Effects of Once and Twice Daily Dosing Regimen of Ertugliflozin (PF-04971729, MK-8835) In Participants With Type 2 Diabetes (MK-8835-040)

Study Overview
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Brief Summary
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This is a Phase 1 randomized, double-blind, sponsor open, 4 arm, 2 way cross-over study using 2 cohorts. The objective of the study is to evaluate the pharmacodynamics (PD) effects and the pharmacokinetic (PK) of single day dosing of 2 mg and 4 mg doses of ertugliflozin (Ertu, PF-04971729/MK-8835) each administered once vs twice daily (morning [AM] and evening [PM]) in adults with type 2 diabetes.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, 2-Period, Cross-Over Single Day Evaluation Of The Pharmacokinetic-Pharmacodynamic Effect Of Once And Twice Daily Oral Administration Of PF-04971729 In Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2, Adult

Intervention / Treatment
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* Drug: Ertugliflozin 2 mg single dose
* Drug: Ertugliflozin 2 mg split into twice daily
* Drug: Ertugliflozin 4 mg single dose
* Drug: Ertugliflozin 4 mg split into twice daily
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with type 2 diabetes mellitus, either treatment-naïve or on up to 2 acceptable oral anti-diabetes drugs for at least 8-weeks prior to study. Exclusion Criteria: Participants with type 1 diabetes mellitus, participants with stroke, unstable angina, heart attack in last 6-months, uncontrolled blood pressure.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Ertu 2 mg/Placebo (Pbo)→Ertu 1 mg/Ertu 1 mg<br>Period 1: Ertu 2 mg in the AM and Pbo in the PM for 1 day. Period 2: Ertu 1 mg in the AM and Ertu 1 mg in the PM for 1 day. There was a >= 7 day washout period between Period 1 and Period 2. | Drug: Ertugliflozin 2 mg single dose<br>* Ertugliflozin 2 mg dose (two 1 mg strength tablets), administered as a single dose<br>Drug: Ertugliflozin 2 mg split into twice daily<br>* Ertugliflozin 1 mg dose (1 mg strength tablet) administered twice daily x 1 day<br>Drug: Placebo<br>* Placebo to ertugliflozin administered as a single dose<br>|
| Experimental: Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo<br>Period 1: Ertu 1 mg in the AM and Ertu 1 mg in the PM for 1 day. Period 2: Ertu 2 mg in the AM and Pbo in the PM for 1 day. There was a >= 7 day washout period between Period 1 and Period 2. | Drug: Ertugliflozin 2 mg single dose<br>* Ertugliflozin 2 mg dose (two 1 mg strength tablets), administered as a single dose<br>Drug: Ertugliflozin 2 mg split into twice daily<br>* Ertugliflozin 1 mg dose (1 mg strength tablet) administered twice daily x 1 day<br>Drug: Placebo<br>* Placebo to ertugliflozin administered as a single dose<br>|
| Experimental: Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg<br>Period 1: Ertu 4 mg in the AM and Pbo in the PM for 1 day. Period 2: Ertu 2 mg in the AM and Ertu 2 mg in the PM for 1 day. There was a >= 7 day washout period between Period 1 and Period 2. | Drug: Ertugliflozin 4 mg single dose<br>* Ertugliflozin 4 mg dose (four 1 mg strength tablets), administered as a single dose<br>Drug: Ertugliflozin 4 mg split into twice daily<br>* Ertugliflozin 2 mg dose (two 1 mg strength tablets) administered twice daily x 1 day<br>Drug: Placebo<br>* Placebo to ertugliflozin administered as a single dose<br>|
| Experimental: Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/Pbo<br>Period 1: Ertu 2 mg in the AM and Ertu 2 mg in the PM for 1 day. Period 2: Ertu 4 mg in the AM and Pbo in the PM for 1 day. There was a >= 7 day washout period between Period 1 and Period 2. | Drug: Ertugliflozin 4 mg single dose<br>* Ertugliflozin 4 mg dose (four 1 mg strength tablets), administered as a single dose<br>Drug: Ertugliflozin 4 mg split into twice daily<br>* Ertugliflozin 2 mg dose (two 1 mg strength tablets) administered twice daily x 1 day<br>Drug: Placebo<br>* Placebo to ertugliflozin administered as a single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Urinary Glucose Excretion Over 0 to 24 Hours | Urine for analysis of glucose was collected at prespecified intervals. Each participant emptied his/her bladder just before dosing, and the collection started after the morning dose (collection times: 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours after the morning dose). The average amount of urinary glucose excreted from 0 to 24 hours after the morning dose is presented in the table below. | 0 to 24 hours after the morning dose | 
| Urinary Glucose Excretion by Time Period | Urine for analysis of glucose was collected at prespecified intervals. Each participant emptied his/her bladder just before dosing, and the collection started after the morning dose (collection times: 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours after the morning dose). The average amount of urinary glucose excreted during the pre-specified time frame is presented in the table below. | At 0-4 hrs, 4-8 hrs, 8-12 hrs, and 12-24 hrs after the AM dose (up to 24 hours) | 
| 24-hour Weighted Mean Plasma Glucose | Blood was collected during each treatment period at pre-dose (fasted) on Day 1 (Hour 0) and post-dose (fed) on Day 1 at 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 12.5, 13, 14, 15, 16, 18, and 24 hours. | Up to 24 hours | 
| Weighted Mean Postprandial Plasma Glucose | The weighted mean postprandial glucose over the specified intervals were analyzed by cohort. | At 0-5 hours, 5-12 hrs, and 12-18 hrs after the morning dose (up to 18 hours) | 
| Fasting Plasma Glucose | Blood samples were to be collected following a fast from all food and drink (except water) for at least 8 hours. Fasting Plasma Glucose was collected as part of the assessment of weighted mean 24-hour plasma glucose. As such, it was not specified as an endpoint in the Statistical Analysis Plan and was not analyzed or summarized separately. | Up to 24 hours | 
| Fasting C-peptide | The fasting c-peptide was analyzed by cohort using a mixed-effects model with sequence, period, and treatment as fixed effects and participant within sequence as a random effect. | Up to 24 hours (0 and 24 hours) | 
| Number of Participants Experiencing an Adverse Event | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a product or medical device. The table below includes all data collected since the first dose of study drug. | Up to 16 days | 
| Number of Participants Discontinuing Study Drug Due to an Adverse Event | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a product or medical device. The table below includes all data collected since the first dose of study drug. Data include participants discontinued due to adverse events, participants with dose reduced or temporary discontinuation due to adverse events. | Up to 8 days (Day 1 in each dosing period) | 
| Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin | Pharmacokinetic (PK) parameter of AUClast for study drug. Actual sample collection times (relative to the AM dose) were used for the pharmacokinetic analysis. | 0 predose, 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 18, 24 hours postdose | 
| Maximum Plasma Concentration (Cmax) of Ertugliflozin | PK parameter of Cmax for study drug. Actual sample collection times (relative to the AM dose) were used for the pharmacokinetic analysis. | 0 predose, 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 18, 24 hours postdose | 
| Time Taken to Reach the Maximum Observed Plasma Concentration (Tmax) of Ertugliflozin | PK parameter of Tmax for study drug. Actual sample collection times (relative to the AM dose) were used for the pharmacokinetic analysis. | 0 predose, 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 18, 24 hours postdose |