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

NCT01054300 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 8835-040B1521007MK-8835-040
• Study Type: interventional
• Target: 52
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Diabetes Mellitus, Type 2; Adult

Outcome Measures

Primary Outcomes (11)

• 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

Study Arms (4)

Cohort 1: Ertu 2 mg/Placebo (Pbo)→Ertu 1 mg/Ertu 1 mg

EXPERIMENTAL

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; Drug: Ertugliflozin 2 mg split into twice daily; Drug: Placebo

Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo

EXPERIMENTAL

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; Drug: Ertugliflozin 2 mg split into twice daily; Drug: Placebo

Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg

EXPERIMENTAL

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; Drug: Ertugliflozin 4 mg split into twice daily; Drug: Placebo

Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/Pbo

EXPERIMENTAL

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; Drug: Ertugliflozin 4 mg split into twice daily; Drug: Placebo

Interventions

Ertugliflozin 2 mg single dose DRUG

Ertugliflozin 2 mg dose (two 1 mg strength tablets), administered as a single dose

Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo; Cohort 1: Ertu 2 mg/Placebo (Pbo)→Ertu 1 mg/Ertu 1 mg

Ertugliflozin 2 mg split into twice daily DRUG

Ertugliflozin 1 mg dose (1 mg strength tablet) administered twice daily x 1 day

Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo; Cohort 1: Ertu 2 mg/Placebo (Pbo)→Ertu 1 mg/Ertu 1 mg

Ertugliflozin 4 mg single dose DRUG

Ertugliflozin 4 mg dose (four 1 mg strength tablets), administered as a single dose

Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/Pbo; Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg

Ertugliflozin 4 mg split into twice daily DRUG

Ertugliflozin 2 mg dose (two 1 mg strength tablets) administered twice daily x 1 day

Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/Pbo; Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg

Placebo DRUG

Placebo to ertugliflozin administered as a single dose

Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo; Cohort 1: Ertu 2 mg/Placebo (Pbo)→Ertu 1 mg/Ertu 1 mg; Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/Pbo; Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Participants with type 1 diabetes mellitus, participants with stroke, unstable angina, heart attack in last 6-months, uncontrolled blood pressure.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead
• Pfizer: collaborator

Related Publications (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.

  PMID: 30802200 RESULT

• 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.

  PMID: 34213819 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

ertugliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 20, 2010
• First Posted: January 22, 2010
• Study Start: February 17, 2010
• Primary Completion: April 7, 2010
• Study Completion: April 7, 2010
• Last Updated: November 21, 2019
• Results First Posted: November 7, 2018

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will share