End Stage Renal Disease
Conditions
Keywords
End stage renal disease, Hemodialysis, Pioglitazone, Adipokines
Brief summary
This is a double blinded randomized clinical trial of pioglitazone vs. placebo in overweight or obese, diabetic and non-diabetic hemodialysis patients. This study will examine whether pioglitazone modulates adipokine production by adipose tissue in hemodialysis patients and whether these changes result in reduction of inflammation, insulin resistance and oxidative stress and increase in muscle mass. In addition, this study will also examine the associations of adiposity with adipokines and the metabolic milieu in hemodialysis patients to better understand the biology of adipocytes in uremic milieu.
Detailed description
Randomization: 100 overweight or obese patients will be randomly allocated to oral pioglitazone 15 mg/d or placebo for two weeks by blocks of five using a random number generator and monitored for adverse events including hypoglycemia. If they tolerate the 15 mg pioglitazone or matching placebo for two weeks, participants will be assigned to 30 mg of pioglitazone or matching placebo for 24 more weeks. Those who received 15 mg of pioglitazone will receive 30 mg of pioglitazone for the next 24 weeks. Those who received placebo for initial 2 weeks will receive another placebo that matches the 30 mg pioglitazone pill for 24 weeks. Baseline: Participants will have fasting blood drawn for adipokines: Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-6 (IL-6), high sensitivity C-Reactive Protein (hsCRP), high molecular weight Adiponectin (HMW-A), and leptin. All patients will undergo MRI scans on the mid-week non-dialysis day. Twenty each of overweight/obese patients randomized to pioglitazone or placebo will also undergo subcutaneous fat biopsy on the mid-week non-dialysis day. Study Period: Participants will return to the dialysis unit at weeks 2, 4, 6, 10, 14, 18, 22, and 26. During these visits, clinical assessments will be conducted including review of blood sugars, jaundice, weight gain, and visual symptoms. Study treatment compliance will be assessed and details of adverse events experienced, particularly hospitalizations and emergency department visits will be collected. Fasting blood draws for primary and secondary outcomes will be collected on visit weeks 10 and 26.
Interventions
DRUGPioglitazone
15mg/day pioglitazone for 2 weeks, then 30mg/day pioglitazone for the remaining 24 weeks
DRUGPlacebo
1 pill a day for 26 weeks
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Colorado, Denver
University of Utah
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Overweight (Body Mass Index ≥ 25 kilograms per meter squared (kg/m2)) * Adult (18 years or older) * Chronic hemodialysis patient * Diabetic (type 2) or insulin resistant
Exclusion criteria
* \<18 years old * No insulin resistance * Active liver disease * Class III or IV New York Heart Association heart failure * Macular edema or hard exudates near macula on fundoscopy * Current active malignancy (excluding squamous and basal cell skin cancers) * Active AIDS * Chronic lung disease requiring supplemental oxygen therapy * Enrolled in interventional trials using drugs or devices * Bone break of long bones, vertebrae, or hips in the past three years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in High Molecular Weight Adiponectin (HMW-A) Concentration in Plasma From Baseline to 6 Months | Baseline and 6 months | The percent difference in HMW-A concentration geometric mean values from baseline to 6 months was calculated for each arm |
| Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 6 Months | Baseline and 6 months | The percent difference in hsCRP concentration geometric mean values from baseline to 6 months was calculated for each arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 6 Months | Baseline and 6 months | The percent difference in TNF-α concentration geometric mean values from baseline to 6 months was calculated for each arm |
| Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 6 Months | Baseline and 6 months | The percent difference in IL-6 concentration geometric mean values from baseline to 6 months was calculated for each arm |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Pioglitazone: 15mg/day pioglitazone for 2 weeks, then 30mg/day pioglitazone for the remaining 24 weeks | 48 |
| Placebo Placebo: 1 pill a day for 26 weeks | 47 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Fracture | 1 | 3 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Transplant | 0 | 2 |
| Overall Study | Volume Overload | 3 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Pioglitazone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 59.17 years STANDARD_DEVIATION 12.01 | 57.45 years STANDARD_DEVIATION 14.12 | 58.32 years STANDARD_DEVIATION 13.05 |
| Body Mass Index | 32.3 kilograms per meter squared STANDARD_DEVIATION 6.6 | 32.9 kilograms per meter squared STANDARD_DEVIATION 7.5 | 32.6 kilograms per meter squared STANDARD_DEVIATION 7 |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 26 Participants |
| Sex: Female, Male Male | 35 Participants | 34 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 48 | 6 / 47 |
| serious Total, serious adverse events | 11 / 48 | 10 / 47 |
Outcome results
Primary
Change in High Molecular Weight Adiponectin (HMW-A) Concentration in Plasma From Baseline to 6 Months
The percent difference in HMW-A concentration geometric mean values from baseline to 6 months was calculated for each arm
Time frame: Baseline and 6 months
Population: 1 participant in the Pioglitazone group and 2 participants in the Placebo group had blood samples collected after the 10 week visit prior to their withdrawal. They did not complete the study, but their results were included in the 6-month analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pioglitazone | Change in High Molecular Weight Adiponectin (HMW-A) Concentration in Plasma From Baseline to 6 Months | 38.3 percent difference in geometric mean |
| Placebo | Change in High Molecular Weight Adiponectin (HMW-A) Concentration in Plasma From Baseline to 6 Months | -3.4 percent difference in geometric mean |
p-value: 0.047t-test, 2 sided
Primary
Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 6 Months
The percent difference in hsCRP concentration geometric mean values from baseline to 6 months was calculated for each arm
Time frame: Baseline and 6 months
Population: 1 participant in the Pioglitazone group and 2 participants in the Placebo group had blood samples collected after the 10 week visit and prior to their withdrawal. They did not complete the study, but their results were included in the 6-month analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pioglitazone | Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 6 Months | -29.0 percent difference in geometric mean |
| Placebo | Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 6 Months | -1.8 percent difference in geometric mean |
p-value: 0.059t-test, 2 sided
Secondary
Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 6 Months
The percent difference in IL-6 concentration geometric mean values from baseline to 6 months was calculated for each arm
Time frame: Baseline and 6 months
Population: 1 participant in the Pioglitazone group and 2 participants in the Placebo group had blood samples collected after the 10 week visit and prior to their withdrawal. They did not complete the study, but their results were included in the 6-month analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pioglitazone | Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 6 Months | -12.3 percent difference in geometric mean |
| Placebo | Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 6 Months | -12.5 percent difference in geometric mean |
p-value: 0.984t-test, 2 sided
Secondary
Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 6 Months
The percent difference in TNF-α concentration geometric mean values from baseline to 6 months was calculated for each arm
Time frame: Baseline and 6 months
Population: 1 participant in the Pioglitazone group and 2 participants in the Placebo group had blood samples collected after the 10 week visit and prior to their withdrawal. They did not complete the study, but their results were included in the 6-month analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pioglitazone | Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 6 Months | 44.9 percent difference in geometric mean |
| Placebo | Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 6 Months | 39.1 percent difference in geometric mean |
p-value: 0.508t-test, 2 sided