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: August 11, 2014
Last verified: August 2014

June 13, 2011
August 11, 2014
June 2011
July 2011   (final data collection date for primary outcome measure)
  • 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).
  • Ambient Glucose Levels During Graded Glucose Infusion (GGI)Assessment [ Time Frame: Baseline and Up to 160 minutes after start of infusion ] [ Designated as safety issue: No ]
  • Change in Beta Cell Sensitivity (Φ) [ Time Frame: 160 minutes after start of infusion ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01373450 on ClinicalTrials.gov Archive Site
  • 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.
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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)
Evaluation of the Glucoregulatory Effects of GLP-1 Receptor Activation in Patients With Type 2 Diabetes Mellitus

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.

Not Provided
Interventional
Phase 1
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Type 2 Diabetes Mellitus
  • 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 → 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
    Interventions:
    • Drug: Oxyntomodulin
    • Drug: Liraglutide 0.6 mg
    • Drug: Placebo for Oxyntomodulin
    • Drug: Placebo for Liraglutide
  • 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
    Interventions:
    • Drug: Oxyntomodulin
    • Drug: Liraglutide 0.6 mg
    • Drug: Placebo for Oxyntomodulin
    • Drug: Placebo for Liraglutide
  • 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
    Interventions:
    • Drug: Oxyntomodulin
    • Drug: Liraglutide 0.6 mg
    • Drug: Placebo for Oxyntomodulin
    • Drug: Placebo for Liraglutide
  • 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
    Interventions:
    • Drug: Oxyntomodulin
    • Drug: Liraglutide 0.6 mg
    • Drug: Liraglutide 1.2 mg
    • Drug: Placebo for Oxyntomodulin
    • Drug: Placebo for Liraglutide
  • 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
    Interventions:
    • Drug: Oxyntomodulin
    • Drug: Liraglutide 0.6 mg
    • Drug: Placebo for Oxyntomodulin
    • Drug: Placebo for Liraglutide
  • 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
    Interventions:
    • Drug: Oxyntomodulin
    • Drug: Liraglutide 0.6 mg
    • Drug: Liraglutide 1.2 mg
    • Drug: Placebo for Oxyntomodulin
    • Drug: Placebo for Liraglutide
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
12
July 2011
July 2011   (final data collection date for primary outcome measure)

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)
Male
18 Years to 64 Years
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
 
NCT01373450
0000-222
No
Merck Sharp & Dohme Corp.
Merck Sharp & Dohme Corp.
Not Provided
Not Provided
Merck Sharp & Dohme Corp.
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP