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)

Study Overview
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Brief Summary
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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.

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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Oxyntomodulin
* Drug: Liraglutide 0.6 mg
* Drug: Liraglutide 1.2 mg
* Drug: Placebo for Oxyntomodulin
* Drug: Placebo for Liraglutide


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OXM → Lg-0.6 → Pbo → Lg-1.2<br>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<br>* 3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)<br>Drug: Liraglutide 0.6 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Placebo for Oxyntomodulin<br>* IV infusion in the morning of the day of GGI (Day 1)<br>Drug: Placebo for Liraglutide<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>|
| Experimental: Lg-0.6 → Pbo → OXM → Pbo<br>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<br>* 3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)<br>Drug: Liraglutide 0.6 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Placebo for Oxyntomodulin<br>* IV infusion in the morning of the day of GGI (Day 1)<br>Drug: Placebo for Liraglutide<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>|
| Experimental: Pbo → OXM → Lg-0.6 → Pbo<br>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<br>* 3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)<br>Drug: Liraglutide 0.6 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Placebo for Oxyntomodulin<br>* IV infusion in the morning of the day of GGI (Day 1)<br>Drug: Placebo for Liraglutide<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>|
| Experimental: Lg-0.6 → OXM → Pbo → Lg-1.2<br>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<br>* 3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)<br>Drug: Liraglutide 0.6 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Liraglutide 1.2 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Placebo for Oxyntomodulin<br>* IV infusion in the morning of the day of GGI (Day 1)<br>Drug: Placebo for Liraglutide<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>|
| Experimental: OXM → Pbo → Lg-0.6 → Pbo<br>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<br>* 3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)<br>Drug: Liraglutide 0.6 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Placebo for Oxyntomodulin<br>* IV infusion in the morning of the day of GGI (Day 1)<br>Drug: Placebo for Liraglutide<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>|
| Experimental: Pbo → Lg-0.6 → OXM → Lg-1.2<br>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<br>* 3.0 pmol/kg/min as an intravenous (IV) infusion in the morning of the day of graded glucose infusion (GGI) (Day 1)<br>Drug: Liraglutide 0.6 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Liraglutide 1.2 mg<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>* Other names: Victoza®;Drug: Placebo for Oxyntomodulin<br>* IV infusion in the morning of the day of GGI (Day 1)<br>Drug: Placebo for Liraglutide<br>* Single subcutaneous dose in the evening of the day before the GGI (Day-1)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and during GGI at time points 0, 20, 40, 60, 80, 100, 120, 140, 160 and 165 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. | Baseline and up to 160 minutes after start of GGI | 
| 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). | Baseline and up to160 minutes after start of GGI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 160 minutes after start of GGI at each placebo treatment period | 
| 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. | Baseline and up to 160 minutes after start of GGI | 
| 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. | Baseline and up to 160 minutes after start of GGI |