Clinical trial NCT01948986: Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Ertugliflozin in Participants With Type 2 Diabetes Mellitus (MK-8835-009)
Official title: A Phase 1, Non-Randomized, Open-Label, Single Dose Study to Evaluate the Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Type 2 Diabetes Mellitus
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2013-09-24
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study to evaluate the effect of renal impairment on the pharmacokinetics, pharmacodynamics, safety and tolerability of ertugliflozin in participants with type 2 diabetes mellitus (T2DM) and in healthy participants with normal renal function.


Eligibility criteria: Inclusion Criteria:

* Body Mass Index (BMI) of approximately 18 to 40 kg/m\^2
* Stable renal function
* Male or female not of reproductive potential
* Female of reproductive potential must agree or have their partner agree to use 2 acceptable methods of contraception
* Healthy subjects determined to be healthy by investigator screening
* T2DM participants have a diagnosis of T2DM as per American Diabetes Association guidelines
* T2DM participants to be on a stable anti-hyperglycemic regimen with no new drug or drug dosage within 8 weeks of study participation. Variations in daily dose of insulin up to 10% are permitted.

Exclusion Criteria:

* A positive urine drug screen for drugs of abuse or recreational drugs
* Pregnant or nursing females
* History of abuse of alcohol or illicit drugs
* Significant renal or urinary disease within 6 months of study participation
* History of malignancy within the past 5 years basal cell carcinoma of the skin or cervical cancer in situ
* History of human immunodeficiency virus (HIV)
* History of blood dyscrasias or any disorders causing hemolysis or unstable red blood cells
* Any acute disease state (eg, , vomiting, fever, diarrhea) within 7 days before study participation
* Treatment with an investigational drug within 30 days of study participation
* Use of herbal supplements within 28 days prior to study participation
* Any clinically significant malabsorption condition
* Blood donation (excluding plasma donations) of approximately 1 pint within 56 days prior to study participation
* History of sensitivity to ertugliflozin or other Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors
* History of sensitivity to heparin or heparin-induced thrombocytopenia
* Unwilling or unable to comply with the study Lifestyle Guidelines
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease including clinically relevant and significant drug allergies
* Use of prescription drugs (hormonal methods of birth control are allowed), vitamins and dietary supplements within 7 days of study participation
* For T2DM participants, history of type 1 diabetes mellitus or a history of ketoacidosis
* For T2DM participants, clinically significant electrocardiogram abnormality
* For T2DM participants, history of myocardial infarction, unstable angina, coronary revascularization, stroke or transient ischemic attack within 3 months of study participation
* For T2DM participants, heart failure defined as New York Heart Association Functional Class III-IV
* For T2DM participants, renal allograft recipients
* For T2DM participants, requiring dialysis
* For T2DM participants, strict fluid restriction
* For T2DM participants, urinary incontinence
* For T2DM participants, acute renal disease
* For T2DM participants, significant hepatic, cardiac, or pulmonary disease or clinically nephrotic
* For T2DM participants, prescription and over-the-counter medication that is not taken according to a stable regimen for 7 days before study participation
* For T2DM participants, on metformin should not be enrolled if their baseline renal function is outside the approved product labeling
* For T2DM participants receiving any of the following medications within 7 days of study participation: 1. Other SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin); 2. Other injectable anti-hyperglycemic agents including pramlintide or Glucagon-like peptide-1 (GLP-1) analogues; 3. Any immunosuppressive drugs, including cyclosporine, tacrolimus, sirolimus; 4. Oral corticosteroids (note that inhaled, nasal and topical corticosteroids are permitted); 5. Any potent drug-metabolizing enzyme-inducing drug, including rifampin, phenytoin, and carbamazepine; 6. Probenecid, valproic acid, gemfibrozil.

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Profile for Ertugliflozin From Time 0 Extrapolated to Infinite Time (AUCinf)
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Area Under the Plasma Concentration-Time Profile for Ertugliflozin From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Apparent Clearance (CL/F) for Plasma Ertugliflozin
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) for Ertugliflozin
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Time for Cmax (Tmax) for Plasma Ertugliflozin
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Terminal Half-Life (t1/2) for Plasma Ertugliflozin
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Apparent Volume of Distribution Following Oral Administration (Vz/F) for Plasma Ertugliflozin
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Unbound Fraction (Fu) for Plasma Ertugliflozin
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96)
timeFrame: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
measure: Percent of Dose Recovered Unchanged in Urine From 0 to 96 Hours Postdose (for Ertugliflozin Only) (Ae96%)
timeFrame: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
measure: Renal Clearance (CLr) for Urinary Ertugliflozin
timeFrame: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 19 days
measure: Number of Participants Who Discontinued Study Due to an AE
timeFrame: Up to 5 days
measure: Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06481944 From Time 0 Extrapolated to Infinite Time (AUCinf)
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06481944 From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) for Glucuronide Metabolite PF-06481944
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Time for Cmax (Tmax) for Plasma Glucuronide Metabolite PF-06481944
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Terminal Half-life (t1/2) for Plasma Glucuronide Metabolite PF-06481944
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96) for Glucuronide Metabolite PF-06481944
timeFrame: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
measure: CLr for Urinary Glucuronide Metabolite PF-06481944
timeFrame: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
measure: Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06685948 From Time 0 Extrapolated to Infinite Time (AUCinf)
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06685948 From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) for Glucuronide Metabolite PF-06685948
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Time for Cmax (Tmax) for Plasma Glucuronide Metabolite PF-06685948
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Terminal Half-life (t1/2) for Plasma Glucuronide Metabolite PF-06685948
timeFrame: Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
measure: Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96) for Glucuronide Metabolite PF-06685948
timeFrame: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
measure: Renal Clearance (CLr) for Urinary Glucuronide Metabolite PF-06685948
timeFrame: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
measure: Change From Baseline in 24 Hour Inhibition of Glucose Reabsorption
timeFrame: Baseline and 24 Hours
measure: Change From Baseline in 24 Hour Fluid Balance
timeFrame: For 24 hours before Baseline (-48 to -24 hours) and up to 24 hours after dosing on Day 1 (Up to 24 hours)
Secondary outcomes:
measure: Urinary Glucose Excretion Over 24 Hours (UGE0-24hr) for Ertugliflozin
timeFrame: 0-4, 4-8, 8-12, 12-24 hours after dosing on Day 1
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Sahasrabudhe V, Terra SG, Hickman A, Saur D, Shi H, O'Gorman M, Zhou Z, Cutler DL. The Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus. J Clin Pharmacol. 2017 Nov;57(11):1432-1443. doi: 10.1002/jcph.955. Epub 2017 Jul 13.
citation: 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.
citation: Marshall JC, Liang Y, Sahasrabudhe V, Tensfeldt T, Fediuk DJ, Zhou S, Krishna R, Dawra VK, Wood LS, Sweeney K. Meta-Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure. J Clin Pharmacol. 2021 Sep;61(9):1220-1231. doi: 10.1002/jcph.1866. Epub 2021 Jun 19.