A Study of LY2881835 in Healthy People and People With Diabetes

Study Overview
=================
Brief Summary
-----------------
This will be the first study in which LY2881835 is given to humans in order to evaluate the safety and any side effects of LY2881835 in humans as well as how long LY2881835 stays in the body and its effect on blood sugar levels. The study consists of two parts. In part A, healthy subjects will participate and in part B, patients with type 2 Diabetes Mellitus (T2DM) will participate.

Official Title
-----------------
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Escalating Oral Doses of LY2881835 in Healthy Subjects and Patients With Type 2 Diabetes Mellitus

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

Intervention / Treatment
-----------------
* Drug: LY2881835
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All subjects: Are a healthy male or a healthy female who cannot become pregnant, or are patients with Type 2 Diabetes Mellitus (T2DM) who are not taking any drugs to lower blood sugar except metformin Have a body mass index (BMI) of at least 18.5 kilograms per meter squared (kg/m²) at screening Have blood pressure, pulse rate and clinical laboratory tests within the normal range for the population or investigator site, or with abnormalities deemed clinical insignificant by the investigator Have veins that are suitable for easy blood collection Are reliable and willing to be available for the whole study and are willing to follow study procedures Must have given written informed consent Subjects with Type 2 Diabetes Mellitus (T2DM) only: Do not have any change to their diabetes treatment for at least 4 weeks prior to screening Have a glycosylated hemoglobin (HbA1c) level greater than or equal to 6% and less than or equal to 11% at screening Exclusion Criteria: All subjects: Are currently participating in or were in another new drug or medical research study in the last 30 days Have participated in this study before Have known allergies to compounds related to the study drug Currently have or used to have health problems or laboratory test results that in the opinion of the doctor, could interfere with understanding the results of this study Intend to use over-the-counter or prescription medications within 14 days prior to dosing or during the study. Hormone replacement therapy and intermittent use of paracetamol during the study is acceptable. For patients with Type 2 Diabetes Mellitus, medicines for control of high fats (For example, cholesterol), high blood pressure, are allowed. Have electrocardiogram (ECG) readings that are not suitable for the study Are unwilling to follow dietary restrictions/requirements for the study including 1) refrain from consuming foods or beverages containing grapefruit pomelo, star fruit, or Seville orange within 14 days of the start of the study drug dosing until collection of the last blood sample for drug assay and 2) consume only the meals provided during inpatient stays at the clinical research unit Have a history of drug or alcohol abuse Are infected with hepatitis B Are infected with human immunodeficiency disease virus (HIV) Have donated 450 milliliters (mL) or more of blood in the last 3 months or provided any blood donation within the last month from screening Have a regular alcohol intake greater than 21 units per week (males) and 14 units per week (females) or are not willing to abstain from alcohol while in the research unit Smoke more than 10 cigarettes per day or are not willing to abstain from smoking while at the clinic The study doctor thinks the subject should not participate for any other reasons Subjects with Type 2 Diabetes Mellitus (T2DM) only: Have health complications due to poorly controlled diabetes as shown by blood and urine laboratory test results or based on physical examination and medical assessment, as determined by the study doctor Were hospitalised for poor control of their diabetes (ketoacidotic episode) in the last 6 months Currently using or have used insulin in the last 1 year to control their diabetes

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 65 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2881835<br>One cohort of healthy participants will receive single oral doses of LY2881835 in up to 3 of the 4 periods in Part A (dose escalation: 0.5 milligram (mg), 1.5 mg, subsequent doses determined based on review of safety, tolerability, glycaemic response and available pharmacokinetic (PK) data from the first 2 dose levels). One cohort of participants with Type 2 Diabetes Mellitus (T2DM) will receive single oral doses of LY2881835 in up to 2 of the 3 periods in Part B (dose escalation: starting dose based on review of safety, tolerability, glycaemic response and available PK data from Part A). There is a washout period of at least 5 days between periods (doses). | Drug: LY2881835<br>* Administered orally<br>|
| Placebo Comparator: placebo<br>One cohort of healthy participants will receive a single oral dose of placebo in 1 of the 4 periods in Part A. Another cohort of participants with T2DM will receive a single oral dose of placebo in 1 of the 3 periods in Part B. There is a washout period of at least 5 days between periods (doses). | Drug: Placebo<br>* Administered orally<br>|

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 are treatment emergent adverse events (TEAEs) possibly related to study drug. | Baseline to study completion up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Area Under the Curve (AUC) of LY2881835 | Not all the participants had quantifiable plasma concentrations at 48 hours, therefore only AUC from time zero to 24 hours [AUC(0-24 hours)] is provided. | Part A: Predose, 0.5, 1.5, 2.5, 4, 6, 12, 18 and 24hours (h) post-dose; Part B: Predose, 0.5, 1.5, 2.5, 4, 6, 12, 18 and 24 h post-dose | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) Of LY2881835 | Not all the participants had quantifiable plasma concentrations at 48 hours, therefore only Cmax up to 24 hours post-dose is provided. | Part A: Predose, 0.5, 1.5, 2.5, 4, 6, 12, 18 and 24 h post-dose; Part B: Predose, 0.5, 1.5, 2.5, 4, 6, 12, 18 and 24 h post-dose | 
| Pharmacokinetics (PK): Time to Maximum Concentration (Tmax) of LY2881835 | Not all the participants had quantifiable plasma concentrations at 48 hours, therefore only Tmax up to 24 hours post dose is provided. | Part A: Predose, 0.5, 1.5, 2.5, 4, 6, 12, 18 and 24 h post-dose; Part B: Predose, 0.5, 1.5, 2.5, 4, 6, 12, 18 and 24 h post-dose | 
| Glucose Area Under the Effective Concentration Curve (AUEC) | Glucose area under the serum concentration versus time curve (AUEC) was calculated using the linear trapezoidal rule from time 0 to 24 hours. | Part A: Predose, 1.0, 1.5, 2.5, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 18 and 24 h post-dose; Part B: Predose, 1.0, 1.5, 2.5, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 18 and 24 h post-dose | 
| Glucagon-Like Peptide (Active GLP-1) Area Under the Effective Concentration Curve (AUEC) | Glucagon-like peptide (active GLP-1) area under the serum concentration versus time curve (AUEC) was calculated using the linear trapezoidal rule from time 0 to 2.5 hours. | Part A: Predose, 1.5 and 2.5 h post-dose; Part B: Predose, 1.5 and 2.5 h post-dose | 
| C-Peptide Area Under the Effective Concentration Curve (AUEC) | C-Peptide area under the serum concentration versus time curve (AUEC) was calculated using the linear trapezoidal rule from time 0 to 6 hours. | Part A: Predose, 1.0, 1.5, 2.5, 4, 5, 6 and 24 h post-dose; Part B: Predose, 1.0, 1.5, 2.5, 4, 5, 6 and 24 h post-dose |