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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Adult
• Intervention / Treatment: Drug: Ertugliflozin 2 mg single dose; Drug: Ertugliflozin 2 mg split into twice daily; Drug: Placebo; Drug: Ertugliflozin 4 mg single dose; Drug: Ertugliflozin 4 mg split into twice daily

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Ertu 2 mg/Placebo (Pbo)→Ertu 1 mg/Ertu 1 mg; 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; Ertugliflozin 2 mg dose (two 1 mg strength tablets), administered as a single dose; Drug: Ertugliflozin 2 mg split into twice daily; Ertugliflozin 1 mg dose (1 mg strength tablet) administered twice daily x 1 day; Drug: Placebo; Placebo to ertugliflozin administered as a single dose
Experimental: Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo; 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; Ertugliflozin 2 mg dose (two 1 mg strength tablets), administered as a single dose; Drug: Ertugliflozin 2 mg split into twice daily; Ertugliflozin 1 mg dose (1 mg strength tablet) administered twice daily x 1 day; Drug: Placebo; Placebo to ertugliflozin administered as a single dose
Experimental: Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg; 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: Placebo; Placebo to ertugliflozin administered as a single dose; Drug: Ertugliflozin 4 mg single dose; Ertugliflozin 4 mg dose (four 1 mg strength tablets), administered as a single dose; Drug: Ertugliflozin 4 mg split into twice daily; Ertugliflozin 2 mg dose (two 1 mg strength tablets) administered twice daily x 1 day
Experimental: Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/Pbo; 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: Placebo; Placebo to ertugliflozin administered as a single dose; Drug: Ertugliflozin 4 mg single dose; Ertugliflozin 4 mg dose (four 1 mg strength tablets), administered as a single dose; Drug: Ertugliflozin 4 mg split into twice daily; Ertugliflozin 2 mg dose (two 1 mg strength tablets) administered twice daily x 1 day

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: Pfizer

Publications and helpful links

General Publications

• Fediuk DJ, Sahasrabudhe V, Dawra VK, Zhou S, Sweeney K. Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1297-1306. doi: 10.1002/cpdd.970. Epub 2021 Jul 2.
• Dawra VK, Liang Y, Shi H, Bass A, Hickman A, Terra SG, Zhou S, Cutler D, Sahasrabudhe V. A PK/PD study comparing twice-daily to once-daily dosing regimens of ertugliflozin in healthy subjects . Int J Clin Pharmacol Ther. 2019 Apr;57(4):207-216. doi: 10.5414/CP203343.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2010
• Primary Completion (Actual): April 7, 2010
• Study Completion (Actual): April 7, 2010

Study Registration Dates

• First Submitted: January 20, 2010
• First Submitted That Met QC Criteria: January 20, 2010
• First Posted (Estimate): January 22, 2010

Study Record Updates

• Last Update Posted (Actual): November 21, 2019
• Last Update Submitted That Met QC Criteria: November 8, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Ertugliflozin
• Other Study ID Numbers: 8835-040; B1521007 (Other Identifier: Pfizer Protocol Number); MK-8835-040 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No