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

Study Overview
=================
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.

Official Title
-----------------
A Phase IIa, Multicenter, Randomized, Placebo- and Active-Comparator Controlled, Cross-Over Clinical Trial to Study the Safety and Efficacy of MK-3577 in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: MK-3577
* Drug: Placebo to MK-3577
* Drug: Metformin
* Drug: Placebo to Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLA→MK-3577 QD AM→MK-3577 QD PM→MK-3577 BID (Arm 1)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>Drug: Placebo to Metformin<br>* Two placebo tablets to metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>|
| Experimental: MK-3577 QD AM→PLA→MK-3577 BID→MK-3577 QD PM (Arm 2)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>Drug: Placebo to Metformin<br>* Two placebo tablets to metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>|
| Experimental: MK-3577 QD PM→MK-3577 BID→PLA→MK-3577 QD AM (Arm 3)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: MK-3577 BID→MK-3577 QD PM→MK-3577 QD AM→PLA (Arm 4)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: PLA→MK-3577 BID→MK-3577 QD AM→MK-3577 QD PM (Arm 5)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: MK-3577 QD AM→MK-3577 QD PM→PLA→MK-3577 BID (Arm 6)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: MK-3577 QD PM→MK-3577 QD AM→MK-3577 BID→PLA (Arm 7)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: MK-3577 BID→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 8)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: PLA→MK-3577 QD PM→MK-3577 BID→MK-3577 QD AM (Arm 9)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>Drug: Placebo to Metformin<br>* Two placebo tablets to metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>|
| Experimental: MK-3577 QD AM→MK-3577 BID→MK-3577 QD PM→PLA (Arm 10)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: MK-3577 QD PM→PLA→MK-3577 QD AM→MK-3577 BID (Arm 11)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>Drug: Placebo to Metformin<br>* Two placebo tablets to metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>|
| Experimental: MK-3577 BID→MK-3577 QD AM→PLA→MK-3577 QD PM (Arm 12)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>|
| Experimental: PLA→METF→MK-3577 QD AM→MK-3577 QD PM (Arm 13)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>Drug: Metformin<br>* Two 500 mg tablets of metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>Drug: Placebo to Metformin<br>* Two placebo tablets to metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>|
| Experimental: METF→PLA→MK-3577 QD PM→MK-3577 QD AM (Arm 14)<br>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. | Drug: MK-3577<br>* MK-3577 oral tablets totaling 6 mg in the evening (PM), 10 mg in the morning (AM), or 25 mg twice daily (BID) depending upon randomization, administered during a 4 week treatment period.<br>Drug: Placebo to MK-3577<br>* Dose-matched placebo tablets to MK-3577 administered during a 4 week treatment period<br>Drug: Metformin<br>* Two 500 mg tablets of metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>Drug: Placebo to Metformin<br>* Two placebo tablets to metformin were administered twice daily (2000 mg total daily dose) to domiciled participants during a 4 week treatment period.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (BL) After 4-Week Treatment in Weighted Mean Glucose (WMG) | 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. | Week 0 Visit (Baseline), Week 4 Visit, Week 8 Visit | 
| Number of Participants With At Least One Adverse Event (AE) in the Treatment or Post-Treatment Periods | 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. | From first dose of study treatment (Week 0 Visit) to Week 18 Post-study Visit (up to 18 weeks). | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | 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. | From first dose of study treatment (Week 0 Visit) to Week 16 Visit (up to 16 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (BL) After 4-Week Treatment in Fasting Plasma Glucose (FPG) | 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. | Week 0 Visit (Baseline), Week 4 Visit, Week 8 Visit, Week 12 Visit, Week 16 Visit | 
| Change From BL After 4-Week Treatment in 2-hour Post-Meal Glucose (PMG) Levels | 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. | Week 0 Visit (Baseline), Week 4 Visit, Week 8 visit | 
| Percentage Change From Baseline (BL) After 4-Week Treatment in Low-Density Lipoprotein C (LDL-C) Levels | 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. | Week 0 Visit (Baseline), Week 4 Visit, Week 8 Visit, Week 12 Visit, and Week 16 Visit |