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This is a study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK-8666 in participants with type 2 diabetes mellitus (T2DM). Participants enrolled in this trial would be either treatment-naive or have washed off of oral anti-hyperglycemic agents. MK-8666 is planned to be administered orally for up to 2 weeks. The primary hypothesis for this study is that after 14 days of once daily treatment with MK-8666, at a dose that is safe and well tolerated, the placebo-corrected fasting plasma glucose reduction from baseline is ≥34 mg/dL.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MK-8666 50 mg | Experimental | MK-8666, 50 mg, oral, once a day (QD) for Days 1 to 14. |
|
| MK-8666 150 mg | Experimental | MK-8666, 150 mg, oral, QD, for Days 1 to 14 |
|
| MK-8666 500 mg | Experimental | MK-8666, 500 mg, oral, QD for Days 1 to 14 |
|
| Placebo | Placebo Comparator | Placebo, oral, QD for Days 1 to 14 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MK-8666 | Drug | MK-8666, capsules, oral, QD, Days 1 to 14 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15 | Blood glucose was measured on a fasting basis (collected after an 8-hour fast). Blood was collected on Day -1 (pre-planned dose), predose on Days 1, 3, 7, and 14, and 24h postdose Day 14 (Day 15). The baseline measurement was computed as the average of the Day -1 and predose Day 1 measurements. FPG is expressed as mg/dL. This change from baseline reflects values for Day 15 FPG minus Day 0 FPG values. | Predose (Baseline) and 24 h postdose Day 14 (Day 15) |
| Number of Participants Who Experienced at Least Once Adverse Event | An adverse event (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 28 days |
| Number of Participants Who Discontinued Study Drug Due to an AE | An adverse event (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 14 days |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | AUC0-last is a measure of the total amount of drug in the plasma from the dose to 24 hours after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for AUC0-24h was geometric mean coefficient of variation percentage. | Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28727908 | Result | Krug AW, Vaddady P, Railkar RA, Musser BJ, Cote J, Ederveen A, Krefetz DG, DeNoia E, Free AL, Morrow L, Chakravarthy MV, Kauh E, Tatosian DA, Kothare PA. Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection. Clin Transl Sci. 2017 Sep;10(5):404-411. doi: 10.1111/cts.12479. Epub 2017 Jul 20. |
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Male and female participants with Type 2 diabetes mellitus between the ages of 18 and 65 years inclusive were enrolled in this trial.
Sixty-three participants were recruited at 4 clinical sites in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | MK-8666 50 mg | MK-8666 50 mg once daily for 14 consecutive days |
| FG001 | MK-8666 150 mg | MK-8666 150 mg once daily for 14 consecutive days |
| FG002 | MK-8666 500 mg | MK-8666 500 mg once daily for 14 consecutive days |
| FG003 | Placebo | Placebo once daily for 14 consecutive days |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | MK-8666 50 mg | MK-8666 50 mg once daily for 14 consecutive days |
| BG001 | MK-8666 150 mg | MK-8666 150 mg once daily for 14 consecutive days |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 15 | Blood glucose was measured on a fasting basis (collected after an 8-hour fast). Blood was collected on Day -1 (pre-planned dose), predose on Days 1, 3, 7, and 14, and 24h postdose Day 14 (Day 15). The baseline measurement was computed as the average of the Day -1 and predose Day 1 measurements. FPG is expressed as mg/dL. This change from baseline reflects values for Day 15 FPG minus Day 0 FPG values. | The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. | Posted | Least Squares Mean | Standard Error | mg/dL | Predose (Baseline) and 24 h postdose Day 14 (Day 15) |
|
Up to 28 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | MK-8666 50 mg | MK-8666 50 mg once daily for 14 consecutive days |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bundle branch block right | Cardiac disorders | MedDRA 17.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| Placebo | Drug | Placebo, capsules, oral, QD, Days 1 to 14 |
|
| Maximum Plasma Drug Concentration After Dosing (Cmax) | Cmax is a measure of the maximum amount of drug in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for Cmax was geometric mean coefficient of variation percentage. | Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose |
| Time to Reach Cmax (Tmax) | Tmax is a measure of the time to reach the maximum concentration in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. | Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose |
| Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15 | The 24h-WMG was considered to provide an integrated assessment of the glycemic exposure over the 24-hour period, and was derived from 18 blood samples collected immediately prior to, and after each meal, and overnight and fasting one hour pre-dose. A "weighted" rather than a "simple" mean is used to avoid overrepresentation of post-meal glucose values. On each day (Day -1 and Day 14), the WMG was computed as a time-weighted average of the 18 individual measurements. | Baseline and Day 15 |
| BG002 | MK-8666 500 mg | MK-8666 500 mg once daily for 14 consecutive days |
| BG003 | Placebo | Placebo once daily for 14 consecutive days |
| BG004 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | MK-8666 150 mg | MK-8666 150 mg once daily for 14 consecutive days |
| OG002 | MK-8666 500 mg | MK-8666 500 mg once daily for 14 consecutive days |
| OG003 | Placebo | Placebo once daily for 14 consecutive days |
|
|
|
| Primary | Number of Participants Who Experienced at Least Once Adverse Event | An adverse event (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. | The Safety population consisted of all participants who received at least one dose of study medication. | Posted | Number | Participants | Up to 28 days |
|
|
|
| Primary | Number of Participants Who Discontinued Study Drug Due to an AE | An adverse event (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. | The Safety population consisted of all participants who received at least one dose of study medication. | Posted | Number | Participants | Up to 14 days |
|
|
|
| Secondary | Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | AUC0-last is a measure of the total amount of drug in the plasma from the dose to 24 hours after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for AUC0-24h was geometric mean coefficient of variation percentage. | The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Pharmacokinetic testing was not performed on the Placebo group. | Posted | Geometric Mean | Geometric Coefficient of Variation | μM·hr | Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose |
|
|
|
| Secondary | Maximum Plasma Drug Concentration After Dosing (Cmax) | Cmax is a measure of the maximum amount of drug in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. Method of dispersion for Cmax was geometric mean coefficient of variation percentage. | The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Pharmacokinetic testing was not performed on the Placebo group. | Posted | Geometric Mean | Geometric Coefficient of Variation | μM | Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose |
|
|
|
| Secondary | Time to Reach Cmax (Tmax) | Tmax is a measure of the time to reach the maximum concentration in the plasma after the dose of study drug. Pharmacokinetic parameter analysis was not performed on the Placebo group. | The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Pharmacokinetic testing was not performed on the Placebo group. | Posted | Median | Full Range | hr | Day 1: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose; Day 14 : Predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours postdose |
|
|
|
| Secondary | Change From Baseline in 24-Hour Weighted Mean Glucose (24h-WMG) at Day 15 | The 24h-WMG was considered to provide an integrated assessment of the glycemic exposure over the 24-hour period, and was derived from 18 blood samples collected immediately prior to, and after each meal, and overnight and fasting one hour pre-dose. A "weighted" rather than a "simple" mean is used to avoid overrepresentation of post-meal glucose values. On each day (Day -1 and Day 14), the WMG was computed as a time-weighted average of the 18 individual measurements. | The Per-Protocol population is the subset of participants who complied with the protocol sufficiently to ensure that these data are likely to exhibit the effects of treatment, according to the underlying scientific model. Data from 1 participant at Day 14 (Placebo group) was missing as the participant had to leave the study site. | Posted | Least Squares Mean | Standard Error | mg/dL | Baseline and Day 15 |
|
|
|
|
| 0 |
| 9 |
| 3 |
| 9 |
| EG001 | MK-8666 150 mg | MK-8666 150 mg once daily for 14 consecutive days | 0 | 18 | 9 | 18 |
| EG002 | MK-8666 500 mg | MK-8666 500 mg once daily for 14 consecutive days | 0 | 18 | 10 | 18 |
| EG003 | Placebo | Placebo once daily for 14 consecutive days | 0 | 18 | 5 | 18 |
| Eye irritation | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Eye redness | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Abdominal cramp | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Loose stools | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Contusion of upper limb | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Post-traumatic pain | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Low back pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Pain in foot | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Pain in leg | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Shoulder pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Drowsiness | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Drug-induced headache | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Occipital headache | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Urine discolouration | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
The sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results.
| D004700 | Endocrine System Diseases |
|
|
|
| Difference in the least squares means |
| 30.6 |
| 2-Sided |
| 90 |
| 17.4 |
| 43.8 |
A cLDA model was used to fit to the FPG data from the MK-8666 dose groups and placebo. Time was treated as a categorical variable so that no restriction was imposed on the trajectory of the means over time. |
| Superiority or Other |
| Difference in the least squares means | 48.8 | 2-Sided | 90 | 35.6 | 62.0 | A cLDA model was used to fit to the FPG data from the MK-8666 dose groups and placebo. Time was treated as a categorical variable so that no restriction was imposed on the trajectory of the means over time. | Superiority or Other |