A Study of Multiple Oral Doses of JNJ-41443532 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, pharmacokinetics (what the body does to the medication) and pharmacodynamics (what the medication does to the body) of treatment with JNJ-41443532 relative to treatment with placebo in type 2 diabetes mellitus participants.

Detailed Description
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This is a randomized (the study medication is assigned by chance), double-blind (neither investigator nor participant knows the treatment that the participant receives), multicenter (study conducted at multiple sites), and placebo (an inactive substance that is compared with a medication to test whether the medication has a real effect in a clinical study) and active comparator (an established effective treatment that is compared with a medication to test whether the medication has a real effect in a clinical study) controlled study (placebo or active comparator is compared with the study medication to test whether the study medication has a real effect in clinical study). The study consists of 4 phases: screening phase (45 days before administration of study medication); pre-dosing run-in phase (a phase before a clinical study is commenced when no treatment is given. In this study, participant's glucose level will be observed during run-in-phase: days 15 to 1 before administration of study medication); treatment phase, and follow-up phase (7 to 10 days after the last dose of the study medication). Approximately 88 participants will be enrolled in this study. All participants will be randomly assigned to 4 treatment arms: JNJ-41443532 250 mg; JNJ-41443532 1000 mg; pioglitazone arm; and placebo. Safety evaluations will include assessment of adverse events including ocular assessments, clinical laboratory tests, electrocardiogram, vital signs, and physical examination which will be monitored throughout the study. The maximum study duration for each participant will be approximately 12 weeks.

Official Title
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A Double-Blind, Randomized, Placebo- and Active Comparator-Controlled, 4-Week Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Oral Doses of JNJ-41443532 in Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: JNJ-41443532
* Drug: Pioglitazone 30 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed Type 2 Diabetes Mellitus (T2DM) for at least 3 months prior screening On a stable treatment regimen for at least 2 months prior screening Medically stable on the basis of physical examination, medical history, and clinical laboratory tests performed at screening and 2 days before administration of the study medication Fasting plasma glucose (FPG) concentrations between 140 mg/dL and 270 mg/dL on 2 days before administration of the study medication Agrees to protocol-defined use of effective contraception Exclusion Criteria: History of other types of diabetes and complications or secondary forms of diabetes History of eating disorder or recent significant changes in body weight (ie, more or equal to 5 percent over 3 months prior to screening) due to dieting or nutritional treatments Taking antihyperglycemic agents (insulin, exenatide, and liraglutide) within 6 months or thiazolidinedione within 3 months of 2 days before administration of the study medication Clinically significant abnormal electrocardiogram History of, or currently active, significant illness or medical disorders, retinal disease, tuberculosis Clinically important serious infection, positive for serology at screening (hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus antibodies)

Ages Eligible for Study
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Minimum Age: 25 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 |
| --- | --- |
| Experimental: JNJ-41443532 250 mg<br>Participants will receive JNJ-41443532 250 mg in morning and evening for 28 days. | Drug: JNJ-41443532<br>* Participants will receive JNJ-41443532 tablet(s) orally in JNJ-41443532 250 mg arm (1 X 250 mg) and JNJ-41443532 1000 mg arm (4 X 250 mg) in morning and evening, for 28 days.<br>Drug: Placebo<br>* Participants will receive matching placebo tablets of JNJ-41443532 and/or matching placebo tablets of pioglitazone orally as per the assigned arms.<br>|
| Experimental: JNJ-41443532 1000 mg<br>Participants will receive JNJ-41443532 1000 mg (4 X 250 mg) in morning and evening for 28 days. | Drug: JNJ-41443532<br>* Participants will receive JNJ-41443532 tablet(s) orally in JNJ-41443532 250 mg arm (1 X 250 mg) and JNJ-41443532 1000 mg arm (4 X 250 mg) in morning and evening, for 28 days.<br>Drug: Placebo<br>* Participants will receive matching placebo tablets of JNJ-41443532 and/or matching placebo tablets of pioglitazone orally as per the assigned arms.<br>|
| Active Comparator: Pioglitazone<br>Participants will receive pioglitazone 30 mg in morning for 28 days. | Drug: Pioglitazone 30 mg<br>* Participants will receive tablet pioglitazone 30 mg orally in morning for 28 days.<br>Drug: Placebo<br>* Participants will receive matching placebo tablets of JNJ-41443532 and/or matching placebo tablets of pioglitazone orally as per the assigned arms.<br>|
| Placebo Comparator: Placebo<br>Participants will receive matching placebo for JNJ-41443532 and pioglitazone for 28 days. | Drug: Placebo<br>* Participants will receive matching placebo tablets of JNJ-41443532 and/or matching placebo tablets of pioglitazone orally as per the assigned arms.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Day -1) to Day 28 in Twenty-Four-Hour Weighted Average Glucose (24-Hour WAG) | Difference is calculated as the change in 24-hour WAG in Least Square Mean (LSM) from baseline to Day 28 of each treatment group (pioglitazone, JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the LSM change. 24-hour WAG is defined as the area under the plasma glucose concentration time curve over 0 to 24 hours, divided by 24. | From baseline (Day -1) to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 28 in Fasting Plasma Glucose (FPG) | Difference is calculated as the change in FPG in Least Square Mean (LSM) from baseline to Day 28 of each treatment group (pioglitazone, JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the LSM change. | From baseline to Day 28 | 
| Change From Baseline to Day 28 in Insulin Secretion | Difference is calculated as the change in insulin secretion in Least Square Mean (LSM) from baseline to Day 28 of each treatment group (pioglitazone, JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the LSM change. Insulin secretion is measured by the absolute change in Homeostasis Model Assessment of steady state islet beta cell (HOMA-%B). HOMA-%B calculated as: (360 multiplied by Insulin [pmol/L]) divided by ([Glucose {mg/dL} minus 63] multiplied by 6.945). Higher value is better (signifies improvement relative to baseline). | From baseline to Day 28 | 
| Change From Baseline to Day 28 in Insulin Resistance | Difference is calculated as the change in insulin resistance in Least Square Mean (LSM) from baseline to Day 28 of each treatment group (pioglitazone, JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the LSM change. Insuline sensitivity is measured by absolute change in Homeostasis Model Assessment of insulin resistance (HOMA-IR). Insulin sensitivity is HOMA-%S and HOMA-IR is the reciprocal of HOMA-%S. HOMA-IR calculated as: (Glucose [mg/dL]) multiplied by Insulin [pmol/L]) divided by (405 multiplied by 6.945). Lower value is better (signifies improvement relative to baseline). | From baseline to Day 28 | 
| Change From Baseline to Day 28 in Systemic Levels of Interleukin 6 (IL-6) | Difference is calculated as the geometric mean change in IL-6 from baseline to Day 28 of each treatment group (JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the geometric mean change. IL-6 is a systemic inflammatory markers and is an independent predictors of insulin resistance and progression to type 2 diabetes mellitus. IL-6 was not measured for pioglitazone guoup. The unit of IL-6 is picograms per milliliter (pg/mL). | From baseline to Day 28 | 
| Change From Baseline to Day 28 in Systemic Levels of Interleukin 18 (IL-18) | Difference is calculated as the geometric mean change in IL-18 from baseline to Day 28 of each treatment group (JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the geometric mean change. IL-18 was not measured for pioglitazone group. The unit of IL-18 is picograms per milliliter (pg/mL) | From baseline to Day 28 | 
| Change From Baseline to Day 28 in Systemic Levels of C-Reactive Protein (CRP) | Difference is calculated as the geometric mean change in CRP from baseline to Day 28 of each treatment group (JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the geometric mean change. CRP was not measured for pioglitazone group. | From baseline to Day 28 | 
| Change From Baseline to Day 29 in Body Weight | Difference is calculated as the change in body weight in Least Square Mean (LSM) from baseline to Day 29 of each treatment group (pioglitazone, JNJ-41443532 250 mg, JNJ-41443532 1000 mg, and placebo). The statistical analyses shows the treatment differences (ie, each study medication group minus placebo) in the LSM change. | From baseline to Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 2, Diabetes Mellitus, Hyperglycemia, JNJ-41443532, Pioglitazone, Placebo