A Study of LY2608204 in Patients With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
Safety study with multiple oral doses of LY2608204 given to patients with type 2 diabetes. Study subjects will receive once daily doses of LY2608204 for a total treatment duration of up to 28 days. In this study, each patient will receive increasing doses of LY2608204 until reaching the highest dose that they can tolerate. Continuous glucose monitoring devices will be employed for each patient to monitor for hypoglycemia during study treatment. Dose titration and dose reduction is determined for each individual patient based on their safety and glycemic data.

Official Title
-----------------
Safety and Tolerability of Multiple Ascending Doses of LY2608204 in Patients With Type 2 Diabetes Mellitus

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: LY2608204


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients diagnosed with Type 2 diabetes mellitus (T2DM) who are currently treated with diet/lifestyle measures alone or in combination with anti-diabetic agents, including insulins Have fasting blood glucose (FBG) greater than or equal to 160 milligram/deciliter (mg/dL), with a subset of patients with FBG greater than or equal to 190 mg/dL in at least 2 measurements on separate days Have a glycated haemoglobin (HbA1c) level of greater than or equal to 8% and less than or equal to 11% at screening If female, are not of child-bearing potential due to surgical sterilisation (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause Are males or females who are at least 18 years old (for sites outside of Singapore) or at least 21 years old (for sites within Singapore) but no more than 70 years old (for all sites) Body mass index (BMI) greater than 18.5 kilogram/square meter (kg/m²) and less than 40.0 kg/m² Have clinical laboratory test results within the normal range for the population or investigator site, or with abnormalities deemed clinically insignificant by the investigator Have supine systolic blood pressure (SBP) greater than 160 millimeters of mercury (mmHg) and supine diastolic blood pressure (DBP) less than 100 mmHg Have venous access sufficient to allow blood sampling as per the protocol Are willing and able to comply with requirements for continuous glucose monitoring (CGM) Are reliable and willing to make themselves available for the duration of the study and who will abide by the Clinical Research Unit (CRU) policy and procedure and study restrictions. This includes staying in-patient at the CRU for a total duration of up to 31 days Have given written informed consent approved by Lilly and the ethical review board governing the site Exclusion Criteria: Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or use of a drug or device other than the study drug used in this study, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have significant history of past or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine (other than diabetes), hematological, or neurological disorders capable of significantly altering the absorption, metabolism or elimination of drugs or of constituting a risk when taking the study drug formulations or interfering with the interpretation of data Have a history of a seizure disorder A corrected QT interval greater than 450 milliseconds (msec) at screening or any personal history of ventricular tachycardia or unexplained syncope, or other abnormality in the 12-lead Electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study Have family history of long QT syndrome or family history of sudden unexplained death Use medications known to prolong the QT interval. Have type 1 diabetes mellitus or a history of ketoacidosis or any other type of diabetes mellitus other than type 2 Use of any known inducers or inhibitors of CYP3A within 14 days prior to the first dosing with study drug or intended use during the study History of a hypoglycemic event with acute mental status alteration that was not preceded by prodromal symptoms recognizable to the patient Fasting serum triglycerides greater than 500mg/dl Serum creatinine greater than 1.3 mg/dL in women, greater than 1.5 mg/dL in men Clinical evidence of active diabetic proliferative retinopathy Known clinically significant autonomic neuropathy as evidenced by urinary retention, orthostatic hypotension, diabetic diarrhea or gastroparesis Clinically significant coronary events or symptoms within 6 months prior to study entry Clinically significant peripheral vascular disease Have known allergies to LY2608204 or related compounds Evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies/antigen Evidence of hepatitis B and/or positive hepatitis B surface antigen (HBsAg) Donation or loss of blood equal to or exceeding 450 milliliter (mL) during the 3 months before the first administration of study drug Patients who have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females) (1 unit equal to 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits) or patients unwilling to stop alcohol consumption 24 hours prior to admission until the completion of each in-patient study period Patients who smoke more than 10 cigarettes or other tobacco products per day before study entry. Patients will not be allowed to smoke while in the study Unit Have a history of drug or alcohol abuse Intended use of over-the counter or prescription medications 7 and 14 days, respectively, prior to dosing. If this situation arises, inclusion of an otherwise suitable volunteer may be at the discretion of the investigator. Use of anti-diabetic medication [metformin, sulphonylureas, glinides, thiazolidinediones, acarbose, DPPIV inhibitors, Byetta (but not liraglutide)] by patients with type 2 diabetes mellitus is acceptable for this study Have repeated alanine transaminase levels greater than 2.5 times the upper limit of the reference range at screening, as determined by the central laboratory Have previously been enrolled in this clinical study or any other study of LY2608204. Exclusion Criteria for EU/UK/US Site(s) only -- Evidence of hepatitis C and/or positive hepatitis C antibodies, at screening Use of known drugs of abuse and/or positive findings on urinary drug screening, other than findings consistent with medication prescribed by the patient's physician or over-the-counter medications

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2608204<br>Oral capsules of LY2608204 given once daily at a starting dose of 160 milligram (mg), which may be titrated in 3 dose escalations to 240 mg, 320 mg and 400 mg, with a 7-day treatment duration at each dose level for up to 28 days total treatment. | Drug: LY2608204<br>* Administered orally.<br>* Other names: Glucokinase Activator;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Adverse Effects | Clinically significant adverse effects refer to any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the investigational product, whether or not related to the medicinal investigational product. | Day 1 through Day 49 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration Time Curve (AUC) | AUC for Day 1 is AUC from 0 to 24 hours. AUC for all other days is AUC at a dosing interval. | Predose, 1, 2, 4, 6, 7, 10, 12 and 24 hours Postdose | 
| Maximum Drug Concentration (Cmax) |  | Predose, 1, 2, 4, 6, 7, 10, 12, 24, 48, 120 and 168 hours Postdose | 
| Time to Maximum Drug Concentration (Tmax) |  | Predose, 1, 2, 4, 6, 7, 10, 12, 24, 48, 120 and 168 hours Postdose | 
| Number of Hypoglycemic Events | Number of hypoglycemia events with blood glucose concentration <70 milligram/deciliter (mg/dL). | Day 1 through Day 29 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes glucokinase safety