Study to Assess Safety & Efficacy of Sitagliptin as Initial Monotherapy for Treatment of Type 2 Diabetes Mellitus in Pediatric Participants (MK-0431-083)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Merck Sharp & Dohme Corp.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01485614
First received: December 1, 2011
Last updated: September 9, 2014
Last verified: September 2014
  Purpose

The purpose of the study is to assess the safety of the addition of sitagliptin, and its effect on hemoglobin A1c (A1C) in pediatric participants 10-17 years of age with type 2 diabetes mellitus (T2DM) with inadequate glycemic control. The primary hypothesis for this study is that sitagliptin reduces A1C more than placebo after 20 weeks of treatment.


Condition Intervention Phase
Diabetes Mellitus
Type 2 Diabetes
Drug: Sitagliptin
Drug: Metformin
Drug: Placebo to sitagliptin
Drug: Placebo to metformin
Drug: Metformin Rescue
Drug: Sitagliptin Rescue
Biological: Insulin Rescue
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Multicenter, Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Sitagliptin in Pediatric Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Change from baseline in A1C [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Number of participants with adverse events (AE) [ Time Frame: Up to 56 weeks ] [ Designated as safety issue: Yes ]
  • Number of participants who discontinued study medication due to an AE [ Time Frame: Up to 54 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Change from baseline in A1C at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Percentage of participants with an A1C target of <7.0%, <6.5% at Week 20 [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  • Percentage of participants with an A1C target of <7.0%, <6.5% at Week 54 [ Time Frame: Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in fasting plasma glucose (FPG) at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in FPG at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in insulin at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in insulin at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in proinsulin at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in proinsulin at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in proinsulin/insulin ratio at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in proinsulin/insulin ratio at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in Homeostatic Model Assessment of β-cell function (HOMA-β) at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in HOMA-β at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in Homeostatic Model Assessment of insulin resistance (HOMA-IR) at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in HOMA-IR at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in endpoints at 2 hours after the start of the meal for 2-hour PMG and 2-hour incremental PMG at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in endpoints at 2 hours after the start of the meal for 2-hour PMG and 2-hour incremental PMG at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Change from baseline in AUC endpoints (Total AUC and Excursion AUC) for glucose, insulin, C-peptide, proinsulin, proinsulin AUC/Insulin AUC, Insulin AUC/ Glucose AUC at Week 20 [ Time Frame: Baseline and Week 20 ] [ Designated as safety issue: No ]
  • Change from baseline in AUC endpoints (Total AUC and Excursion AUC) for glucose, insulin, C-peptide, proinsulin, proinsulin AUC/Insulin AUC, Insulin AUC/ Glucose AUC at Week 54 [ Time Frame: Baseline and Week 54 ] [ Designated as safety issue: No ]
  • Proportion of patients requiring glycemic rescue therapy at Week 20 [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  • Proportion of patients requiring glycemic rescue therapy at Week 54 [ Time Frame: Week 54 ] [ Designated as safety issue: No ]

Estimated Enrollment: 170
Study Start Date: February 2012
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sitagliptin
Sitagliptin 100 mg oral tablet once a day and placebo to metformin oral tablet (500 mg), 2 tablets twice daily prior to morning and evening meals for 20 weeks (Phase A). Participants who have not initiated glycemic rescue therapy will continue to receive Phase A treatment during Phase B (34 weeks).
Drug: Sitagliptin
100 mg oral tablet of sitagliptin prior to the morning meal in Phase A and Phase B.
Other Name: Januvia
Drug: Placebo to sitagliptin
After randomization: Participants randomized to the Placebo Phase A/Metformin Phase B arm will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. Phase B: Participants in the Placebo Phase A/Metformin Phase B arm will continue to receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. For 1 week, participants will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal.
Drug: Placebo to metformin
After randomization: Participants randomized to the Sitagliptin Arm and those randomized to the Placebo Phase A/Metformin Phase B arm will receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. Phase B: Participants in the Sitagliptin Arm will continue to receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. For 1 week participants will receive oral tablets of placebo to metformin (500 mg), 2 tablets prior to the morning and evening meals.
Drug: Metformin Rescue
Mandatory glycemic rescue will be initiated in both Phase A and Phase B for participants meeting defined glycemic thresholds. For Rescue Step 1 (blinded), eligible participants receiving sitagliptin or placebo (in Phase A), or sitagliptin (in Phase B) will initiate metformin.
Drug: Sitagliptin Rescue
Mandatory glycemic rescue will be initiated in both Phase A and Phase B for participants meeting defined glycemic thresholds. For Rescue Step 1 (blinded), eligible participants receiving metformin (in Phase B) will initiate sitagliptin.
Biological: Insulin Rescue
Mandatory glycemic rescue will be initiated in both Phase A and Phase B for participants meeting defined glycemic thresholds. For Rescue Step 2 (open-label), participants receiving sitagliptin, placebo or metformin will receive insulin according to routine clinical practice.
Active Comparator: Metformin
Metformin (500 mg) oral tablets, 2 tablets twice daily prior to morning and evening meals and placebo to sitagliptin (100 mg), oral tablet once daily for 20 weeks (Phase A). Participants who have not initiated glycemic rescue therapy will continue to receive Phase A treatment for 34 weeks (Phase B). This arm of the study was removed by a protocol amendment.
Drug: Metformin
Metformin (500 mg), 2 tablets twice daily prior to morning and evening meals
Other Name: Glucophage
Drug: Placebo to sitagliptin
After randomization: Participants randomized to the Placebo Phase A/Metformin Phase B arm will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. Phase B: Participants in the Placebo Phase A/Metformin Phase B arm will continue to receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. For 1 week, participants will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal.
Drug: Placebo to metformin
After randomization: Participants randomized to the Sitagliptin Arm and those randomized to the Placebo Phase A/Metformin Phase B arm will receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. Phase B: Participants in the Sitagliptin Arm will continue to receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. For 1 week participants will receive oral tablets of placebo to metformin (500 mg), 2 tablets prior to the morning and evening meals.
Drug: Metformin Rescue
Mandatory glycemic rescue will be initiated in both Phase A and Phase B for participants meeting defined glycemic thresholds. For Rescue Step 1 (blinded), eligible participants receiving sitagliptin or placebo (in Phase A), or sitagliptin (in Phase B) will initiate metformin.
Drug: Sitagliptin Rescue
Mandatory glycemic rescue will be initiated in both Phase A and Phase B for participants meeting defined glycemic thresholds. For Rescue Step 1 (blinded), eligible participants receiving metformin (in Phase B) will initiate sitagliptin.
Biological: Insulin Rescue
Mandatory glycemic rescue will be initiated in both Phase A and Phase B for participants meeting defined glycemic thresholds. For Rescue Step 2 (open-label), participants receiving sitagliptin, placebo or metformin will receive insulin according to routine clinical practice.
Experimental: Placebo Phase A/Sitagliptin B
Placebo to sitagliptin oral tablet once a day and placebo to metformin oral tablets (500 mg), 2 tablets twice daily prior to morning and evening meals for 20 weeks (Phase A). Participants who have not initiated glycemic rescue therapy will receive 1 tablet of sitagliptin daily and 2 tablets of metformin placebo twice daily prior to morning and evening meals (Phase B). This arm of the study was removed by a protocol amendment.
Drug: Sitagliptin
100 mg oral tablet of sitagliptin prior to the morning meal in Phase A and Phase B.
Other Name: Januvia
Drug: Placebo to sitagliptin
After randomization: Participants randomized to the Placebo Phase A/Metformin Phase B arm will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. Phase B: Participants in the Placebo Phase A/Metformin Phase B arm will continue to receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. For 1 week, participants will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal.
Drug: Placebo to metformin
After randomization: Participants randomized to the Sitagliptin Arm and those randomized to the Placebo Phase A/Metformin Phase B arm will receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. Phase B: Participants in the Sitagliptin Arm will continue to receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. For 1 week participants will receive oral tablets of placebo to metformin (500 mg), 2 tablets prior to the morning and evening meals.
Experimental: Placebo Phase A / Metformin Phase B
Placebo to sitagliptin oral tablet once a day and placebo to metformin oral tablets (500 mg), 2 tablets twice daily prior to morning and evening meals for 20 weeks (Phase A). Participants who have not initiated glycemic rescue therapy will receive 1 tablet of sitagliptin-placebo daily and metformin oral tablets (500 mg), 2 tablets twice daily prior to morning and evening meals during Phase B (34 weeks).
Drug: Metformin
Metformin (500 mg), 2 tablets twice daily prior to morning and evening meals
Other Name: Glucophage
Drug: Placebo to sitagliptin
After randomization: Participants randomized to the Placebo Phase A/Metformin Phase B arm will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. Phase B: Participants in the Placebo Phase A/Metformin Phase B arm will continue to receive 1 oral tablet of placebo to sitagliptin prior to the morning meal. For 1 week, participants will receive 1 oral tablet of placebo to sitagliptin prior to the morning meal.
Drug: Placebo to metformin
After randomization: Participants randomized to the Sitagliptin Arm and those randomized to the Placebo Phase A/Metformin Phase B arm will receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. Phase B: Participants in the Sitagliptin Arm will continue to receive 2 oral tablets of placebo to metformin prior to the morning and evening meals. For 1 week participants will receive oral tablets of placebo to metformin (500 mg), 2 tablets prior to the morning and evening meals.

Detailed Description:

This trial is of approximately 56 weeks in duration, including a screening period of up to 1 week, a 1-week single-blind placebo run-in period, a 20-week placebo-controlled, double blind treatment period [Phase A] and a 34-week double-blind active controlled treatment period [Phase B] during which participants randomized to the placebo arm who have not initiated glycemic rescue therapy with metformin during Phase A will receive metformin (in a blinded manner). A telephone contact will be performed 14 days after the last dose of study medication to assess for any serious adverse events (SAEs).

Two arms of the study were removed from the study by a protocol amendment.

  Eligibility

Ages Eligible for Study:   10 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 Diabetes Mellitus (T2DM)
  • Has not received treatment with an oral antihyperglycemic agent (AHA) or insulin for ≥12 weeks prior to the Screening Visit/Visit 1.
  • An A1C of ≥6.5% and ≤10.0%.

Exclusion Criteria:

  • History of type 1 diabetes mellitus, autoimmune diabetes mellitus or has a positive antibody screen for anti-GAD (Glutamic Acid Decarboxylase) or (Islet cell autoantigen) ICA-512.
  • Known monogenic diabetes, secondary diabetes, or a genetic syndrome or disorder known to affect glucose tolerance other than diabetes.
  • Symptomatic hyperglycemia and/or moderate to large ketonuria and/or positive test for ketonemia requiring immediate initiation of antihyperglycemic therapy.
  • Previously taken a DPP-4 (Dipeptidyl peptidase-4) inhibitor (such as sitagliptin, vildagliptin, alogliptin, or saxagliptin) or (Glucagon-like peptide-1) GLP-1 receptor agonist (such as exenatide or liraglutide).
  • Hypersensitivity or contraindication (according to the product circular in the country of the investigational site) to metformin.
  • Chronic treatment with a medication known to cause weight gain within 30 days of study start or weight loss or increased blood glucose within 8 weeks of study start or treated with an anti-psychotic within the past 12 weeks.
  • On a weight loss program and not in the maintenance phase or have undergone bariatric surgery within 12 months prior to study start.
  • On or likely to require treatment with ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids.
  • Undergone a surgical procedure within the prior 4 weeks or has major surgery planned during the study.
  • History of congenital heart disease or cardiovascular disease other than hypertension.
  • Medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease.
  • Active nephropathy (i.e., nephrotic syndrome or glomerulonephritis).
  • Chronic myopathy, mitochondrial disorder, or a progressive neurological or neuromuscular disorder (e.g., polymyositis, or multiple sclerosis).
  • Human immunodeficiency virus (HIV) as assessed by medical history.
  • Clinically significant hematological disorder (such as aplastic anemia, thrombocytopenia, myeloproliferative or myelodysplastic syndrome).
  • Under treatment for hyperthyroidism.
  • Exhibits abnormal growth patterns or is being treated with growth hormone.
  • History of malignancy or clinically important hematologic disorder.
  • History of idiopathic acute pancreatitis or chronic pancreatitis.
  • Known history of recreational or illicit drug use, or of alcohol abuse or dependence (within the past year).
  • Donated blood products or has had phlebotomy of >10% of estimated total blood volume within 8 weeks of signing informed consent, or intends to donate blood products or receive blood products within the projected duration of the study.
  • Pregnant, has a positive urine pregnancy test at Screening Visit/Visit 1, is expecting to conceive within the projected duration of the study, or is breast-feeding.
  • Exclusionary laboratory values.
  • History of idiopathic acute pancreatitis or chronic pancreatitis.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01485614

Contacts
Contact: Toll Free Number 1-888-577-8839

  Show 61 Study Locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

No publications provided by Merck Sharp & Dohme Corp.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01485614     History of Changes
Other Study ID Numbers: 0431-083
Study First Received: December 1, 2011
Last Updated: September 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Metformin
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors
Enzyme Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on October 23, 2014