Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes Mellitus, Type 2, Diabetes Mellitus, Hyperglycemia, JNJ-41443532, Pioglitazone, Placebo
Brief summary
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
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.
Interventions
DRUGJNJ-41443532
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.
Participants will receive tablet pioglitazone 30 mg orally in morning for 28 days.
DRUGPlacebo
Participants will receive matching placebo tablets of JNJ-41443532 and/or matching placebo tablets of pioglitazone orally as per the assigned arms.
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Day -1) to Day 28 in Twenty-Four-Hour Weighted Average Glucose (24-Hour WAG) | From baseline (Day -1) to Day 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 28 in Insulin Secretion | From baseline to Day 28 | 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). |
| Change From Baseline to Day 28 in Insulin Resistance | From baseline to Day 28 | 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). |
| Change From Baseline to Day 28 in Systemic Levels of Interleukin 6 (IL-6) | From baseline to Day 28 | 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). |
| Change From Baseline to Day 28 in Fasting Plasma Glucose (FPG) | From baseline to Day 28 | 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. |
| Change From Baseline to Day 28 in Systemic Levels of C-Reactive Protein (CRP) | From baseline to Day 28 | 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. |
| Change From Baseline to Day 29 in Body Weight | From baseline to Day 29 | 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. |
| Change From Baseline to Day 28 in Systemic Levels of Interleukin 18 (IL-18) | From baseline to Day 28 | 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) |
Participant flow
Recruitment details
89 participants were enrolled at 7 study sites in United States.
Pre-assignment details
89 participants were randomly assigned to 4 treatment groups (Placebo: 22; Pioglitazone 30 mg: 22; JNJ41443532 250 mg: 23, and JNJ41443532 1000 mg: 22) and all participants received at least one dose of the study medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo tablets orally, twice a day for 29 days. | 22 |
| Pioglitazone 30 mg Participants received pioglitazone 30 mg tablet orally, once a day for 29 days. | 22 |
| JNJ41443532 250 mg Participants received JNJ-41443532 250 mg tablet orally, twice a day for 29 days. | 23 |
| JNJ41443532 1000 mg Participants received JNJ-41443532 1000 mg (4 X 250 mg tablet) orally, twice a day for 29 days. | 22 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Fasting glucose more than 270 mg/dL | 0 | 1 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Pioglitazone 30 mg | JNJ41443532 250 mg | JNJ41443532 1000 mg | Total |
|---|---|---|---|---|---|
| Age Continuous | 52.7 years STANDARD_DEVIATION 8.93 | 54.5 years STANDARD_DEVIATION 8.93 | 51.7 years STANDARD_DEVIATION 7.06 | 57.1 years STANDARD_DEVIATION 6.03 | 54 years STANDARD_DEVIATION 7.96 |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 7 Participants | 11 Participants | 34 Participants |
| Sex: Female, Male Male | 13 Participants | 15 Participants | 16 Participants | 11 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 22 | 7 / 22 | 9 / 23 | 4 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 23 | 1 / 22 |
Outcome results
Primary
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.
Time frame: From baseline (Day -1) to Day 28
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline (Day -1) to Day 28 in Twenty-Four-Hour Weighted Average Glucose (24-Hour WAG) | -18.88 mg/dL | Standard Error 7.74 |
| JNJ41443532 250 mg | Change From Baseline (Day -1) to Day 28 in Twenty-Four-Hour Weighted Average Glucose (24-Hour WAG) | -11.95 mg/dL | Standard Error 7.33 |
| JNJ41443532 1000 mg | Change From Baseline (Day -1) to Day 28 in Twenty-Four-Hour Weighted Average Glucose (24-Hour WAG) | -4.72 mg/dL | Standard Error 7.56 |
| Placebo | Change From Baseline (Day -1) to Day 28 in Twenty-Four-Hour Weighted Average Glucose (24-Hour WAG) | 8.52 mg/dL | Standard Error 7.23 |
p-value: 0.00695% CI: [-46.792, -8.008]ANCOVA
p-value: 0.03895% CI: [-39.801, -1.142]ANCOVA
p-value: 0.17895% CI: [-32.635, 6.151]ANCOVA
Secondary
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.
Time frame: From baseline to Day 28
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment. Two participants (1 in JNJ-41443532 250-mg group and 1 in Pioglitazone group) were excluded from the analysis because a blood sample for FPG was not collected on Day 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline to Day 28 in Fasting Plasma Glucose (FPG) | -14.57 mg/dL | Standard Error 7.93 |
| JNJ41443532 250 mg | Change From Baseline to Day 28 in Fasting Plasma Glucose (FPG) | -8.26 mg/dL | Standard Error 7.47 |
| JNJ41443532 1000 mg | Change From Baseline to Day 28 in Fasting Plasma Glucose (FPG) | -4.00 mg/dL | Standard Error 7.29 |
| Placebo | Change From Baseline to Day 28 in Fasting Plasma Glucose (FPG) | 13.71 mg/dL | Standard Error 7.23 |
p-value: 0.00595% CI: [-47.606, -8.957]ANCOVA
p-value: 0.02595% CI: [-41.154, -2.786]ANCOVA
p-value: 0.06995% CI: [-36.86, 1.431]ANCOVA
Secondary
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).
Time frame: From baseline to Day 28
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment. Two participants (1 in JNJ-41443532 250-mg group and 1 in Pioglitazone group) were excluded from the analysis because a blood sample for HOMA-IR was not collected on Day 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline to Day 28 in Insulin Resistance | -1.52 HOMA-IR score | Standard Error 0.739 |
| JNJ41443532 250 mg | Change From Baseline to Day 28 in Insulin Resistance | 0.07 HOMA-IR score | Standard Error 0.689 |
| JNJ41443532 1000 mg | Change From Baseline to Day 28 in Insulin Resistance | -0.35 HOMA-IR score | Standard Error 0.675 |
| Placebo | Change From Baseline to Day 28 in Insulin Resistance | 0.33 HOMA-IR score | Standard Error 0.666 |
p-value: 0.04195% CI: [-3.634, -0.082]ANCOVA
p-value: 0.76995% CI: [-2.033, 1.509]ANCOVA
p-value: 0.44495% CI: [-2.463, 1.091]ANCOVA
Secondary
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).
Time frame: From baseline to Day 28
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment. Two participants (1 in JNJ-41443532 250-mg group and 1 in Pioglitazone group) were excluded from the analysis because a blood sample for HOMA-%B was not collected on Day 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline to Day 28 in Insulin Secretion | -4.00 HOMA-B score | Standard Error 4.644 |
| JNJ41443532 250 mg | Change From Baseline to Day 28 in Insulin Secretion | 6.94 HOMA-B score | Standard Error 4.415 |
| JNJ41443532 1000 mg | Change From Baseline to Day 28 in Insulin Secretion | -0.89 HOMA-B score | Standard Error 4.301 |
| Placebo | Change From Baseline to Day 28 in Insulin Secretion | -6.76 HOMA-B score | Standard Error 4.255 |
p-value: 0.62895% CI: [-8.542, 14.054]ANCOVA
p-value: 0.01895% CI: [2.392, 25.008]ANCOVA
p-value: 0.30395% CI: [-5.417, 17.148]ANCOVA
Secondary
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.
Time frame: From baseline to Day 28
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline to Day 28 in Systemic Levels of C-Reactive Protein (CRP) | 1.12 mg/dL | Standard Deviation 0.56 |
| JNJ41443532 250 mg | Change From Baseline to Day 28 in Systemic Levels of C-Reactive Protein (CRP) | 0.86 mg/dL | Standard Deviation 0.3 |
| JNJ41443532 1000 mg | Change From Baseline to Day 28 in Systemic Levels of C-Reactive Protein (CRP) | 0.84 mg/dL | Standard Deviation 0.63 |
p-value: 0.09790% CI: [100.275, 177.115]ANCOVA
p-value: 0.91790% CI: [76.26, 135.942]ANCOVA
Secondary
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)
Time frame: From baseline to Day 28
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline to Day 28 in Systemic Levels of Interleukin 18 (IL-18) | 1.02 pg/mL | Standard Deviation 0.16 |
| JNJ41443532 250 mg | Change From Baseline to Day 28 in Systemic Levels of Interleukin 18 (IL-18) | 1.03 pg/mL | Standard Deviation 0.12 |
| JNJ41443532 1000 mg | Change From Baseline to Day 28 in Systemic Levels of Interleukin 18 (IL-18) | 1.02 pg/mL | Standard Deviation 0.15 |
p-value: 0.96890% CI: [93.217, 107.647]ANCOVA
p-value: 0.78590% CI: [94.179, 108.7]ANCOVA
Secondary
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).
Time frame: From baseline to Day 28
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline to Day 28 in Systemic Levels of Interleukin 6 (IL-6) | 0.86 pg/mL | Standard Deviation 0.85 |
| JNJ41443532 250 mg | Change From Baseline to Day 28 in Systemic Levels of Interleukin 6 (IL-6) | 0.81 pg/mL | Standard Deviation 0.34 |
| JNJ41443532 1000 mg | Change From Baseline to Day 28 in Systemic Levels of Interleukin 6 (IL-6) | 0.91 pg/mL | Standard Deviation 0.71 |
p-value: 0.77490% CI: [71.031, 127.324]ANCOVA
p-value: 0.55590% CI: [66.567, 121.403]ANCOVA
Secondary
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.
Time frame: From baseline to Day 29
Population: Analyses included all participants who received at least 1 dose of JNJ-41443532 or placebo and had at least 1 pharmacodynamic assessment posttreatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone 30 mg | Change From Baseline to Day 29 in Body Weight | -0.75 Kilograms | Standard Error 0.35 |
| JNJ41443532 250 mg | Change From Baseline to Day 29 in Body Weight | -1.18 Kilograms | Standard Error 0.34 |
| JNJ41443532 1000 mg | Change From Baseline to Day 29 in Body Weight | -0.19 Kilograms | Standard Error 0.34 |
| Placebo | Change From Baseline to Day 29 in Body Weight | -1.21 Kilograms | Standard Error 0.32 |
p-value: 0.29595% CI: [-0.408, 1.323]ANCOVA
p-value: 0.94195% CI: [-0.838, 0.904]ANCOVA
p-value: 0.02295% CI: [0.15, 1.892]ANCOVA