Evaluation of the Glucoregulatory Effects of Glucagon-like Peptide-1 Receptor (GLP-1 Receptor) Activation in Participants With Type 2 Diabetes Mellitus (MK-0000-222)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01373450
First received: June 13, 2011
Last updated: February 10, 2014
Last verified: February 2014
  Purpose

This was a four-period crossover study to assess the glycemic effects of a single dose of oxyntomodulin (OXM) on the glucose levels in participants with Type 2 diabetes mellitus (T2DM). Participants were randomly assigned to 1 of 6 treatment sequences consisting of 4 treatment periods, with a 7-day wash-out between each treatment period. The primary hypothesis was that during graded glucose infusion (GGI) oxyntomodulin (OXM) is neutral or better than placebo (Pbo) at lowering ambient plasma glucose levels, and at significantly enhancing insulin secretion.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: Oxyntomodulin
Drug: Liraglutide 0.6 mg
Drug: Liraglutide 1.2 mg
Drug: Placebo for Oxyntomodulin
Drug: Placebo for Liraglutide
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: Evaluation of the Glucoregulatory Effects of GLP-1 Receptor Activation in Patients With Type 2 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Change From Baseline in Time-weighted Average of Glucose Measured by Area Under the Curve (AUC) After a Single Dose of Oxyntomodulin (OXM) [ Time Frame: Baseline and during GGI at time points 0, 20, 40, 60, 80, 100, 120, 140, 160 and 165 minutes ] [ Designated as safety issue: No ]
    Participants received on Day (-1) an overnight intravenous (IV) infusion of insulin titrated to achieve baseline fasting plasma glucose on Day 1 of between 90 and 130 mg/dL. Participants also received on Day (-1) a single dose of liraglutide (Lg) or placebo for Lg, after which insulin infusion was discontinued. Following overnight fast, participants received on Day 1 OXM or placebo for OXM, accompanied by up to 160 minutes of graded glucose infusion (GGI). During GGI glucose (20% D/W) was gradually infused at rates of 2,4,6 and 10 mg/kg/min, with each rate lasting approximately 40 minutes. Glucose levels were measured from blood collected at baseline and during GGI at the following minutes: 0, 20, 40, 60, 80, 100, 120, 140, 160 and 165 in order to calculate the time-weighted average change from baseline in glucose AUC from 0-160 minutes.

  • Change From Baseline in Maximum Ambient Glucose Concentration (Gmax) After a Single Dose of OXM [ Time Frame: Baseline and up to 160 minutes after start of GGI ] [ Designated as safety issue: No ]
    Participants received on Day (-1) an overnight IV infusion of insulin titrated to achieve baseline fasting plasma glucose on Day 1 of between 90 and 130 mg/dL. Participants also received on Day (-1) a single dose of Lg or placebo for Lg, after which insulin infusion was discontinued. Following overnight fast, participants received on Day 1 OXM or placebo for OXM, accompanied by up to 160 minutes of GGI. During GGI glucose (20% D/W) was gradually infused at rates of 2,4,6 and 10 mg/kg/min, with each rate lasting approximately 40 minutes. Glucose levels were measured from blood collected at baseline and during GGI to determine the maximum ambient glucose concentration above baseline.

  • Change From Baseline in Beta Cell Sensitivity to Glucose (Φ) After a Single Dose of OXM [ Time Frame: Baseline and up to160 minutes after start of GGI ] [ Designated as safety issue: No ]
    Beta cell sensitivity measures the ability to mount an insulin secretory response relative to the level of ambient plasma glucose. Participants received on Day (-1) an overnight IV infusion of insulin titrated to achieve baseline fasting plasma glucose on Day 1 of between 90 and 130 mg/dL. Participants also received on Day (-1) a single dose of Lg or placebo for Lg, after which insulin infusion was discontinued. Following overnight fast, participants received on Day 1 a single dose of OXM or placebo for OXM, accompanied by up to 160 minutes of GGI. During GGI glucose (20% D/W) was gradually infused at rates of 2,4,6 and 10 mg/kg/min, with each rate lasting 40 minutes. Glucose (G), insulin and C-peptide levels were measured from blood collected at baseline and during GGI, with the decay in C-peptide concentration used to indirectly estimate the Insulin Secretion Rate (ISR). Beta Cell Sensitivity (Φ) was determined from the regression of the ISR on ambient plasma glucose (G).


Secondary Outcome Measures:
  • Change From Baseline in Insulinotrophic Effect (ISR/G) at the Highest Glucose Infusion Rate After Two Periods of Placebo Treatment [ Time Frame: Baseline and 160 minutes after start of GGI at each placebo treatment period ] [ Designated as safety issue: No ]
    The reproducibility of insulinotrophic effects was compared after two separate placebo treatment periods within the same treatment sequence. Participants received on Day (-1) an overnight IV infusion of insulin titrated to achieve baseline fasting plasma glucose on Day 1 of between 90 and 130 mg/dL. Participants also received on Day (-1) a single subcutaneous dose of placebo for Lg, after which insulin infusion was discontinued. Following overnight fast, participants received on Day 1 placebo for OXM, accompanied by up to 160 minutes of GGI. During GGI glucose (20% D/W) was gradually infused at rates of 2,4,6 and 10 mg/kg/min, with each rate lasting approximately 40 minutes. Over these two treatment periods glucose (G), insulin and C-peptide levels were measured from blood collected at the highest glucose infusion rate; with the decay in C-peptide concentration used to indirectly estimate the Insulin Secretion Rate (ISR), and hence to determine the insulinotrophic effect, ISR/G.

  • Change From Baseline in Gmax After Single Doses of 0.6 mg Lg, or 1.2 mg Lg, Compared With Single Doses of Placebo or OXM [ Time Frame: Baseline and up to 160 minutes after start of GGI ] [ Designated as safety issue: No ]
    Participants received on Day (-1) an overnight IV infusion of insulin titrated to achieve baseline fasting plasma glucose on Day 1 of between 90 and 130 mg/dL. Participants also received on Day (-1) a single dose of Lg or placebo for Lg, after which insulin infusion was discontinued. Following overnight fast, participants received on Day 1 a single dose of OXM or placebo for OXM, accompanied by up to 160 minutes of GGI. During GGI glucose (20% D/W) was gradually infused at rates of 2,4,6 and 10 mg/kg/min, with each rate lasting approximately 40 minutes. Glucose levels were measured from blood collected at baseline and during GGI to determine the maximum ambient glucose concentration above baseline.

  • Change From Baseline in Insulinotrophic Effect (ISR/G) After Single Doses of 0.6 mg Lg, or 1.2 mg Lg, Compared With Single Doses of Placebo or OXM [ Time Frame: Baseline and up to 160 minutes after start of GGI ] [ Designated as safety issue: No ]
    Participants received on Day (-1) an overnight IV infusion of insulin titrated to achieve baseline fasting plasma glucose on Day 1 of between 90 and 130 mg/dL. Participants also received on Day (-1) a single dose of Lg or placebo for Lg, after which insulin infusion was discontinued. Following overnight fast, participants received on Day 1 a single dose of OXM or placebo for OXM, accompanied by up to 160 minutes of GGI. During GGI glucose (20% D/W) was gradually infused at rates of 2,4,6 and 10 mg/kg/min, with each rate lasting approximately 40 minutes. Glucose (G), insulin and C-peptide levels were measured from blood collected at baseline and during GGI; with the decay in C-peptide concentration used to indirectly estimate the Insulin Secretion Rate (ISR) and hence determine ISR/G.


Enrollment: 12
Study Start Date: June 2011
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: OXM → Lg-0.6 → Pbo → Lg-1.2
Participants received Oxyntomodulin 3.0 pmol/kg/min in the first, Liraglutide 0.6 mg in the second, Placebo in the third, and Liraglutide 1.2 mg in the fourth period
Drug: Oxyntomodulin
3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)
Drug: Liraglutide 0.6 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Placebo for Oxyntomodulin
IV infusion in the morning of the day of GGI (Day 1)
Drug: Placebo for Liraglutide
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Experimental: Lg-0.6 → Pbo → OXM → Pbo
Participants received Liraglutide 0.6 mg in the first, Placebo in the second, Oxyntomodulin 3.0 pmol/kg/min in the third, and Placebo in the fourth period
Drug: Oxyntomodulin
3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)
Drug: Liraglutide 0.6 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Placebo for Oxyntomodulin
IV infusion in the morning of the day of GGI (Day 1)
Drug: Placebo for Liraglutide
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Experimental: Pbo → OXM → Lg-0.6 → Pbo
Participants received Placebo in the first, Oxyntomodulin 3.0 pmol/kg/min in the second, Liraglutide 0.6 mg in the third, and Placebo in the fourth period
Drug: Oxyntomodulin
3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)
Drug: Liraglutide 0.6 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Placebo for Oxyntomodulin
IV infusion in the morning of the day of GGI (Day 1)
Drug: Placebo for Liraglutide
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Experimental: Lg-0.6 → OXM → Pbo → Lg-1.2
Participants received Liraglutide 0.6 mg in the first, Oxyntomodulin 3.0 pmol/kg/min in the second, Placebo in the third and Liraglutide 1.2 mg in the fourth period
Drug: Oxyntomodulin
3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)
Drug: Liraglutide 0.6 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Liraglutide 1.2 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Placebo for Oxyntomodulin
IV infusion in the morning of the day of GGI (Day 1)
Drug: Placebo for Liraglutide
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Experimental: OXM → Pbo → Lg-0.6 → Pbo
Participants received Oxyntomodulin 3.0 pmol/kg/min in the first; Placebo in the second, Liraglutide 0.6 mg in the third, and Placebo in the fourth period
Drug: Oxyntomodulin
3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)
Drug: Liraglutide 0.6 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Placebo for Oxyntomodulin
IV infusion in the morning of the day of GGI (Day 1)
Drug: Placebo for Liraglutide
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Experimental: Pbo → Lg-0.6 → OXM → Lg-1.2
Participants received Placebo in the first, Liraglutide 0.6 mg in the second, Oxyntomodulin 3.0 pmol/kg/min in the third, and Liraglutide 1.2 mg in the fourth period
Drug: Oxyntomodulin
3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)
Drug: Liraglutide 0.6 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Liraglutide 1.2 mg
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Other Name: Victoza®
Drug: Placebo for Oxyntomodulin
IV infusion in the morning of the day of GGI (Day 1)
Drug: Placebo for Liraglutide
Single subcutaneous dose in the evening of the day before the GGI (Day-1)

  Eligibility

Ages Eligible for Study:   18 Years to 64 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have a body mass index (BMI) of ≤38.0 kg/m^2
  • Have a clinical diagnosis of Type 2 diabetes mellitus
  • Have a glycated hemoglobin (HbA1C) at screening ≤9.0%; fasting plasma glucose should not exceed 300 mg/dL (16.8 mmol/L)
  • Judged to be in good health

Exclusion Criteria:

  • Have a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the subject by their participation in the study
  • Have a history of stroke, chronic seizures, major neurological disorder, clinically significant endocrine, cardiovascular, hematological, hepatic, renal, respiratory, or genitourinary abnormalities or diseases
  • Have untreated hypertension with blood pressure of >160/95 mmHg
  • Have a history of neoplastic disease within the past 5 years
  • Have a history of hypersensitivity to OXM, liraglutide, insulin or Haemaccel®
  • Unable or unwilling to comply with restrictions around concomitant medications
  • Consume excessive amounts of alcohol, coffee, tea, cola, or other caffeinated beverages daily
  • Have had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks
  • Have a history of significant multiple and/or severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food
  • Currently a regular user (including use of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 months
  • Are unwilling or unable to consume the standardized meals during the study and/or is on a carbohydrate restricted diet (i.e., a diet <100 grams per day of carbohydrate)
  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.

No Contacts or Locations Provided
  More Information

No publications provided

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01373450     History of Changes
Other Study ID Numbers: 0000-222
Study First Received: June 13, 2011
Results First Received: May 20, 2013
Last Updated: February 10, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

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

ClinicalTrials.gov processed this record on July 23, 2014