Effect of LY2189265 on Insulin Secretion in Response to I... | NCT01300260

ID	Type	Description	Link
H9X-MC-GBCI	Other Identifier	Eli Lilly and Company

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
LY2189265 then Placebo	Experimental	LY2189265 (Dulaglutide) then Placebo: A single 1.5 milligram (mg) subcutaneous (SC) injection of LY2189265 on Day 1 in Period 1, followed by a single SC injection of Placebo on Day 1 in Period 2. On Day 3 of each period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose bolus (0.3 gram/kilogram [g/kg] over approximately 2 minutes). Three hours later, participants were administered a second IV dextrose bolus of 25 g of 50% dextrose or a suitably adjusted dose according to glycemic status (20 g of 50% dextrose for participants with 3-hour glucose between 5.2 and 10 millimole/liter [mmol/L] or 15 g of 50% dextrose for participants with 3-hour glucose >10 mmol/L), followed by a 20% dextrose at the set infusion rate of 600 milliliter/hour [mL/h] for 35 minutes. Fifteen minutes after the start of the 20% dextrose infusion, an IV 1-mg glucagon bolus was administered. There was a washout period of at least 28 days between Periods 1 and 2.	Biological: LY2189265 Drug: Placebo Drug: Insulin Drug: Glucose Drug: Glucagon
Placebo then LY2189265	Experimental	Placebo then LY2189265 (Dulaglutide): A single subcutaneous injection of Placebo on Day 1 in Period 1, followed by a single 1.5 milligrams (mg) subcutaneous injection of LY2189265 on Day 1 in Period 2. On Day 3 of each period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose bolus (0.3 gram/kilogram [g/kg] over approximately 2 minutes). Three hours later, participants were administered a second IV dextrose bolus of 25 g of 50% dextrose or a suitably adjusted dose according to glycemic status (20 g of 50% dextrose for participants with 3-hour glucose between 5.2 and 10 millimole/liter [mmol/L] or 15 g of 50% dextrose for participants with 3-hour glucose >10 mmol/L), followed by a 20% dextrose at the set infusion rate of 600 milliliter/hour [mL/h] for 35 minutes. Fifteen minutes after the start of the 20% dextrose infusion, an IV 1-mg glucagon bolus was administered. There was a washout period of at least 28 days between Periods 1 and 2.

Name	Type	Description	Arm Group Labels	Other Names
LY2189265	Biological	Administered subcutaneously	LY2189265 then Placebo Placebo then LY2189265

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Maximum Insulin Concentration (Cmax) - First Phase Response	On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus [T2DM]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Maximum plasma insulin concentration from 0 to 10 minutes (INSCmax[0-10]) following the first dextrose bolus (the first phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.	0-10 minutes after dextrose bolus on Day 3 postdose
Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response	On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus [T2DM]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Area under the plasma insulin concentration time curve from 0 to 10 minutes (INSAUC[0-10]) following the first dextrose bolus (the first phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.	0-10 minutes after dextrose bolus on Day 3 postdose
Maximum Insulin Concentration (Cmax) - Second Phase Response	On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus [T2DM]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Maximum plasma insulin concentration from 10 to 180 minutes (INSCmax[10-180]) following the first dextrose bolus (the second phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.

Secondary Outcomes

Measure	Description	Time Frame
Insulin Maximum Concentration (Cmax)	On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus [T2DM]) received a single subcutaneous dose of either LY2189265 or placebo. Maximum plasma insulin concentration from -2 to 20 minutes following the glucagon bolus (INSCmaxG) is presented.	After glucagon bolus on Day 3 postdose

Other Outcomes

Measure	Description	Time Frame
Area Under the Insulin Concentration-time Curve (AUC)	On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus [T2DM]) received a single subcutaneous dose of either LY2189265 or placebo. Area under the plasma insulin concentration-time curve from -2 to 20 minutes following the glucagon bolus (INSAUCG) is presented.	After glucagon bolus on Day 3 postdose

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

All Participants

Women must be surgically sterile (hysterectomy or bilateral oophorectomy or tubal ligation) or postmenopausal as defined by age >45 years without use of oral contraceptive agents for greater than 1 year and have either:
- spontaneous amenorrhea greater than 12 months, or
- spontaneous amenorrhea 6 to 12 months with documented follicle stimulating hormone (FSH) >25 milli international units/milliliter (mIU/mL) and serum estradiol <73 picomoles/liter (pmol/L) (20 picograms/milliliter [pg/mL])
Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures
Have given written informed consent approved by Lilly and the ethical review board governing the site
Have serum creatinine <150 micromoles/liter (µmol/L) (<1.3 milligrams/deciliter [mg/dl] in women, <170 µmol/L [<1.5 mg/dL] in men)
Have normal hemoglobin result, as determined by the investigator

Healthy Participants

Overtly healthy men and women as determined by medical history, normal lab results and physical examination.
Body mass index (BMI) between 19 and 25 kilograms/meter squared (kg/m^2), inclusive.
Normal blood pressure and heart rate as determined by the investigator
Have a normal response to an oral glucose tolerance test (OGTT) (glucose <7.8 millimoles/liter [mmol/L] [<140 mg/dL] at 2 hours after 75 grams (g) oral glucose load)

Participants with type 2 diabetes mellitus (T2DM)

Participants will have a BMI between 22.0 and 40.0 kg/m^2
Have T2DM controlled with diet and exercise alone or metformin for at least 4 weeks prior to admission
Have a hemoglobin A1c (HbA1c) value at screening (or within 4 weeks prior to screening) of 6.0% to 9.5%
Diagnosed with T2DM within the past 10 years
Clinical laboratory test results within normal range or deemed clinically insignificant by the Investigator. Abnormalities of serum glucose, serum lipids, urinary glucose, and urinary protein consistent with T2DM are acceptable.
Participants who are taking stable-dose prescription medications (for example, antihypertensive agents, aspirin, lipid-lowering agents) for treatment of concurrent medical conditions are permitted to participate providing the medication is not associated with development of torsade de pointes. However, use of beta-blockers and thiazide diuretics are not permitted during this study.

Exclusion Criteria:

All Participants

Within 30 days of the initial dose of study drug, have received treatment with a drug that has not received regulatory approval for any indication
Known allergies to Glucagon-Like Peptide 1 (GLP-1) related compounds
Have previously completed or withdrawn from this study or any other study in the last year investigating glucagon-like peptides or incretin mimetics including exenatide (Byetta®)
Regular use of known drugs of abuse and/or positive findings on urinary drug screening, other than findings consistent with medication prescribed by the participant's physician(s)
History or presence of cardiovascular, respiratory, renal, endocrine (except T2DM), hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs or of constituting a risk when taking the study medication or interfering with the interpretation of data
Have a history or presence of gastrointestinal disorder
Poorly controlled hypertension (systolic greater than 160 millimeters of mercury [mmHg], diastolic greater than 95 mmHg) and/or evidence of labile blood pressure including symptomatic postural hypotension. Use of beta-blockers or thiazide diuretics is not permitted during the study
Have a clinically significant history of cardiac disease or presence of active cardiac disease within 1 year of the screening period
Evidence of hepatitis C and/or positive hepatitis C antibody
Evidence of hepatitis B and/or positive hepatitis B surface antigen
Evidence of human immunodeficiency virus (HIV) and/or positive for HIV antibodies
Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females) or are unwilling to follow alcohol restrictions (1 unit = 12 ounces [oz] or 360 milliliters[mL] of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits).
Smoke more than 10 cigarettes or equivalent in nicotine use or nicotine substitutes per day
Regular use of systemic corticosteroids by oral, intravenous, or intramuscular route, or potent, inhaled, or intranasal steroids known to have a high rate of systemic absorption
Have a history or presence of significant active neuropsychiatric disease
Blood donation of more than 500 mL in the last 3 months or any blood donation within the last month
Any other condition, which in the opinion of the investigator would preclude participation in the study
An abnormality in the 12-lead electrocardiogram (ECG) that in the opinion of the investigator increases the risk of participating in the study.
Any clinically significant abnormal hematology, clinical chemistry, or urinary result(s) as determined by the investigator
Evidence of significant active uncontrolled endocrine or autoimmune abnormalities (for example thyroid disease, or pernicious anemia) as judged by the screening physician

Healthy Participants

Intended use of over-the-counter or prescription medication 7 and 14 days, respectively, prior to dosing.

Participants with T2DM

Clinically significant peripheral vascular occlusive disease (PVOD).
Known severe exudative diabetic retinopathy
Known significant autonomic neuropathy as evidenced by urinary retention, diabetic diarrhea, or gastroparesis
Have experienced a ketoacidotic episode (pH less than 7.3) requiring hospitalization in the last 6 months
Outpatient use of insulin for control of diabetes within the past 2 years
Use of antidiabetic agents other than metformin in the 4 weeks prior to study entry or use of thiazolidinediones within 12 weeks of study entry

Name	Affiliation	Role
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)	Eli Lilly and Company	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.		Neuss		D-41460

Arm/Group Information

ID	Title	Description
FG000	LY2189265 First, Then Placebo	Includes healthy participants or participants with T2DM. LY2189265 (Dulaglutide): Single 1.5 milligram (mg) subcutaneous (SC) injection on Day 1 of Period 1. Placebo: Single SC injection of Placebo on Day 1 of Period 2. On Day 3 of each period, participants received a 6-hour (hr) insulin infusion, followed by an intravenous (IV) dextrose bolus (50% dextrose bolus, 0.3 gram/kilogram [g/kg] over approximately 2 minutes [min]). Three hr later, a 2nd IV dextrose bolus 25 g of 50% dextrose or a suitably adjusted dose according to glycemic status (20 g of 50% dextrose for participants with 3-hr glucose between 5.2 and 10 millimole/liter [mmol/L] or 15 g of 50% dextrose for participants with 3-hr glucose >10 mmol/L) was administered, followed by a 20% dextrose at the set infusion rate of 600 milliliter/hr [mL/hr] for 35 min. Fifteen min after the start of the 20% dextrose infusion, an IV 1-mg glucagon bolus was administered. There was a washout period of ≥28 days between Periods 1 & 2.
FG001	Placebo First, Then LY2189265	Includes healthy participants and participants with T2DM. Placebo: Single subcutaneous (SC) injection of Placebo on Day 1 of Period 1. LY2189265 (Dulaglutide): Single 1.5 milligram (mg) SC injection on Day 1 of Period 2. On Day 3 of each period, participants received a 6-hour (hr) insulin infusion, followed by an intravenous (IV) dextrose bolus (50% dextrose bolus, 0.3 gram/kilogram [g/kg] over approximately 2 minutes [min]). Three hr later, a 2nd IV dextrose bolus 25 g of 50% dextrose or a suitably adjusted dose according to glycemic status (20 g of 50% dextrose for participants with 3-hr glucose between 5.2 and 10 millimole/liter [mmol/L] or 15 g of 50% dextrose for participants with 3-hr glucose >10 mmol/L) was administered, followed by a 20% dextrose at the set infusion rate of 600 milliliter/hr [mL/hr] for 35 min. Fifteen min after the start of the 20% dextrose infusion, an IV 1-mg glucagon bolus was administered. There was a washout period of ≥28 days between Periods 1 & 2.

ID	Title	Description
BG000	Healthy Participants	Includes healthy participants randomized to receive 1.5 milligram (mg) LY2189265 (Dulaglutide) first or Placebo first on Day 1 of either treatment sequence.
BG001	Participants With Type 2 Diabetes Mellitus (T2DM)

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Maximum Insulin Concentration (Cmax) - First Phase Response

On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus [T2DM]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Maximum plasma insulin concentration from 0 to 10 minutes (INSCmax[0-10]) following the first dextrose bolus (the first phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.

All participants (healthy and with type 2 diabetes mellitus [T2DM]) who received at least 1 dose of study drug (LY2189265 or Placebo) with evaluable INSCmax(0-10) first response phase data.

Geometric Mean

95% Confidence Interval

picomole per liter (pmol/L)

0-10 minutes after dextrose bolus on Day 3 postdose

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases

ID	Term
C555680	dulaglutide
D007328	Insulin
D061268	Insulin Lispro
D005947	Glucose
D005934	Glucagon

ID	Term
D011384	Proinsulin
D061385	Insulins
D010187	Pancreatic Hormones
D036361	Peptide Hormones

OG000	Healthy Participants: Placebo	Healthy participants first received a single subcutaneous injection of Placebo on Day 1. On Day 3, participants received a 6-hour insulin infusion followed by a dextrose bolus (50% dextrose bolus, 0.3 gram/kilogram [g/kg] over approximately 2 minutes).
OG001	Healthy Participants: LY2189265	Healthy participant first received a single subcutaneous injection of 1.5 milligram (mg) LY2189265 on Day 1. On Day 3, participants received a 6-hour insulin infusion followed by a dextrose bolus (50% dextrose bolus, 0.3 gram/kilogram [g/kg] over approximately 2 minutes).
OG002	Participants With Type 2 Diabetes Mellitus (T2DM): Placebo	T2DM participants first received a single subcutaneous injection of Placebo on Day 1. On Day 3, participants received a 6-hour insulin infusion followed by a dextrose bolus (50% dextrose bolus, 0.3 gram/kilogram [g/kg] over approximately 2 minutes).
OG003	Participants With Type 2 Diabetes Mellitus (T2DM): LY2189265	T2DM participants first received a single subcutaneous injection of 1.5 milligram (mg) LY2189265 on Day 1. On Day 3, participants received a 6-hour insulin infusion followed by a dextrose bolus (50% dextrose bolus, 0.3 gram/kilogram [g/kg] over approximately 2 minutes).