Randomized Sitagliptin Withdrawal Study (MK-0431-845)

Study Overview
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Brief Summary
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This is a trial of continuing sitagliptin versus withdrawing sitagliptin in participants with Type 2 diabetes mellitus (T2DM) and inadequate glycemic control who initiate and titrate insulin glargine (LANTUS®) based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L). A primary hypothesis of this trial is that after 30 weeks, continuing sitagliptin results in a greater reduction of hemoglobin A1C (A1C) relative to withdrawing sitagliptin.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety of the Continuation of Sitagliptin Compared With the Withdrawal of Sitagliptin During Initiation and Titration of Insulin Glargine (LANTUS®) in Subjects With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Placebo to sitagliptin
* Drug: Metformin
* Drug: Metformin XR
* Drug: Insulin glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have T2DM based on American Diabetes Association guidelines Be on one of the following treatment regimens: Stable dose of sitagliptin (100 mg/day) and metformin IR or XR (metformin) (≥1500 mg/day) either co-administered or as a fixed dose combination (FDC) for ≥12 weeks with A1C between 7.5% and 11.0%, inclusive. OR Stable dose of metformin (≥1500 mg/day) and another dipeptidyl peptidase-4 (DPP-4) inhibitor (at maximum labeled dose, other than sitagliptin, either co-administered or as a FDC, for ≥12 weeks with A1C between 7.5% and 11.0%, inclusive. OR Stable dose of sitagliptin (100 mg/day) and metformin (≥1500 mg/day) either co administered or as a FDC, and a sulfonylurea for ≥12 weeks OR stable dose of metformin (≥1500 mg/day) and a sulfonylurea administered as a FDC and sitagliptin (100 mg/day) with A1C between 7.0% and 10.0%, inclusive. OR Stable dose of metformin (≥1500 mg/day) and another DPP-4 inhibitor (at maximum labeled dose), other than sitagliptin, either co-administered or as a FDC, and a sulfonylurea for ≥12 weeks OR stable dose of metformin (≥1500 mg/day) and a sulfonylurea administered as a FDC and another DPP-4 inhibitor other than sitagliptin with A1C between 7.0% and 10.0%, inclusive OR Stable dose of metformin (≥1500 mg/day) and a sulfonylurea either co-administered or as a FDC for ≥12 weeks with A1C between 7.5% and 11.0%, inclusive. Meet one of the following categories: The participant is a male The participant is a female who is not of reproductive potential The participant is a female who is of reproductive potential and agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by practicing abstinence from heterosexual activity OR use (or have her partner use) acceptable contraception during heterosexual activity Exclusion Criteria: Has been treated with any anti-hyperglycemic agent (AHA) other than protocol-specified agents (i.e., other than metformin, DPP-4 inhibitor, or sulfonylurea agent) within the prior 12 weeks. Has a history of 2 or more episodes of hypoglycemia resulting in seizure, coma, or loss of consciousness, OR has had recurrent (≥3 times per week) episodes of hypoglycemia over the past 8 weeks. Has a history of type 1 diabetes mellitus (T1DM) or ketoacidosis, or has a history of latent autoimmune diabetes of adults (LADA), is assessed by the investigator as possibly having T1DM or LADA confirmed with a C-peptide <0.7 ng/mL (<0.23 nmol/L), or has a history of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, or post-organ transplant). Is assessed by the investigator to be not appropriate for, or does not agree to target, a fasting glucose of 72-100 mg/dL (4.0-5.6 mmol/L).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin<br>Sitagliptin 100 mg, oral, once daily for 30 weeks | Drug: Sitagliptin<br>* Sitagliptin 100 mg, oral, once daily for 30 weeks<br>* Other names: Januvia®;Drug: Metformin<br>* At least 1500 mg/day, oral, twice daily for participants entering the study on immediate-release metformin + sitagliptin or a fixed dose combination (FDC).<br>Drug: Metformin XR<br>* At least 1500 mg/day, oral, once daily for participants entering the study on extended-release metformin + sitagliptin or a FDC.<br>Drug: Insulin glargine<br>* Insulin glargine (LANTUS®) initiated at 10 units and titrated based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L); administered once daily subcutaneously.<br>* Other names: LANTUS®);|
| Placebo Comparator: Placebo<br>Placebo to sitagliptin, 100 mg, oral, once daily for 30 weeks | Drug: Placebo to sitagliptin<br>* Placebo to sitagliptin, 100 mg, oral, once daily for 30 weeks<br>Drug: Metformin<br>* At least 1500 mg/day, oral, twice daily for participants entering the study on immediate-release metformin + sitagliptin or a fixed dose combination (FDC).<br>Drug: Metformin XR<br>* At least 1500 mg/day, oral, once daily for participants entering the study on extended-release metformin + sitagliptin or a FDC.<br>Drug: Insulin glargine<br>* Insulin glargine (LANTUS®) initiated at 10 units and titrated based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L); administered once daily subcutaneously.<br>* Other names: LANTUS®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in A1C at Week 30 | A1C is 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. Thus, this change from baseline reflects the Week 30 A1C minus the Week 0 A1C. | Baseline and Week 30 | 
| Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. | Up to 30 weeks | 
| Percentage of Participants Who Discontinued Study Drug Due to an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to 30 weeks | 
| Percentage of Participants Who Experienced One or More Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Events of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The incidence (number of participants with ≥1 event divided by number of participants) of documented symptomatic hypoglycemia was determined. | Up to 30 weeks | 
| Change From Baseline in Total Daily Insulin Dose (Units) at Week 30 | Change from baseline reflects the Week 30 total daily insulin dose minus the Week 0 total daily insulin dose. The Week 0 total daily insulin dose was 0, by definition, because insulin was not administered at baseline. | Baseline and Week 30 | 
| Event Rate of Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. | Up to 30 weeks | 
| Event Rate of Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. | Up to 30 weeks | 
| Percentage of Participants With Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). | Up to 30 weeks | 
| Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol) at Week 30 | A1C is 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. | Week 30 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30 | Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 30 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 30 minus FPG at Week 0). | Baseline and Week 30 | 
| Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. | Up to 30 weeks | 
| Percentage of Participants With Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). | Up to 30 weeks | 
| Percentage of Participants With Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). | Up to 30 weeks | 
| Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol at Week 30 and No Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) up to Week 30 | A1C is 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. | Week 30 |