Trial Outcomes & Findings for 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) (NCT NCT01373450)

Last Updated: 2015-09-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

12 participants

Primary outcome timeframe

Baseline and during GGI at time points 0, 20, 40, 60, 80, 100, 120, 140, 160 and 165 minutes

Results posted on

2015-09-02

Participant Flow

Participant milestones

Participant milestones
Measure	OXM --> Lg-0.6--> Pbo--> Lg-1.2 Participants received Oxyntomodulin (OXM) 3.0 pmol/kg/min in the first, Liraglutide (Lg) 0.6 mg in the second, Placebo (Pbo) in the third, and Liraglutide 1.2 mg in the fourth period	Lg-0.6 mg--> 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	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	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	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	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
Crossover Period 1 STARTED	2	2	2	2	2	2
Crossover Period 1 COMPLETED	2	2	2	2	2	2
Crossover Period 1 NOT COMPLETED	0	0	0	0	0	0
7 Day Wash-out STARTED	2	2	2	2	2	2
7 Day Wash-out COMPLETED	2	2	2	2	2	2
7 Day Wash-out NOT COMPLETED	0	0	0	0	0	0
Crossover Period 2 STARTED	2	2	2	2	2	2
Crossover Period 2 COMPLETED	2	2	2	2	2	2
Crossover Period 2 NOT COMPLETED	0	0	0	0	0	0
Crossover Period 3 STARTED	2	2	2	2	2	2
Crossover Period 3 COMPLETED	2	2	2	2	2	2
Crossover Period 3 NOT COMPLETED	0	0	0	0	0	0
Crossover Period 4 STARTED	2	2	2	2	2	2
Crossover Period 4 COMPLETED	2	2	2	2	2	2
Crossover Period 4 NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Treated Participants n=12 Participants
Age, Continuous	58.8 years STANDARD_DEVIATION 3.8 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and during GGI at time points 0, 20, 40, 60, 80, 100, 120, 140, 160 and 165 minutes

Population: Participants treated with Oxyntomodulin or placebo. Six participants were treated for two periods with placebo, resulting in placebo n = 18. Participants treated with Liraglutide were not analyzed for this outcome measure.

Outcome measures

Outcome measures
Measure	Oxyntomodulin n=12 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=18 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous	Oxyntomodulin Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous
Change From Baseline in Time-weighted Average of Glucose Measured by Area Under the Curve (AUC) After a Single Dose of Oxyntomodulin (OXM)	106.3 mg/dL Standard Deviation 23.03	122.6 mg/dL Standard Deviation 35.29	—	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Oxyntomodulin n=12 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=18 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous	Oxyntomodulin Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous
Change From Baseline in Maximum Ambient Glucose Concentration (Gmax) After a Single Dose of OXM	211.0 mg/dL Standard Deviation 63.00	272.9 mg/dL Standard Deviation 50.05	—	—

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Oxyntomodulin n=12 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=18 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous	Oxyntomodulin Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous
Change From Baseline in Beta Cell Sensitivity to Glucose (Φ) After a Single Dose of OXM	0.019 ISR (ng/mL) / Glucose (mg/dL) Standard Deviation 0.010 • Interval 0.013 to	0.006 ISR (ng/mL) / Glucose (mg/dL) Standard Deviation 0.003	—	—

SECONDARY outcome

Timeframe: Baseline and 160 minutes after start of GGI at each placebo treatment period

Population: Participants within the same treatment sequence who were treated with Placebo in two separate treatment periods. Participants treated with Oxyntomodulin or Liraglutide were not analyzed for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Oxyntomodulin n=6 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=6 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous	Oxyntomodulin Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous
Change From Baseline in Insulinotrophic Effect (ISR/G) at the Highest Glucose Infusion Rate After Two Periods of Placebo Treatment	0.0075 ISR (ng/mg) / Glucose (mg/dL) Standard Deviation 0.0031	0.0070 ISR (ng/mg) / Glucose (mg/dL) Standard Deviation 0.0027	—	—

SECONDARY outcome

Timeframe: Baseline and up to 160 minutes after start of GGI

Population: All treated participants. Six participants were treated for two periods with placebo, resulting in a placebo n = 18.

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.

Outcome measures

Outcome measures
Measure	Oxyntomodulin n=12 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=6 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous	Oxyntomodulin n=12 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=18 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous
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	209.7 mg/dL Standard Deviation 66.08	157.9 mg/dL Standard Deviation 93.36	211.0 mg/dL Standard Deviation 63.00	272.9 mg/dL Standard Deviation 50.05

SECONDARY outcome

Timeframe: Baseline and up to 160 minutes after start of GGI

Population: All treated participants. Six participants were treated for two periods with placebo, resulting in placebo n = 18.

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.

Outcome measures

Outcome measures
Measure	Oxyntomodulin n=12 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=6 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous	Oxyntomodulin n=12 Participants Oxyntomodulin 3.0 pmol/kg/min IV infusion	Placebo n=18 Participants Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous
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	0.026 ISR (ng/min) / Glucose (mg/dL) Standard Deviation 0.015	0.035 ISR (ng/min) / Glucose (mg/dL) Standard Deviation 0.018	0.019 ISR (ng/min) / Glucose (mg/dL) Standard Deviation 0.010	0.006 ISR (ng/min) / Glucose (mg/dL) Standard Deviation 0.003

Adverse Events

Oxyntomodulin

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Liraglutide 0.6 mg

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Liraglutide 1.2 mg

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Oxyntomodulin n=12 participants at risk Oxyntomodulin 3.0 pmol/kg/min IV infusion	Liraglutide 0.6 mg n=12 participants at risk Liraglutide 0.6 mg subcutaneous	Liraglutide 1.2 mg n=6 participants at risk Liraglutide 1.2 mg subcutaneous	Placebo n=12 participants at risk Placebo for Oxyntomodulin IV infusion and Placebo for Liraglutide subcutaneous
Gastrointestinal disorders Dry Mouth	0.00% 0/12 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
Gastrointestinal disorders Nausea	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
Gastrointestinal disorders Salivary Hypersecretion	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
General disorders Catheter Site Pain	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	16.7% 1/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
General disorders Catheter Site Related Reaction	8.3% 1/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	16.7% 2/12 • Up to 14 days after last dose of study medication
General disorders Fatigue	16.7% 2/12 • Up to 14 days after last dose of study medication	25.0% 3/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
General disorders Oedema Peripheral	8.3% 1/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication
Infections and infestations Rhinitis	8.3% 1/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
Musculoskeletal and connective tissue disorders Back Pain	8.3% 1/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
Musculoskeletal and connective tissue disorders Musculoskeletal Stiffness	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
Nervous system disorders Headache	16.7% 2/12 • Up to 14 days after last dose of study medication	33.3% 4/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	25.0% 3/12 • Up to 14 days after last dose of study medication
Skin and subcutaneous tissue disorders Acne	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication
Skin and subcutaneous tissue disorders Pruritis	0.00% 0/12 • Up to 14 days after last dose of study medication	8.3% 1/12 • Up to 14 days after last dose of study medication	0.00% 0/6 • Up to 14 days after last dose of study medication	0.00% 0/12 • Up to 14 days after last dose of study medication

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission.
Publication restrictions are in place

Restriction type: OTHER