A Study of the Efficacy and Safety of Ertugliflozin in Participants With Type 2 Diabetes Mellitus With Stage 3 Chronic Kidney Disease Who Have Inadequate Glycemic Control on Antihyperglycemic Therapy (MK-8835-001)

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of ertugliflozin (MK-8835/PF-04971729) in participants with Type 2 diabetes mellitus with Stage 3 Chronic Kidney Disease (CKD) who have inadequate glycemic control on background antihyperglycemic therapy. The duration of this trial will be up to 67 weeks. This study will consist of a 1-week Screening Period, a 10-week wash-off period from metformin, if needed, and a 2-week placebo run-in period, a 52-week double-blind treatment period, and a 14-day post-treatment follow-up period. The primary objective of this trial is to assess the hemoglobin A1C (A1C)-lowering efficacy of the addition of ertugliflozin compared to the addition of placebo with an underlying hypothesis that addition of treatment with ertugliflozin provides greater reduction in A1C compared to the addition of placebo; the primary objective will be tested for both 5-mg and 15-mg doses of ertugliflozin.

Detailed Description
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Participants who meet protocol-defined glycemic rescue criteria will be permitted to have an adjustment in the dose(s) of background antihyperglycemic agent (AHA) therapy or addition of new AHA therapy as directed by their investigator until the participant no longer meets the rescue criteria.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Ertugliflozin (MK-8835/PF-04971729) in Subjects With Type 2 Diabetes Mellitus With Stage 3 Chronic Kidney Disease Who Have Inadequate Glycemic Control on Background Antihyperglycemic Therapy

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ertugliflozin 5 mg
* Drug: Placebo 5 mg
* Drug: Ertugliflozin 10 mg
* Drug: Placebo 10 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Type 2 diabetes mellitus in accordance with American Diabetes Association guidelines Have Stage 3 chronic kidney disease On stable diabetes therapy (diet/exercise therapy alone or anti-hyperglycemic agents [AHA] monotherapy or combination therapy) for at least 6 weeks prior to study participation OR on metformin (with or without diet/exercise therapy or other AHA therapy) and is willing to undergo a 10-week metformin wash-off period Have an estimated glomerular filtration rate (eGFR) of ≥30 to <60 mL/min/1.73m^2 Body Mass Index (BMI) greater than or equal to 18.0 kg/m^2 Male, postmenopausal female or surgically sterile female If a female of reproductive potential, agrees to remain abstinent or to use (or have their partner use) 2 acceptable combinations of birth control while participating in the trial and for 14 days after the last use of study drug. Exclusion Criteria: History of type 1 diabetes mellitus or a history of ketoacidosis History of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrine disorders, drug - or chemical-induced, and post-organ transplant) History of nephrotic range proteinuria with hypoalbuminemia and edema History of rapidly progressive glomerulonephritis, lupus nephritis, renal or systemic vasculitis, renal artery stenosis with renovascular hypertension, or ischemic nephropathy History of familial renal glucosuria History of renal dialysis or renal transplant or renal disease requiring treatment with any immunosuppressive agent A known hypersensitivity or intolerance to any (sodium-glucose co-transporter 2) SGLT2 inhibitor On a weight-loss program or weight-loss medication or other medication associated with weight changes and is not weight stable Has undergone bariatric surgery within the past 12 months Has been treated with rosiglitazone or other SGLT2 inhibitors within 12 weeks of study participation Has active, obstructive uropathy or indwelling urinary catheter History of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or New York Heart Association (NYHA) functional class III-IV heart failure within 3 months of study participation A history of malignancy ≤5 years prior to study participation, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer Known history of Human Immunodeficiency Virus (HIV) Has blood dyscrasias or any disorders causing hemolysis or unstable red blood cells or any other clinically significant hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) A medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or active symptomatic gallbladder disease Has any clinically significant malabsorption condition If taking thyroid replacement therapy, has not been on a stable dose for at least 6 weeks prior to study participation Has been previously randomized in a study with ertugliflozin Has participated in other studies involving an investigational drug within 30 days prior or during study participation Has undergone a surgical procedure within 6 weeks prior to or during study participation Has a positive urine pregnancy test Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of study medication Planning to undergo hormonal therapy in preparation to donate eggs during the trial, including 14 days following the last dose of study medication Excessive consumption of alcoholic beverages or binge drinking Has donated blood or blood products within 6 weeks of study participation or plans to donate blood or blood products at any time during the trial

Ages Eligible for Study
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Minimum Age: 25 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertugliflozin (5 mg)<br>Ertugliflozin, 5 mg, oral, one 5 mg ertugliflozin tablet and one placebo tablet, once daily for 52 weeks | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks<br>* Other names: PF-04971729;Drug: Placebo 10 mg<br>* Placebo to ertugliflozin, oral, tablet, 10 mg tablet once daily for 52 weeks<br>|
| Experimental: Ertugliflozin (15 mg)<br>Ertugliflozin, 15 mg, oral, one 5 mg and one 10 mg tablet, once daily for 52 weeks | Drug: Ertugliflozin 10 mg<br>* Ertugliflozin, oral, tablet, 10 mg tablet once daily for 52 weeks<br>* Other names: PF-04971729;|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Placebo 5 mg<br>* Placebo to ertugliflozin, oral, tablet, 5 mg tablet once daily for 52 weeks<br>Drug: Placebo 10 mg<br>* Placebo to ertugliflozin, oral, tablet, 10 mg tablet once daily for 52 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in A1C at Week 26 - Excluding Rescue Approach | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. | Baseline and Week 26 | 
| Percentage of Participants Who Experienced an Adverse Event (AE) | An 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 54 weeks | 
| Percentage of Participants Who Discontinued Study Treatment Due to an AE | An 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 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. | Baseline and Week 26 | 
| Change From Baseline in Body Weight at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. | Baseline and Week 26 | 
| Change From Baseline in Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | This change from baseline reflects the Week 26 sitting systolic blood pressure minus the Week 0 sitting systolic blood pressure. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. | Baseline and Week 26 | 
| Change From Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. | Baseline and Week 26 | 
| Percentage of Participants With A1C <7.0% (<53 mmol/Mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. | Week 26 |