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)

NCT01373450 | Completed Phase 1 Results

• 1 other identifier: 0000-222
• Study Type: interventional
• Target: 12
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Change From Baseline in Insulinotrophic Effect (ISR/G) at the Highest Glucose Infusion Rate After Two Periods of Placebo Treatment

  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

  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

  Baseline and up to 160 minutes after start of GGI

Study Arms (6)

OXM → Lg-0.6 → Pbo → Lg-1.2

EXPERIMENTAL

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; Drug: Liraglutide 0.6 mg; Drug: Placebo for Oxyntomodulin; Drug: Placebo for Liraglutide

Lg-0.6 → Pbo → OXM → Pbo

EXPERIMENTAL

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; Drug: Liraglutide 0.6 mg; Drug: Placebo for Oxyntomodulin; Drug: Placebo for Liraglutide

Pbo → OXM → Lg-0.6 → Pbo

EXPERIMENTAL

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; Drug: Liraglutide 0.6 mg; Drug: Placebo for Oxyntomodulin; Drug: Placebo for Liraglutide

Lg-0.6 → OXM → Pbo → Lg-1.2

EXPERIMENTAL

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; Drug: Liraglutide 0.6 mg; Drug: Liraglutide 1.2 mg; Drug: Placebo for Oxyntomodulin; Drug: Placebo for Liraglutide

OXM → Pbo → Lg-0.6 → Pbo

EXPERIMENTAL

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; Drug: Liraglutide 0.6 mg; Drug: Placebo for Oxyntomodulin; Drug: Placebo for Liraglutide

Pbo → Lg-0.6 → OXM → Lg-1.2

EXPERIMENTAL

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; Drug: Liraglutide 0.6 mg; Drug: Liraglutide 1.2 mg; Drug: Placebo for Oxyntomodulin; Drug: Placebo for Liraglutide

Interventions

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)

Lg-0.6 → OXM → Pbo → Lg-1.2; Lg-0.6 → Pbo → OXM → Pbo; OXM → Lg-0.6 → Pbo → Lg-1.2; OXM → Pbo → Lg-0.6 → Pbo; Pbo → Lg-0.6 → OXM → Lg-1.2; Pbo → OXM → Lg-0.6 → Pbo

Liraglutide 0.6 mg DRUG

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

Also known as: Victoza®

Lg-0.6 → OXM → Pbo → Lg-1.2; Lg-0.6 → Pbo → OXM → Pbo; OXM → Lg-0.6 → Pbo → Lg-1.2; OXM → Pbo → Lg-0.6 → Pbo; Pbo → Lg-0.6 → OXM → Lg-1.2; Pbo → OXM → Lg-0.6 → Pbo

Liraglutide 1.2 mg DRUG

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

Also known as: Victoza®

Lg-0.6 → OXM → Pbo → Lg-1.2; Pbo → Lg-0.6 → OXM → Lg-1.2

Placebo for Oxyntomodulin DRUG

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

Lg-0.6 → OXM → Pbo → Lg-1.2; Lg-0.6 → Pbo → OXM → Pbo; OXM → Lg-0.6 → Pbo → Lg-1.2; OXM → Pbo → Lg-0.6 → Pbo; Pbo → Lg-0.6 → OXM → Lg-1.2; Pbo → OXM → Lg-0.6 → Pbo

Placebo for Liraglutide DRUG

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

Lg-0.6 → OXM → Pbo → Lg-1.2; Lg-0.6 → Pbo → OXM → Pbo; OXM → Lg-0.6 → Pbo → Lg-1.2; OXM → Pbo → Lg-0.6 → Pbo; Pbo → Lg-0.6 → OXM → Lg-1.2; Pbo → OXM → Lg-0.6 → Pbo

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (2)

• 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.

  PMID: 29545266 DERIVED

• 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.

  PMID: 27072496 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Oxyntomodulin; Liraglutide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon-Like Peptide 1; Glucagon-Like Peptides

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2011
• First Posted: June 15, 2011
• Study Start: June 1, 2011
• Primary Completion: July 1, 2011
• Study Completion: July 1, 2011
• Last Updated: September 2, 2015
• Results First Posted: July 8, 2013

Record last verified: 2015-09