s-corrected QT interval) interval greater than 450 msec for men or greater than 470 for women at Visit 1 or any personal history of ventricular tachycardia or unexplained syncope.
[20] Have family history of long QT syndrome or family history of sudden death.
[21] Use prescriptions or over-the-counter medications known to prolong the QT interval.
[22] Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or repeated alanine transaminase (ALT) levels >2.5 times the upper limit of the reference range at Visit 1, as determined by the central laboratory. (Patients with alanine aminotransferase [ALT] >2 times the upper limit of normal [ULN] should be evaluated for hepatitis).
[23] Have a serum creatinine >2.0 mg/dL (177 μmol/L) or in patients being treated with metformin, a serum creatinine above (or creatinine clearance below) what is approved in the metformin product labeling in the respective country, or are currently receiving renal dialysis.
[24] Have fed or fasting state hypertriglyceridemia (defined as >6.8 mmol/L, 600 mg/dl) at Visit 1. If taking lipid-lowering agents, doses of these medications must be stable for 30 days prior to randomization.
[25] Have evidence of inadequately treated hypothyroidism or hyperthyroidism based on clinical evaluation and/or an abnormal TSH result and which would confound data interpretation or pose a risk to patient safety. Subjects on a stable dose of thyroid replacement therapy may be eligible if they meet the other criteria.
[26] Have a history of a transplanted organ (except for corneal keratoplasty).
[27] Have evidence of a significant active, uncontrolled endocrine or autoimmune abnormality.
[28] Are receiving chronic (>2 weeks) systemic glucocorticoid therapy (excluding topical or inhaled preparations) or have received such therapy within 4 weeks immediately prior to Visit 2.
[29] Have an active or untreated malignancy or have been in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years.
[30] Are currently taking central nervous system stimulants or other over-the-counter herbal or health food stimulants with the exception of caffeinated beverages.
[31] Have known allergies to LY2599506 or related compounds.
[32] Are currently using or intend to use potent inhibitors of cytochrome P450 (CYP) 3A.
[33] Have any other condition that, in the opinion of the Investigator, may preclude the patient from following and completing the protocol.
[34] Are Investigator site personnel or have immediate family members who are directly affiliated with this study.
[35] Are Lilly employees.
[36] Have received treatment with a drug that has not received regulatory approval for any indication (within 30 days of the initial dose of study drug) unless the experimental agent was an antibody in which case, exclusion period for participation in the current study is 90 days.
[37] Have participated in an interventional medical, surgical, or pharmaceutical study in which a medical or surgical treatment was given within 30 days prior to the initial dose of study drug.
[38] Have previously completed or withdrawn from this study after providing informed consent.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The mean change in HbA1c from baseline to endpoint is the primary efficacy measure. |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 16 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 16 |
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