Clinical trial NCT01485614: Study to Assess Safety & Efficacy of Sitagliptin as Initial Oral Therapy for Treatment of Type 2 Diabetes Mellitus in Pediatric Participants. (MK-0431-083)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus
Type 2 Diabetes
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2011-12-05
Enrollment: 200
Sex: ALL
Minimum age (years): 10
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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).

Participants enrolled in the metformin and placebo/sitagliptin arms prior to implementation of Protocol Amendment 05 completed the study on their original treatment assignments.

EUPASS4468 is a follow-up, non-interventional, observational assessment of safety of participants who participated in the MK-0431-083 study for up to 5 years.

Eligibility criteria: Inclusion Criteria:

* Type 2 Diabetes Mellitus (T2DM)
* Has not received treatment with an antihyperglycemic agent (AHA) for ≥12 weeks prior to the Screening Visit/Visit 1, or is on a stable dose of insulin (without any other AHA) for at least 12 weeks prior to the Screening Visit/Visit 1. At screening, participants on insulin doses that are not stable can have their insulin doses adjusted and be eligible to participate after their dose remains stable for ≥12 weeks, if they meet all other eligibility criteria. In India, only participants on stable doses of insulin will be eligible.
* An A1C of ≥6.5% and ≤10.0% (For participants on insulin: an A1C ≥7.0% 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 GLP-1 (Glucagon-like peptide-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.

Primary outcomes:
measure: Change From Baseline in Hemoglobin A1C (A1C) at Week 20
timeFrame: Baseline and Week 20
measure: Baseline Glycated Hemoglobin (A1C) for the Placebo (Pooled) Arm
timeFrame: Baseline
measure: Change From Baseline In A1C at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled))
timeFrame: Baseline and Week 20
measure: Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56
timeFrame: Up to Week 56
measure: Percentage of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56 (Analysis of Selected Arms: Sitagliptin and Placebo/Metformin)
timeFrame: Up to Week 56
measure: Number of Participants Who Discontinued Study Drug Due to an Adverse Event During Weeks 0-54
timeFrame: Up to Week 54
measure: Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event During Weeks 0-54 (Analysis of Selected Arms: Sitagliptin and Placebo/Metformin)
timeFrame: Up to Week 54
Secondary outcomes:
measure: Change From Baseline in A1C at Week 54
timeFrame: Baseline and Week 54
measure: Percentage of Participants With A1C at Goal (<7.0%) at Week 20
timeFrame: Week 20
measure: Percentage of Participants With A1C at Goal (<7.0%) at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled))
timeFrame: Week 20
measure: Percentage of Participants With A1C at Goal (<6.5%) at Week 20
timeFrame: Week 20
measure: Percentage of Participants With A1C at Goal (<6.5%) at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled))
timeFrame: Week 20
measure: Percentage of Participants With A1C at Goal (<7.0%) at Week 54
timeFrame: Week 54
measure: Percentage of Participants With A1C at Goal (<6.5%) at Week 54
timeFrame: Week 54
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20
timeFrame: Baseline and Week 20
measure: Baseline Fasting Plasma Glucose (FPG) for the Placebo (Pooled) Arm
timeFrame: Baseline
measure: Change From Baseline in FPG at Week 20 (Analysis of Selected Arms: Sitagliptin and Placebo (Pooled))
timeFrame: Baseline and Week 20
measure: Change From Baseline in FPG at Week 54
timeFrame: Baseline and Week 54
measure: Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 20
timeFrame: Baseline and Week 20
measure: Change From Baseline in 2-hour PMG at Week 54
timeFrame: Baseline and Week 54
measure: Change From Baseline in 2-hour Incremental PMG at Week 20
timeFrame: Baseline and Week 20
measure: Change From Baseline in 2-Hour Incremental PMG at Week 54
timeFrame: Baseline and Week 54
measure: Change From Baseline in Insulin at Week 20 for Participants Not on Background Insulin
timeFrame: Baseline and Week 20
measure: Change From Baseline in Insulin at Week 54 For Participants Not on Background Insulin
timeFrame: Baseline and Week 54
measure: Change From Baseline in Proinsulin at Week 20 For Participants Not on Background Insulin
timeFrame: Baseline and Week 20
measure: Change From Baseline in Proinsulin at Week 54 For Participants Not on Background Insulin
timeFrame: Baseline and Week 54
measure: Change From Baseline in Proinsulin/Insulin Ratio at Week 20 for Participants Not on Background Insulin
timeFrame: Baseline and Week 20
measure: Change From Baseline in Proinsulin/Insulin Ratio at Week 54 For Participants Not on Background Insulin
timeFrame: Baseline and Week 54
measure: Change From Baseline in Homeostatic Model Assessment of β-cell Function (HOMA-β) at Week 20 For Participants Not on Background Insulin
timeFrame: Baseline and Week 20
measure: Change From Baseline in HOMA-β at Week 54 For Participants Not on Background Insulin
timeFrame: Baseline and Week 54
measure: Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at Week 20 For Participants Not on Background Insulin
timeFrame: Baseline and Week 20
measure: Change From Baseline in HOMA-IR at Week 54 For Participants Not on Background Insulin
timeFrame: Baseline and Week 54
measure: Change From Baseline in Glucose 3-Hour Total Area Under the Curve (AUC) at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin 3-hour AUC at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in C-peptide 3-Hour AUC at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin 3-Hour AUC/ Glucose 3-Hour AUC Ratio at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Glucose Excursion 3-Hour AUC at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin Excursion 3-Hour AUC at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in C-peptide Excursion 3-Hour AUC at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin Excursion 3-Hour AUC/Glucose Excursion 3-Hour AUC Ratio at Week 20
timeFrame: Baseline and Week 20 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Glucose 3-Hour AUC at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin 3-Hour AUC at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in C-peptide 3-Hour AUC at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin 3-Hour AUC/Glucose 3-Hour AUC Ratio at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Glucose Excursion 3-Hour AUC at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin Excursion 3-Hour AUC at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in C-Peptide Excursion 3-Hour AUC at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Change From Baseline in Insulin Excursion 3-Hour AUC/Glucose Excursion 3-Hour AUC Ratio at Week 54
timeFrame: Baseline and Week 54 (-10 min. before ingesting the meal, 0 min. prior to the meal, 10, 20, 30, 60, 90, 120, 180 minutes after ingesting the meal)
measure: Percentage of Participants Initiating Glycemic Rescue Therapy by Week 20
timeFrame: Up to Week 20
measure: Percentage of Participants Initiating Glycemic Rescue Therapy by Week 54
timeFrame: Up to Week 54
measure: Change From Baseline in Body Mass Index (BMI) at Week 20
timeFrame: Baseline and Week 20
measure: Change From Baseline in BMI at Week 54
timeFrame: Baseline and Week 54
measure: Mean Percent Change of Peripheral Blood Mononuclear Cells Expressing CD26 From Baseline at Week 20
timeFrame: Baseline and Week 20
measure: Mean Percent Change of Peripheral Blood Mononuclear Cells Expressing CD26 From Baseline at Week 54
timeFrame: Baseline and Week 54
measure: Change From Baseline in Calcitonin at Week 20 - Females
timeFrame: Baseline and Week 20
measure: Change From Baseline in Calcitonin at Week 54 - Females
timeFrame: Baseline and Week 54
measure: Change From Baseline in Calcitonin at Week 20 - Males
timeFrame: Baseline and Week 20
measure: Change From Baseline in Calcitonin at Week 54 - Males
timeFrame: Baseline and Week 54
measure: Change From Baseline in Urine N-terminal Cross-linking Telopeptide of Bone Collagen [u-NTx]/Creatinine Ratio at Week 20 - Females
timeFrame: Baseline and Week 20
measure: Change From Baseline u-NTx/Creatinine Ratio at Week 20 - Males
timeFrame: Baseline and Week 20
measure: Change From Baseline in u-NTx/Creatinine Ratio at Week 54 - Females
timeFrame: Baseline and Week 54
measure: Change From Baseline in u-NTx/Creatinine Ratio at Week 54 - Males
timeFrame: Baseline and Week 54
measure: Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 20 - Females
timeFrame: Baseline and Week 20
measure: Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 54 - Females
timeFrame: Baseline and Week 54
measure: Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 20 - Males
timeFrame: Baseline and Week 20
measure: Change From Baseline in Bone-Specific Alkaline Phosphatase at Week 54 - Males
timeFrame: Baseline and Week 54
measure: Percent Change From Baseline in Insulin-like Growth Factor-1 (IGF-1) at Week 20 - Females
timeFrame: Baseline and Week 20
measure: Percent Change From Baseline in IGF-1 at Week 54 - Females
timeFrame: Baseline and Week 54
measure: Percent Change From Baseline in IGF-1 at Week 20 - Males
timeFrame: Baseline and Week 20
measure: Percent Change From Baseline in IGF-1 at Week 54 - Males
timeFrame: Baseline and Week 54
measure: Percent Change From Baseline in Insulin-like Growth Factor Binding Protein 3 (IGF-BP3) at Week 20 - Females
timeFrame: Baseline and Week 20
measure: Percent Change From Baseline in IGF-BP3 at Week 54 - Females
timeFrame: Baseline and Week 54
measure: Percent Change From Baseline in IGF-BP3 at Week 20 - Males
timeFrame: Baseline and Week 20
measure: Percent Change From Baseline in IGF-BP3 at Week 54 - Males
timeFrame: Baseline and Week 54
measure: Growth Velocity at Week 20 - Females
timeFrame: Week 20
measure: Growth Velocity at Week 54 - Females
timeFrame: Week 54
measure: Growth Velocity at Week 20 - Males
timeFrame: Week 20
measure: Growth Velocity at Week 54 - Males
timeFrame: Week 54
measure: Skeletal Maturation at Week 20 - Females
timeFrame: Week 20
measure: Skeletal Maturation at Week 54 - Females
timeFrame: Week 54
measure: Skeletal Maturation at Week 20 - Males
timeFrame: Week 20
measure: Skeletal Maturation at Week 54 - Males
timeFrame: Week 54
measure: Change From Baseline in Tanner Staging for Genitalia at Week 20 - Males
timeFrame: Baseline and Week 20
measure: Change From Baseline in Tanner Staging for Genitalia at Week 54 - Males
timeFrame: Baseline and Week 54
measure: Change From Baseline in Tanner Staging for Breasts at Week 20 - Females
timeFrame: Baseline and Week 20
measure: Change From Baseline in Tanner Staging for Breasts at Week 54 - Females
timeFrame: Baseline and Week 54
measure: Change From Baseline in Tanner Stage for Pubic Hair at Week 20 - Females
timeFrame: Baseline and Week 20
measure: Change From Baseline in Tanner Stage for Pubic Hair at Week 54 - Females
timeFrame: Baseline and Week 54
measure: Change From Baseline in Tanner Stage for Pubic Hair at Week 20 - Males
timeFrame: Baseline and Week 20
measure: Change From Baseline in Tanner Stage for Pubic Hair at Week 54 - Males
timeFrame: Baseline and Week 54
measure: Participants With Worsening in Dental Status at Week 20
timeFrame: Week 20
measure: Participants With Worsening in Dental Status at Week 54
timeFrame: Week 54
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Shankar RR, Zeitler P, Deeb A, Jalaludin MY, Garcia R, Newfield RS, Samoilova Y, Rosario CA, Shehadeh N, Saha CK, Zhang Y, Zilli M, Scherer LW, Lam RLH, Golm GT, Engel SS, Kaufman KD. A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes. Pediatr Diabetes. 2022 Mar;23(2):173-182. doi: 10.1111/pedi.13279. Epub 2021 Dec 22.