Back to resultsEvaluation of the Glucoregulatory Effects of Glucagon-like Peptide-1 Receptor (GLP-1 Receptor) Activation in Participants With Type 2 Diabetes Mellitus (MK-0000-222)
Primary Purpose
Type 2 Diabetes Mellitus
Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Oxyntomodulin
Liraglutide 0.6 mg
Liraglutide 1.2 mg
Placebo for Oxyntomodulin
Placebo for Liraglutide
Sponsored by
About this trial
This is an interventional treatment trial for Type 2 Diabetes Mellitus
Eligibility 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)
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
OXM → Lg-0.6 → Pbo → Lg-1.2
Lg-0.6 → Pbo → OXM → Pbo
Pbo → OXM → Lg-0.6 → Pbo
Lg-0.6 → OXM → Pbo → Lg-1.2
OXM → Pbo → Lg-0.6 → Pbo
Pbo → Lg-0.6 → OXM → Lg-1.2
Arm Description
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
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
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
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
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
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
Outcomes
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)
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
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
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
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
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
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.
Full Information
NCT ID
NCT01373450
First Posted
June 13, 2011
Last Updated
September 1, 2015
Sponsor
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT01373450
Brief Title
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)
Official Title
Evaluation of the Glucoregulatory Effects of GLP-1 Receptor Activation in Patients With Type 2 Diabetes Mellitus
Study Type
Interventional
2. Study Status
Record Verification Date
September 2015
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
July 2011 (Actual)
Study Completion Date
July 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
OXM → Lg-0.6 → Pbo → Lg-1.2
Arm Type
Experimental
Arm Description
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
Arm Title
Lg-0.6 → Pbo → OXM → Pbo
Arm Type
Experimental
Arm Description
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
Arm Title
Pbo → OXM → Lg-0.6 → Pbo
Arm Type
Experimental
Arm Description
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
Arm Title
Lg-0.6 → OXM → Pbo → Lg-1.2
Arm Type
Experimental
Arm Description
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
Arm Title
OXM → Pbo → Lg-0.6 → Pbo
Arm Type
Experimental
Arm Description
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
Arm Title
Pbo → Lg-0.6 → OXM → Lg-1.2
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Oxyntomodulin
Intervention Description
3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)
Intervention Type
Drug
Intervention Name(s)
Liraglutide 0.6 mg
Other Intervention Name(s)
Victoza®
Intervention Description
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Intervention Type
Drug
Intervention Name(s)
Liraglutide 1.2 mg
Other Intervention Name(s)
Victoza®
Intervention Description
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Intervention Type
Drug
Intervention Name(s)
Placebo for Oxyntomodulin
Intervention Description
IV infusion in the morning of the day of GGI (Day 1)
Intervention Type
Drug
Intervention Name(s)
Placebo for Liraglutide
Intervention Description
Single subcutaneous dose in the evening of the day before the GGI (Day-1)
Primary Outcome Measure Information:
Title
Change From Baseline in Time-weighted Average of Glucose Measured by Area Under the Curve (AUC) After a Single Dose of Oxyntomodulin (OXM)
Description
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.
Time Frame
Baseline and during GGI at time points 0, 20, 40, 60, 80, 100, 120, 140, 160 and 165 minutes
Title
Change From Baseline in Maximum Ambient Glucose Concentration (Gmax) After a Single Dose of OXM
Description
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.
Time Frame
Baseline and up to 160 minutes after start of GGI
Title
Change From Baseline in Beta Cell Sensitivity to Glucose (Φ) After a Single Dose of OXM
Description
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).
Time Frame
Baseline and up to160 minutes after start of GGI
Secondary Outcome Measure Information:
Title
Change From Baseline in Insulinotrophic Effect (ISR/G) at the Highest Glucose Infusion Rate After Two Periods of Placebo Treatment
Description
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.
Time Frame
Baseline and 160 minutes after start of GGI at each placebo treatment period
Title
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
Description
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.
Time Frame
Baseline and up to 160 minutes after start of GGI
Title
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
Description
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.
Time Frame
Baseline and up to 160 minutes after start of GGI
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility 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)
12. IPD Sharing Statement
Citations:
PubMed Identifier
29545266
Citation
Shankar SS, Shankar RR, Mixson LA, Miller DL, Pramanik B, O'Dowd AK, Williams DM, Frederick CB, Beals CR, Stoch SA, Steinberg HO, Kelley DE. Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes. Diabetes. 2018 Jun;67(6):1105-1112. doi: 10.2337/db17-1331. Epub 2018 Mar 15.
Results Reference
derived
PubMed Identifier
27072496
Citation
Shankar SS, Shankar RR, Mixson LA, Miller DL, Chung C, Cilissen C, Beals CR, Stoch SA, Steinberg HO, Kelley DE. Linearity of beta-cell response across the metabolic spectrum and to pharmacology: insights from a graded glucose infusion-based investigation series. Am J Physiol Endocrinol Metab. 2016 Jun 1;310(11):E865-73. doi: 10.1152/ajpendo.00527.2015. Epub 2016 Apr 12.
Results Reference
derived
Learn more about this trial
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)
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