A Study of the Safety and Efficacy of MK-3577 in Participants With Type 2 Diabetes Mellitus (MK-3577-009)

Phase 2

Terminated

• Conditions: Type 2 Diabetes Mellitus
• Interventions: Drug: MK-3577; Drug: Placebo to MK-3577; Drug: Placebo to Metformin; Drug: Metformin

• Registration Number: NCT00868790
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

This study assessed the safety and efficacy of MK-3577. The primary efficacy hypothesis was that, after 4 weeks of treatment, either the morning (AM) administration or the evening (PM) administration of MK-3577 provides superior reduction of 24-hour weighted mean glucose (WMG) levels compared to placebo (PLA). The primary safety hypothesis was that MK-3577 is well tolerated compared to placebo.

Detailed Description

This was a 4-period/5-treatment crossover study. Each period was 4 weeks. The 5 treatments consisted of MK-3577 10 mg once daily (QD) in the AM, MK-3577 6 mg QD in the evening (PM), MK-3577 25 mg twice daily (BID), metformin 1000 mg BID, and placebo to MK-3577/placebo to metformin. Participants were to be randomized to one of 14 treatment sequence arms. A subset of participants in each group was to domicile (stay overnight) at selected clinical sites at Baseline, Week 4 (end of Period 1), and Week 8 (end of Period 2) to undergo 24-hr blood sample.

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study Start: 2009-03-24
• Study First Submitted: 2009-03-24
• Study First Submitted QC: 2009-03-24
• Study First Posted: 2009-03-25
• Primary Completion: 2010-07-12
• Study Completion: 2010-07-13
• Results First Submitted: 2016-11-14
• Results First Submitted QC: 2016-11-14
• Results First Posted: 2017-01-11
• Status Verified: 2018-08
• Last Update Submitted: 2018-08-09
• Last Update Posted: 2018-09-10

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 118

Inclusion Criteria

• Participant has type 2 diabetes
• Participant is either not taking antihyperglycemic medications for the last 10 weeks OR is taking a single oral antihyperglycemic medication (but not a Peroxisome Proliferator-Activated Receptor gamma [PPARg] agonist) OR is taking a low-dose combination oral antihyperglycemic medication (not a PPARg agonist) at dose less than or equal to 50% of the maximum dose
• Female participant is unable to have children

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Exclusion Criteria

• Participant has a history of type 1 diabetes or ketoacidosis
• Participant has been treated with a PPARg agonist in the last 12 weeks
• Participant has been treated with insulin in the last 12 weeks
• Participant has had prescription lipid-modifying drug therapy in the last 12 weeks
• Participant has a history of coronary artery disease
• Participant has had a stroke or transient ischemic attack
• Participant has congestive heart failure

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
MK-3577 BID→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 8)	MK-3577	Participants were to receive oral treatment with MK-3577 25 mg BID for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4.
MK-3577 QD AM→PLA→MK-3577 BID→MK-3577 QD PM (Arm 2)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 10 mg QD AM for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 QD PM→MK-3577 QD AM→MK-3577 BID→PLA (Arm 7)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 6 mg QD PM for 4 weeks during Period 1, followed by MK-3577 10 mg QD AM for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 4.
PLA→MK-3577 QD AM→MK-3577 QD PM→MK-3577 BID (Arm 1)	Placebo to MK-3577	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 10 mg QD AM for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
PLA→MK-3577 BID→MK-3577 QD AM→MK-3577 QD PM (Arm 5)	Placebo to MK-3577	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 25 mg BID for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4.
PLA→METF→MK-3577 QD AM→MK-3577 QD PM (Arm 13)	Placebo to MK-3577	Domiciled participants were to receive oral treatment with dose-matched placebo to metformin (METF) for 4 weeks during Period 1, followed by metformin 1000 mg BID for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4. Participants in this arm were administered metformin placebo during Period 1 and active metformin during Period 2.
MK-3577 BID→MK-3577 QD PM→MK-3577 QD AM→PLA (Arm 4)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 25 mg BID for 4 weeks during Period 1, followed by MK-3577 6 mg QD PM for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 4.
PLA→MK-3577 QD AM→MK-3577 QD PM→MK-3577 BID (Arm 1)	Placebo to Metformin	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 10 mg QD AM for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 QD PM→MK-3577 BID→PLA→MK-3577 QD AM (Arm 3)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 6 mg QD PM for 4 weeks during Period 1, followed MK- 3577 25 mg BID for 4 weeks during Period 2, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4.
PLA→MK-3577 QD PM→MK-3577 BID→MK-3577 QD AM (Arm 9)	Placebo to Metformin	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 6 mg QD PM for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 QD PM→PLA→MK-3577 QD AM→MK-3577 BID (Arm 11)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 6 mg QD PM for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
PLA→METF→MK-3577 QD AM→MK-3577 QD PM (Arm 13)	MK-3577	Domiciled participants were to receive oral treatment with dose-matched placebo to metformin (METF) for 4 weeks during Period 1, followed by metformin 1000 mg BID for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4. Participants in this arm were administered metformin placebo during Period 1 and active metformin during Period 2.
MK-3577 QD AM→PLA→MK-3577 BID→MK-3577 QD PM (Arm 2)	Placebo to Metformin	Participants were to receive oral treatment with MK-3577 10 mg QD AM for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 BID→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 8)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 25 mg BID for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4.
PLA→MK-3577 QD PM→MK-3577 BID→MK-3577 QD AM (Arm 9)	Placebo to MK-3577	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 6 mg QD PM for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 QD AM→MK-3577 BID→MK-3577 QD PM→PLA (Arm 10)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 10 mg QD AM for 4 weeks during Period 1, followed by MK-3577 25 mg BID for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 4.
MK-3577 QD AM→MK-3577 QD PM→PLA→MK-3577 BID (Arm 6)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 10 mg QD AM for 4 weeks during Period 1, followed by MK-3577 6 mg QD PM for 4 weeks during Period 2, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4.
MK-3577 QD PM→PLA→MK-3577 QD AM→MK-3577 BID (Arm 11)	Placebo to Metformin	Participants were to receive oral treatment with MK-3577 6 mg QD PM for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 BID→MK-3577 QD AM→PLA→MK-3577 QD PM (Arm 12)	Placebo to MK-3577	Participants were to receive oral treatment with MK-3577 25 mg BID for 4 weeks during Period 1, followed by MK-3577 10 mg QD AM for 4 weeks during Period 2, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4.
PLA→METF→MK-3577 QD AM→MK-3577 QD PM (Arm 13)	Placebo to Metformin	Domiciled participants were to receive oral treatment with dose-matched placebo to metformin (METF) for 4 weeks during Period 1, followed by metformin 1000 mg BID for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4. Participants in this arm were administered metformin placebo during Period 1 and active metformin during Period 2.
METF→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 14)	Placebo to MK-3577	Domiciled participants were to receive oral treatment with metformin 1000 mg BID for 4 weeks during Period 1, followed by dose-matched placebo to metformin for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4. Participants in this arm were administered active metformin during Period 1 and metformin placebo during Period 2.
METF→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 14)	Placebo to Metformin	Domiciled participants were to receive oral treatment with metformin 1000 mg BID for 4 weeks during Period 1, followed by dose-matched placebo to metformin for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4. Participants in this arm were administered active metformin during Period 1 and metformin placebo during Period 2.
PLA→MK-3577 QD PM→MK-3577 BID→MK-3577 QD AM (Arm 9)	MK-3577	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 6 mg QD PM for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 QD PM→PLA→MK-3577 QD AM→MK-3577 BID (Arm 11)	MK-3577	Participants were to receive oral treatment with MK-3577 6 mg QD PM for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
PLA→METF→MK-3577 QD AM→MK-3577 QD PM (Arm 13)	Metformin	Domiciled participants were to receive oral treatment with dose-matched placebo to metformin (METF) for 4 weeks during Period 1, followed by metformin 1000 mg BID for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4. Participants in this arm were administered metformin placebo during Period 1 and active metformin during Period 2.
METF→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 14)	Metformin	Domiciled participants were to receive oral treatment with metformin 1000 mg BID for 4 weeks during Period 1, followed by dose-matched placebo to metformin for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4. Participants in this arm were administered active metformin during Period 1 and metformin placebo during Period 2.
PLA→MK-3577 QD AM→MK-3577 QD PM→MK-3577 BID (Arm 1)	MK-3577	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 10 mg QD AM for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 QD AM→PLA→MK-3577 BID→MK-3577 QD PM (Arm 2)	MK-3577	Participants were to receive oral treatment with MK-3577 10 mg QD AM for 4 weeks during Period 1, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4. Domiciled participants were also to receive placebo to metformin during Period 1 and Period 2.
MK-3577 QD PM→MK-3577 BID→PLA→MK-3577 QD AM (Arm 3)	MK-3577	Participants were to receive oral treatment with MK-3577 6 mg QD PM for 4 weeks during Period 1, followed MK- 3577 25 mg BID for 4 weeks during Period 2, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4.
MK-3577 BID→MK-3577 QD PM→MK-3577 QD AM→PLA (Arm 4)	MK-3577	Participants were to receive oral treatment with MK-3577 25 mg BID for 4 weeks during Period 1, followed by MK-3577 6 mg QD PM for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 4.
PLA→MK-3577 BID→MK-3577 QD AM→MK-3577 QD PM (Arm 5)	MK-3577	Participants were to receive oral treatment with dose-matched placebo to MK-3577 for 4 weeks during Period 1, followed by MK-3577 25 mg BID for 4 weeks during Period 2, followed by MK-3577 10 mg QD AM for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4.
MK-3577 QD AM→MK-3577 QD PM→PLA→MK-3577 BID (Arm 6)	MK-3577	Participants were to receive oral treatment with MK-3577 10 mg QD AM for 4 weeks during Period 1, followed by MK-3577 6 mg QD PM for 4 weeks during Period 2, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 3, followed by MK-3577 25 mg BID for 4 weeks during Period 4.
MK-3577 QD PM→MK-3577 QD AM→MK-3577 BID→PLA (Arm 7)	MK-3577	Participants were to receive oral treatment with MK-3577 6 mg QD PM for 4 weeks during Period 1, followed by MK-3577 10 mg QD AM for 4 weeks during Period 2, followed by MK-3577 25 mg BID for 4 weeks during Period 3, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 4.
MK-3577 QD AM→MK-3577 BID→MK-3577 QD PM→PLA (Arm 10)	MK-3577	Participants were to receive oral treatment with MK-3577 10 mg QD AM for 4 weeks during Period 1, followed by MK-3577 25 mg BID for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 4.
MK-3577 BID→MK-3577 QD AM→PLA→MK-3577 QD PM (Arm 12)	MK-3577	Participants were to receive oral treatment with MK-3577 25 mg BID for 4 weeks during Period 1, followed by MK-3577 10 mg QD AM for 4 weeks during Period 2, followed by dose-matched placebo to MK-3577 for 4 weeks during Period 3, followed by MK-3577 6 mg QD PM for 4 weeks during Period 4.
METF→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 14)	MK-3577	Domiciled participants were to receive oral treatment with metformin 1000 mg BID for 4 weeks during Period 1, followed by dose-matched placebo to metformin for 4 weeks during Period 2, followed by MK-3577 6 mg QD PM for 4 weeks during Period 3, followed by MK-3577 10 mg QD AM for 4 weeks during Period 4. Participants in this arm were administered active metformin during Period 1 and metformin placebo during Period 2.

Primary Outcome Measures

Name	Time	Method
Number of Participants With At Least One Adverse Event (AE) in the Treatment or Post-Treatment Periods	From first dose of study treatment (Week 0 Visit) to Week 18 Post-study Visit (up to 18 weeks).	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of the SPONSOR's product, is also an AE.
Change From Baseline (BL) After 4-Week Treatment in Weighted Mean Glucose (WMG)	Week 0 Visit (Baseline), Week 4 Visit, Week 8 Visit	The primary efficacy outcome in this study was the assessment of 24-hour weighted mean glucose (WMG) levels for domiciled participants after 4-week treatment (Periods 1 and 2 only). At selected study sites, a subset of participants domiciled (stayed) overnight and underwent 24-hour blood sampling at the Week 0 Visit (Baseline), Week 4 Visit (end of Period 1), and Week 8 Visit (end of Period 2). Domiciled participants were not expected to follow a weight-maintaining diet while receiving standard meals from a dietician or licensed healthcare professional. WMG was calculated as the weighted average value of the glucose from the 24-hour blood sample (for Baseline, Week 4, and Week 8) and analyzed using a Longitudinal Data Analysis (LDA) model. Results were expressed as the change from baseline after 4-week treatment in 24-hour WMG.
Number of Participants Who Discontinued Study Treatment Due to an AE	From first dose of study treatment (Week 0 Visit) to Week 16 Visit (up to 16 weeks).	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of the SPONSOR's product, is also an AE.

Secondary Outcome Measures

Name	Time	Method
Change From BL After 4-Week Treatment in 2-hour Post-Meal Glucose (PMG) Levels	Week 0 Visit (Baseline), Week 4 Visit, Week 8 visit	Two-hour PMG was analyzed in both non-domiciled and domiciled participants. Non-domiciled participants completed a 3-point meal tolerance test (MTT) at Week 0 (Baseline) and Week 4 Visits of Treatment Period 1. Participants completed 12-hr fasting prior to the Week 0 (Baseline) and Week-4 clinic visits. Fasting blood samples were obtained at the beginning of these clinic visits, after which participants consumed a standardized meal (1 nutrition bar and 1 can of nutrition drink), and then completed the MTT, in which plasma glucose was measured at 30 min and 120 min (2 hr) post-meal. The 2-hr PMG data also include data from domiciled participants, based on 2-hr post-morning meal glucose levels in the 24-hr blood glucose sample at the Week 4 and Week 8 Visits. The 2-hour PMG was analyzed using an LDA model, and change from baseline (Week 0) after 4-week treatment in 2-hour PMG was reported.
Change From Baseline (BL) After 4-Week Treatment in Fasting Plasma Glucose (FPG)	Week 0 Visit (Baseline), Week 4 Visit, Week 8 Visit, Week 12 Visit, Week 16 Visit	Fasting blood samples were obtained during study site visits at Baseline (Week 0 Visit) and Week 4 of each treatment period (Week 4 Visit, Week 8 Visit, Week 12 Visit, Week 16 Visit). Participants were counseled to fast (no food or drink except water and non-study medications, as directed) for at least 12 hours prior to all study visits. FPG was analyzed using an LDA model, and change from baseline (Week 0) after 4-week treatment in FPG was reported.
Percentage Change From Baseline (BL) After 4-Week Treatment in Low-Density Lipoprotein C (LDL-C) Levels	Week 0 Visit (Baseline), Week 4 Visit, Week 8 Visit, Week 12 Visit, and Week 16 Visit	Blood samples were obtained from all participants to measure LDL-C levels at Week 0 (Baseline) and Week 4 of each treatment period (Week 4 Visit, Week 8 Visit, Week 12 Visit, and Week 16 Visit). For each visit, LDL-C was measured over 2 days. The average of duplicate measurements (when available) was used in the analysis.