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Completed

NCT Number: NCT01373450

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 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.

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Key information

Conditions

Type 2 Diabetes Mellitus Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–64 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 1

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Oxyntomodulin

Drug

3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)

Liraglutide 0.6 mg

Drug

Single subcutaneous dose in the evening of the day before the GGI (Day-1)

Other names: Victoza®

Liraglutide 1.2 mg

Drug

Single subcutaneous dose in the evening of the day before the GGI (Day-1)

Other names: Victoza®

Placebo for Oxyntomodulin

Drug

IV infusion in the morning of the day of GGI (Day 1)

Placebo for liraglutide

Drug

Single subcutaneous dose in the evening of the day before the GGI (Day-1)

Primary outcomes

  1. 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

    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.

  2. 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

    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.

  3. 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

    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 outcomes

  1. 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

    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.

  2. 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

    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.

  3. 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

    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.

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study title

Evaluation of the Glucoregulatory Effects of GLP-1 Receptor Activation in Patients With Type 2 Diabetes Mellitus

Important dates

Study start
2011
Primary completion
2011
Study completion
2011
First posted
Jun 15, 2011
Registry last updated
Sep 2, 2015

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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