Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01300260
First received: February 3, 2011
Last updated: October 3, 2014
Last verified: October 2014
  Purpose

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


Condition Intervention Phase
Diabetes Mellitus, Type 2
Biological: LY2189265
Drug: Placebo
Drug: Insulin
Drug: Glucose
Drug: Glucagon
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: The Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose Infusion

Resource links provided by NLM:


Further study details as provided by Eli Lilly and Company:

Primary Outcome Measures:
  • Maximum Insulin Concentration (Cmax) - First Phase Response [ Time Frame: 0-10 minutes after dextrose bolus on Day 3 postdose ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Insulin Maximum Concentration (Cmax) [ Time Frame: After glucagon bolus on Day 3 postdose ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Area Under the Insulin Concentration-time Curve (AUC) [ Time Frame: After glucagon bolus on Day 3 postdose ] [ Designated as safety issue: No ]
    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.


Enrollment: 32
Study Start Date: February 2011
Study Completion Date: August 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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
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.

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

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01300260

Locations
Germany
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, Germany, D-41460
Sponsors and Collaborators
Eli Lilly and Company
Investigators
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
  More Information

No publications provided

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01300260     History of Changes
Other Study ID Numbers: 11371, H9X-MC-GBCI
Study First Received: February 3, 2011
Results First Received: October 3, 2014
Last Updated: October 3, 2014
Health Authority: United States: Food and Drug Administration
Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Glucagon
Glucagon-Like Peptide 1
Insulin
Insulin, Globin Zinc
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014