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

NCT ID: NCT01485614

Last Updated: 2022-09-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-10
• Study Completion Date: 2019-10-09

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.

Conditions

Diabetes Mellitus; Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Sitagliptin

Participants will receive 1 tablet of sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will continue to receive 1 tablet of sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 20-54.

Group Type: EXPERIMENTAL

Sitagliptin

Intervention Type: DRUG

Sitagliptin 100 mg tablet administered orally once daily

Placebo to metformin

Intervention Type: DRUG

Matching placebo to metformin 500 mg tablets, 2 tablets administered orally twice daily

Glycemic Rescue 1

Intervention Type: DRUG

Participants in the sitagliptin arm who require glycemic rescue will receive metformin during Weeks 0-20 and Weeks 20-54. Participants in the placebo arm who require glycemic rescue will receive metformin during Weeks 0-20. Participants in the placebo arm who have switched to metformin during Weeks 20-54 and require glycemic rescue will receive sitagliptin.

Glycemic Rescue 2

Intervention Type: BIOLOGICAL

Participants who require glycemic rescue after Glycemic Rescue 1 will receive open-label insulin. Participants on background insulin therapy will have the dose of their background insulin up-titrated.

Placebo/Metformin

Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of metformin 500 mg prior to both the morning and evening meals during Weeks 20-54.

Group Type: PLACEBO_COMPARATOR

Metformin

Intervention Type: DRUG

Metformin 500 mg tablets administered orally starting at 500 mg/day and uptitrated by 500 mg every week to a final dose of 1000 mg twice daily

Placebo to sitagliptin

Intervention Type: DRUG

Matching placebo to sitagliptin 100 mg tablet administered orally once daily

Placebo to metformin

Intervention Type: DRUG

Matching placebo to metformin 500 mg tablets, 2 tablets administered orally twice daily

Glycemic Rescue 1

Intervention Type: DRUG

Participants in the sitagliptin arm who require glycemic rescue will receive metformin during Weeks 0-20 and Weeks 20-54. Participants in the placebo arm who require glycemic rescue will receive metformin during Weeks 0-20. Participants in the placebo arm who have switched to metformin during Weeks 20-54 and require glycemic rescue will receive sitagliptin.

Glycemic Rescue 2

Intervention Type: BIOLOGICAL

Participants who require glycemic rescue after Glycemic Rescue 1 will receive open-label insulin. Participants on background insulin therapy will have the dose of their background insulin up-titrated.

Metformin

Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will continue to receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of metformin 500 mg prior to both the morning and evening meals during Weeks 20-54.

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

Metformin 500 mg tablets administered orally starting at 500 mg/day and uptitrated by 500 mg every week to a final dose of 1000 mg twice daily

Placebo/Sitagliptin

Participants will receive 1 tablet of placebo matching sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 0-20. Participants will receive 1 tablet of sitagliptin 100 mg prior to the morning meal and 2 tablets of placebo matching metformin 500 mg prior to both the morning and evening meals during Weeks 20-54.

Group Type: PLACEBO_COMPARATOR

Sitagliptin

Intervention Type: DRUG

Sitagliptin 100 mg tablet administered orally once daily

Placebo to sitagliptin

Intervention Type: DRUG

Matching placebo to sitagliptin 100 mg tablet administered orally once daily

Placebo to metformin

Intervention Type: DRUG

Matching placebo to metformin 500 mg tablets, 2 tablets administered orally twice daily

Interventions

Sitagliptin

Sitagliptin 100 mg tablet administered orally once daily

Intervention Type: DRUG

Metformin

Metformin 500 mg tablets administered orally starting at 500 mg/day and uptitrated by 500 mg every week to a final dose of 1000 mg twice daily

Intervention Type: DRUG

Placebo to sitagliptin

Matching placebo to sitagliptin 100 mg tablet administered orally once daily

Intervention Type: DRUG

Placebo to metformin

Matching placebo to metformin 500 mg tablets, 2 tablets administered orally twice daily

Intervention Type: DRUG

Glycemic Rescue 1

Participants in the sitagliptin arm who require glycemic rescue will receive metformin during Weeks 0-20 and Weeks 20-54. Participants in the placebo arm who require glycemic rescue will receive metformin during Weeks 0-20. Participants in the placebo arm who have switched to metformin during Weeks 20-54 and require glycemic rescue will receive sitagliptin.

Intervention Type: DRUG

Glycemic Rescue 2

Participants who require glycemic rescue after Glycemic Rescue 1 will receive open-label insulin. Participants on background insulin therapy will have the dose of their background insulin up-titrated.

Intervention Type: BIOLOGICAL

Other Intervention Names

Januvia®, Tesavel®, Xelevia®, Ristaben®, Glactiv®; Glucophage®, Metgluco®, Glycoran®

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.

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

References

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.

Reference Type: DERIVED

PMID: 34779087 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2011-002528-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MK-0431-083

Identifier Type: OTHER

Identifier Source: secondary_id

0431-083

Identifier Type: -

Identifier Source: org_study_id