A Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of JNJ-28431754 in Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetic characteristics of JNJ-28431754 after multiple dosing in patients with Type 2 Diabetes Mellitus who are on a stable dose of insulin.

Detailed Description
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This is a randomized (study drug assigned by chance), double-blind (neither the patient or the study doctor will know the name of the assigned treatment), parallel-group (each group of patients will be treated at the same time) to determine the safety, tolerability, pharmacokinetics (PK) (how drugs are absorbed in the body, how they are distributed within the body and how they are removed from the body over time) and the pharmacodynamics (PD) (the action or effects a drug has on the body) of oral (taken by mouth) doses of JNJ 28431754 taken once or twice daily compared to placebo (treatment identical in appearance to JNJ-2843174 but contains no active drug) in patients with Type 2 Diabetes Mellitus (T2DM) who are receiving therapy with a fixed-dose regimen of insulin. Two groups of 14 patients will be studied; one group will receive JNJ-2843174 (100 mg) or placebo once daily for 4 weeks and the other group will receive JNJ-2843174 (300 mg) or placebo twice daily for 4 weeks. In the 3 days immediately prior to the beginning of the 4-week treatment period, all patients will take a single oral dose of placebo once daily and have blood and urine samples collected for laboratory testing. During the study, all patients will be allowed to continue on their normal medication regimen of insulin and other allowed anti-diabetic medications. On selected days during the study, patients will be required to stay overnight at the study center to have study drug administered and/or to have blood and urine samples collected for laboratory testing. During the study, if patients experience worsened glycemia (blood sugar), rescue therapy with additional insulin of the same type but at a higher dose may be initiated by the Investigator if medically appropriate. During the study, patients will be monitored for safety by review of adverse events and results from laboratory tests, 12-lead electrocardiograms (ECGs), vital signs measurements, body weight, physical examinations, and self-monitored blood glucose (SMGB) measurements. Unless otherwise specified, study drug will be taken orally (by mouth) after an overnight fast for at least 8 hours followed by a meal within 10 minutes; for twice daily dosing, the evening dose will be taken just prior to the evening meal (dinner). All patients will take one placebo capsule once daily for 3 days immediately prior to randomization. After randomization, patients will take JNJ-28431754 (100 mg) or placebo once daily or JNJ-28431754 (300 mg) or placebo twice daily for 4 weeks.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-28431754 in Type-2 Diabetes Mellitus Subjects Not Optimally Controlled (A1C >=7.0%) on Fixed Doses of Insulin Therapy

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Placebo
* Drug: JNJ 28431754 300 mg/placebo
* Drug: JNJ 28431754 100 mg/placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have been diagnosed with T2DM for at least 6 months prior to study screening Be on stable insulin regimens at the time of screening Have a stable weight (ie, no change more than 5% in the 3 months prior to screening) Have a glycosylated hemoglobin (A1C) of >=7% and <=10.5% at study screening Exclusion Criteria: Have history of Type 1 diabetes mellitus, secondary forms of diabetes, diabetic ketoacidosis, pancreas or beta cell transplantation Have a known history of more than 2 severe hypoglycemic episodes as defined by the protocol within the past year Have history of, or currently active, significant illness as determined by the Investigator

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 001<br>Placebo one placebo capsule once daily for 3 days immediately prior to randomization to double-blind treatment with JNJ 28431754 or placebo | Drug: Placebo<br>* one placebo capsule once daily for 3 days immediately prior to randomization to double-blind treatment with JNJ 28431754 or placebo<br>|
| Experimental: 002<br>JNJ 28431754 100 mg/placebo one 100-mg capsule of JNJ-28431754 or placebo once-daily for 4 weeks | Drug: JNJ 28431754 100 mg/placebo<br>* one 100-mg capsule of JNJ-28431754 or placebo once-daily for 4 weeks<br>|
| Experimental: 003<br>JNJ 28431754 300 mg/placebo one 300-mg capsule of JNJ-28431754 or placebo twice-daily for 4 weeks | Drug: JNJ 28431754 300 mg/placebo<br>* one 300-mg capsule of JNJ-28431754 or placebo twice-daily for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients who need to decrease insulin dosage from prestudy dosage levels because of hypoglycemia |  | From time of signed informed consent (Days -52 to -32) through to the end of the study (Days 34 to 39) or at the time of early withdrawal | 
| The number of patients with specific treatment-emergent adverse events |  | From time of signed informed consent (Days -52 to -32) through to the end of the study (Days 34 to 39) or at the time of early withdrawal | 
| The number of patients with symptomatic hypoglycemia and severe hypoglycemia |  | From time of signed informed consent (Days -52 to -32) through to the end of the study (Days 34 to 39) or at the time of early withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations and pharmacokinetics parameters for JNJ 28431754 |  | At protocol-specified timepoints from Day 1 (pre-dose) to Day 29 | 
| Plasma glucose concentration-time profiles (pharmacodynamics parameter) |  | At protocol specified timepoints on Day -1, Day 1, and Day 27 | 
| Change in urine glucose excretion (pharmacodynamics parameter) |  | At protocol specified timepoints on Day -1, Day 1, and Day 27 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, Canagliflozin, JNJ-28431754, Insulin, Pharmacokinetic, Pharmacodynamic, SGLT-1