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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)

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ClinicalTrials.gov Identifier: NCT01760447
Recruitment Status : Completed
First Posted : January 4, 2013
Results First Posted : October 5, 2020
Last Update Posted : November 16, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Sitagliptin plus metformin Drug: Placebo to metformin Drug: Metformin Drug: Placebo to sitagliptin plus metformin Drug: Sitagliptin plus metformin XR Drug: Placebo to metformin XR Drug: Insulin Drug: Placebo to sitagliptin plus metformin XR Drug: Metformin XR Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 223 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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."
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: A Pooled Analysis of the Safety and Efficacy of MK-0431A and MK-0431A XR in Pediatric Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Therapy (Alone or in Combination With Insulin)
Actual Study Start Date : December 7, 2011
Actual Primary Completion Date : September 17, 2019
Actual Study Completion Date : September 17, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sitagliptin/Metformin
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
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.
Other Name: MK-0431A

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

Drug: Insulin
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.

Placebo Comparator: Metformin
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
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.

Drug: Placebo to sitagliptin plus metformin
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.
Other Name: Placebo to MK-0431A

Drug: Insulin
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.

Experimental: Sitagliptin/Metformin XR
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
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.
Other Name: MK-0431A XR

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

Drug: Insulin
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.

Placebo Comparator: Metformin XR
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
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.

Drug: Placebo to sitagliptin plus metformin XR
Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to sitagliptin plus metformin XR.
Other Name: Placebo to MK-0431A XR

Drug: Metformin XR
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.




Primary Outcome Measures :
  1. Change From Baseline in A1C at Week 20 [ Time Frame: Baseline and 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.

  2. Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-20 [ Time Frame: Up to Week 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.

  3. Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-20 [ Time Frame: Up to Week 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.

  4. Number of Participants Who Experienced ≥1 Adverse Event During Weeks 0-56 [ Time Frame: Up to approximately Week 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.

  5. Number of Participants Who Discontinued Study Drug Due to Experiencing an Adverse Event During Weeks 0-54 [ Time Frame: Up to Week 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.


Secondary Outcome Measures :
  1. Change From Baseline in A1C at Week 54 [ Time Frame: Baseline and Week 54 ]
    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 54 was estimated from a longitudinal data analysis model.

  2. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20 [ Time Frame: Baseline and Week 20 ]
    Blood glucose was measured on a fasting basis. Mean change from baseline at Week 20 was estimated from a longitudinal data analysis model.

  3. Change From Baseline in FPG at Week 54 [ Time Frame: Baseline and Week 54 ]
    Blood glucose was measured on a fasting basis. Mean change from baseline at Week 54 was estimated from a longitudinal data analysis model.

  4. Percentage of Participants With A1C at Goal (<7.0%) at Week 20 [ Time Frame: 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. Percentage of participants with A1C at goal (<7.0%) at Week 20 was presented.

  5. Percentage of Participants With A1C at Goal (<6.5%) at Week 20 [ Time Frame: 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. Percentage of participants with A1C at goal (<6.5%) at Week 20 was presented.

  6. Percentage of Participants With A1C at Goal (<7.0%) at Week 54 [ Time Frame: Week 54 ]
    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. Percentage of participants with A1C at goal (<7.0%) at Week 54 was presented.

  7. Percentage of Participants With A1C at Goal (<6.5%) at Week 54 [ Time Frame: Week 54 ]
    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. Percentage of participants with A1C at goal (<6.5%) at Week 54 was presented.

  8. Percentage of Participants Initiating Glycemic Rescue Therapy by Week 20 [ Time Frame: Up to Week 20 ]
    Percentage of participants who initiated glycemic rescue therapy prior to Week 20 was reported.

  9. Percentage of Participants Initiating Insulin Glargine During Weeks 20-54 [ Time Frame: Week 20 up to Week 54 ]
    Percentage of participants who initiated insulin glargine therapy from Weeks 20 through 54 was reported.


Other Outcome Measures:
  1. Baseline A1C [ Time Frame: Baseline ]
    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.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   10 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
    • History of idiopathic acute pancreatitis or chronic pancreatitis
    • History of recreational or illicit drug use, or of alcohol abuse or dependence (within the past year)
    • Has donated blood products or has had phlebotomy of >10% of estimated total blood volume within 8 weeks of study participation, or intends to donate blood products or receive blood products within the projected duration of the study
    • Is pregnant or breast-feeding, or is expecting to conceive or donate eggs during the study, including 14 days following the last dose of study drug
  • For MK-0431A-170 extension protocol:

    • Participant meets a study medication discontinuation criterion at the last visit of the MK-0431A-170 base study (Week 20)
    • Has taken the last dose of study medication for the MK-0431A-170 base study more than 14 days prior to Extension Visit 1
    • Has initiated another oral antihyperglycemic agent
    • Participant does not agree to refrain from participating in any other double-blind interventional study while participating in the P170 extension study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01760447


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01760447    
Obsolete Identifiers: NCT01472367
Other Study ID Numbers: 0431A-289
2012-004035-23 ( EudraCT Number )
2011-002529-23 ( EudraCT Number )
2014-003583-20 ( EudraCT Number )
MK-0431A-170 ( Other Identifier: Merck Protocol Number )
MK-0431A-289 ( Other Identifier: Merck Protocol Number )
CTRI/2012/09/003025 ( Registry Identifier: CTRI )
First Posted: January 4, 2013    Key Record Dates
Results First Posted: October 5, 2020
Last Update Posted: November 16, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action