Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose

NCT01300260 | Completed Phase 1 Results

• 2 other identifiers: 11371H9X-MC-GBCI
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to measure the effect of LY2189265 to increase insulin levels in response to glucose intake.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (4)

• 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.

  10-180 minutes after dextrose bolus on Day 3 postdose

• Insulin Area Under the Curve (AUC) - 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. 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.

  10-180 minutes after dextrose bolus on Day 3 post dose

Secondary Outcomes (1)

• Insulin Maximum Concentration (Cmax)

  After glucagon bolus on Day 3 postdose

Other Outcomes (1)

• Area Under the Insulin Concentration-time Curve (AUC)

  After glucagon bolus on Day 3 postdose

Study Arms (2)

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.

Biological: LY2189265; Drug: Placebo; Drug: Insulin; Drug: Glucose; Drug: Glucagon

Interventions

LY2189265 BIOLOGICAL

Administered subcutaneously

Also known as: Dulaglutide

LY2189265 then Placebo; Placebo then LY2189265

Placebo DRUG

Administered subcutaneously

LY2189265 then Placebo; Placebo then LY2189265

Insulin DRUG

Administered intravenously

Also known as: Lispro

LY2189265 then Placebo; Placebo then LY2189265

Glucose DRUG

Administered intravenously

Also known as: Dextrose

LY2189265 then Placebo; Placebo then LY2189265

Glucagon DRUG

Administered intravenously

Also known as: Glucagon hydrochloride

LY2189265 then Placebo; Placebo then LY2189265

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (1)

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, Germany

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

dulaglutide; Insulin; Insulin Lispro; Glucose; Glucagon

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Insulin, Short-Acting; Hexoses; Monosaccharides; Sugars; Carbohydrates; Proglucagon

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Eli Lilly and Company

800-545-5979

Study Officials

• 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

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2011
• First Posted: February 21, 2011
• Study Start: February 1, 2011
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: October 7, 2014
• Results First Posted: October 7, 2014

Record last verified: 2014-10

Locations

DE (1)