A Pooled Analysis of the Safety and Efficacy of MK-0431A and MK-0431A XR in Pediatric Participants With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Therapy (Alone or in Combination With Insulin) (MK-0431A-170/MK-0431A-289)

NCT01760447 | Completed Phase 3 Results DMC

• 7 other identifiers: 0431A-2892012-004035-232011-002529-232014-003583-20MK-0431A-170MK-0431A-289CTRI/2012/09/003025
• Study Type: interventional
• Target: 223
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to assess the effect of the addition of sitagliptin (administered as MK-0431A or MK-0431A XR) relative to the addition of placebo on glycated hemoglobin (A1C), and the safety and tolerability of the addition of sitagliptin, in pediatric participants (ages 10-17 years) with type 2 diabetes mellitus with inadequate glycemic control on metformin therapy (alone or in combination with insulin). The primary hypothesis is that the addition of sitagliptin reduces glycated hemoglobin (A1C) more than the addition of placebo after 20 weeks of treatment.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (5)

• Change From Baseline in A1C at Week 20

  Glycated hemoglobin (A1C) is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Mean change from baseline at Week 20 was estimated from a longitudinal data analysis model.

  Baseline and Week 20

• Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-20

  The number of participants experiencing ≥1 adverse event during Weeks 0-20 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  Up to Week 20

• Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-20

  The number of participants who discontinued from study drug due to an adverse event during Weeks 0-20 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  Up to Week 20

• Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56

  The number of participants experiencing ≥1 adverse event during Weeks 0-56 were reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  Up to approximately Week 56

• Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-54

  The number of participants who discontinued from study drug due to an adverse event during Weeks 0-54 was reported. An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  Up to Week 54

Secondary Outcomes (9)

• Change From Baseline in A1C at Week 54

  Baseline and Week 54

• Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20

  Baseline and Week 20

• Change From Baseline in FPG at Week 54

  Baseline and Week 54

• Percentage of Participants With A1C at Goal (<7.0%) at Week 20

  Week 20

• Percentage of Participants With A1C at Goal (<6.5%) at Week 20

  Week 20

Other Outcomes (1)

• Baseline A1C

  Baseline

Study Arms (4)

Sitagliptin/Metformin

EXPERIMENTAL

Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, for up to 20 weeks in the base study alone, or for up to 54 weeks if the participant also entered the extension study. Participants in this arm were enrolled in protocol MK-0431A-170.

Drug: Sitagliptin plus metformin; Drug: Placebo to metformin; Drug: Insulin

Metformin

PLACEBO COMPARATOR

Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, for up to 20 weeks in the base study alone, or for up to 54 weeks if the participant also entered the extension study. Participants in this arm were enrolled in protocol MK-0431A-170.

Drug: Metformin; Drug: Placebo to sitagliptin plus metformin; Drug: Insulin

Sitagliptin/Metformin XR

EXPERIMENTAL

Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, for up to 54 weeks. Participants in this arm were enrolled in protocol MK-0431A-289.

Drug: Sitagliptin plus metformin XR; Drug: Placebo to metformin XR; Drug: Insulin

Metformin XR

PLACEBO COMPARATOR

Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, for up to 54 weeks. Participants in this arm were enrolled in protocol MK-0431A-289.

Drug: Insulin; Drug: Placebo to sitagliptin plus metformin XR; Drug: Metformin XR

Interventions

Sitagliptin plus metformin DRUG

Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 100 mg of sitagliptin and 1000 mg, 1700 mg or 2000 mg of metformin. Dosage of metformin was based on each participant's daily metformin dose prior to enrollment.

Also known as: MK-0431A

Sitagliptin/Metformin

Placebo to metformin DRUG

Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to metformin.

Sitagliptin/Metformin

Metformin DRUG

Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 1000 mg, 1700 mg or 2000 mg of metformin. Dosage was based on each participant's daily metformin dose prior to enrollment.

Metformin

Placebo to sitagliptin plus metformin DRUG

Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to sitagliptin plus metformin.

Also known as: Placebo to MK-0431A

Metformin

Sitagliptin plus metformin XR DRUG

Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 100 mg of sitagliptin and 1000 mg, 1500 mg or 2000 mg of metformin. Dosage of metformin XR was based on each participant's daily metformin dose prior to enrollment.

Also known as: MK-0431A XR

Sitagliptin/Metformin XR

Placebo to metformin XR DRUG

Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to metformin XR.

Sitagliptin/Metformin XR

Insulin DRUG

Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue. During Weeks 20-54, for participants who were not on background insulin or rescued with insulin during Weeks 0-20 in the "Sitagliptin/Metformin" and "Metformin" arms (protocol MK-0431A-170), and during Weeks 0-54 for participants not on background insulin in the "Sitagliptin/Metformin XR" and "Metformin XR" arms (protocol MK-0431A-289), the type of insulin for glycemic rescue was specified to be insulin glargine.

Metformin; Metformin XR; Sitagliptin/Metformin; Sitagliptin/Metformin XR

Placebo to sitagliptin plus metformin XR DRUG

Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to sitagliptin plus metformin XR.

Also known as: Placebo to MK-0431A XR

Metformin XR

Metformin XR DRUG

Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 1000 mg, 1500 mg or 2000 mg of metformin XR. Dosage was based on each participant's daily metformin dose prior to enrollment.

Metformin XR

Eligibility Criteria

• Age: 10 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• For MK-0431A-170 base study and MK-0431A-289:
• Has type 2 diabetes mellitus (T2DM)
• Is on metformin monotherapy (≥1500 mg/day) for ≥12 weeks with glycated hemoglobin (A1C) ≥6.5% and ≤10.0% OR is on stable doses of metformin (≥1500 mg/day) and insulin for ≥12 weeks with an A1C ≥7.0% and ≤10%. NOTE: Participants on a daily dose of metformin greater than or equal to 1000 mg/day, but less than 1500 mg/day may be eligible if there is documentation that higher doses are not tolerated.
• Participant and a family member or adult closely involved in the daily activities will participate in the participant's treatment and study protocol (i.e., available for telephone calls, study visits and administration of study medication as needed).
• Male, or female who is unlikely to conceive (non-sterilized, and is not sexually active or agrees to abstain from heterosexual activity or agrees to use an adequate method of contraception) during the study and for 14 days after the last dose of study drug
• For MK-0431A-170 extension protocol:
• Has completed the P170 base study
• Participant and a family member or adult closely involved in the daily activities will participate in the participant's treatment and study protocol (i.e., available for telephone calls, study visits and administration of study medication as needed).
• Male, or female who is unlikely to conceive (non-sterilized, and is not sexually active or agrees to abstain from heterosexual activity or agrees to use an adequate method of contraception) during the study and for 14 days after the last dose of study drug

You may not qualify if:

• For MK-0431A-170 base study and MK-0431A-289:
• Has type 1 diabetes mellitus
• Has monogenic diabetes or secondary diabetes
• Has symptomatic hyperglycemia and/or moderate to large ketonuria and/or positive test for ketonemia, requiring immediate initiation of another antihyperglycemic agent
• Has previously taken a dipeptidyl peptidase IV (DPP-4) inhibitor (such as sitagliptin, vildagliptin, alogliptin, saxagliptin, or linagliptin) or glucagon-like peptide-1 (GLP-1) receptor agonist (such as exenatide or liraglutide)
• Is on or likely to require treatment for ≥2 consecutive weeks or repeated courses of corticosteroids (inhaled, nasal and topical corticosteroids are permitted)
• Has undergone a surgical procedure within 4 weeks of study participation or has planned major surgery during the study
• History of congenital heart disease or cardiovascular disease other than hypertension
• History of active liver disease (other than non-alcoholic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease
• Active neuropathy (such as nephrotic syndrome or glomerulonephritis)
• Chronic myopathy, mitochondrial disorder or a progressive neurological or neuromuscular disorder
• Human immunodeficiency virus (HIV)
• Hematological disorder (such as aplastic anemia, thrombocytopenia, myeloproliferative or myelodysplastic syndromes)
• Is currently being treated for hyperthyroidism or is on thyroid hormone therapy and has not been on a stable dose for at least 6 weeks
• History of malignancy for ≤5 years prior to study participation, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Jalaludin MY, Deeb A, Zeitler P, 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, Shankar RR. Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin. Pediatr Diabetes. 2022 Mar;23(2):183-193. doi: 10.1111/pedi.13282. Epub 2021 Dec 20.

  PMID: 34779103 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Sitagliptin Phosphate; Metformin; Insulin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Biguanides; Guanidines; Amidines; Organic Chemicals; Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Clinical Trials Disclosure
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants enrolled in protocol MK-0431A-170 were aware that they would receive either sitagliptin and metformin, or metformin. Participants in protocol MK-0431A-289 were aware that they would receive either sitagliptin and metformin XR, or metformin XR.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants enrolled in protocol MK-0431A-170 were randomized between the arms "Sitagliptin/Metformin" and "Metformin." Participants enrolled in protocol MK-0431A-289 were randomized between the arms "Sitagliptin/Metformin XR" and "Metformin XR."

Study Record Dates

• First Submitted: January 2, 2013
• First Posted: January 4, 2013
• Study Start: December 7, 2011
• Primary Completion: September 17, 2019
• Study Completion: September 17, 2019
• Last Updated: September 23, 2022
• Results First Posted: October 5, 2020

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share