Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose

Tracking Information
First Submitted Date ICMJE	February 3, 2011
First Posted Date ICMJE	February 21, 2011
Results First Submitted Date	October 3, 2014
Results First Posted Date	October 7, 2014
Last Update Posted Date	October 7, 2014
Study Start Date ICMJE	February 2011
Actual Primary Completion Date	August 2011 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 3, 2014)	Maximum Insulin Concentration (Cmax) - First Phase Response [ Time Frame: 0-10 minutes after dextrose bolus on Day 3 postdose ]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.; Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response [ Time Frame: 0-10 minutes after dextrose bolus on Day 3 postdose ]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.; Maximum Insulin Concentration (Cmax) - Second Phase Response [ Time Frame: 10-180 minutes after dextrose bolus on Day 3 postdose ]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.; Insulin Area Under the Curve (AUC) - Second Phase Response [ Time Frame: 10-180 minutes after dextrose bolus on Day 3 post dose ]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 10 to 180 minutes (INSAUC[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.
Original Primary Outcome Measures ICMJE; (submitted: February 18, 2011)	Maximum insulin concentration (Cmax)-first phase response [ Time Frame: 0-10 minutes after dextrose bolus on Day 3 post dose ]; Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response [ Time Frame: 0-10 minutes after dextrose bolus on Day 3 post dose ]; Maximum Insulin Concentration (Cmax) - Second Phase Response [ Time Frame: 10 -180 minutes after dextrose bolus on Day 3 post dose ]; Insulin Area Under the Curve (AUC) - Second Phase Response [ Time Frame: 10-180 minutes after dextrose bolus on Day 3 post dose ]
Change History	Complete list of historical versions of study NCT01300260 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: October 3, 2014)	Insulin Maximum Concentration (Cmax) [ Time Frame: After glucagon bolus on Day 3 postdose ]; 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.
Original Secondary Outcome Measures ICMJE; (submitted: February 18, 2011)	Insulin Maximum Concentration (Cmax) [ Time Frame: After glucagon bolus on Day 3 post dose ]
Current Other Outcome Measures ICMJE; (submitted: October 3, 2014)	Area Under the Insulin Concentration-time Curve (AUC) [ Time Frame: After glucagon bolus on Day 3 postdose ]; 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.
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose
Official Title ICMJE	The Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose Infusion
Brief Summary	The purpose of this study is to measure the effect of LY2189265 to increase insulin levels in response to glucose intake.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition ICMJE	Diabetes Mellitus, Type 2
Intervention ICMJE	Biological: LY2189265 Administered subcutaneously Other Name: Dulaglutide; Drug: Placebo Administered subcutaneously; Drug: Insulin Administered intravenously Other Name: Lispro; Drug: Glucose Administered intravenously Other Name: Dextrose; Drug: Glucagon Administered intravenously Other Name: Glucagon hydrochloride
Study Arms	Experimental: LY2189265 then Placebo 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. Interventions: Biological: LY2189265 Drug: Placebo Drug: Insulin Drug: Glucose Drug: Glucagon; Experimental: Placebo then LY2189265 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. Interventions: Biological: LY2189265 Drug: Placebo Drug: Insulin Drug: Glucose Drug: Glucagon
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: October 3, 2014)	32
Original Estimated Enrollment ICMJE; (submitted: February 18, 2011)	35
Actual Study Completion Date	August 2011
Actual Primary Completion Date	August 2011 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 65 Years (Adult)
Accepts Healthy Volunteers	Yes
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Germany
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01300260
Other Study ID Numbers ICMJE	11371; H9X-MC-GBCI ( Other Identifier: Eli Lilly and Company )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Eli Lilly and Company
Study Sponsor ICMJE	Eli Lilly and Company
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: 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
PRS Account	Eli Lilly and Company
Verification Date	October 2014
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP