Polycystic Kidney Disease
Conditions
Brief summary
Funding Source - FDA OOPD Pioglitazone is currently used in clinical practice to treat diabetes and this study will examine the potential use of a low dose of the same drug for the treatment of polycystic kidney disease. The purpose of this study is to determine whether the diabetes drug pioglitazone (Actos) is a safe and effective treatment of autosomal dominant polycystic kidney disease when treated in its early stages. Pioglitazone is approved by the FDA for the treatment of diabetes. Pre-clinical models of polycystic kidney disease have shown that low dose treatment with pioglitazone decreases the growth of the cysts. The studies also suggest that effective pioglitazone dosing for polycystic kidney disease may be lower than that used to treat diabetes. The purpose of this study is to see if pioglitazone might slow cyst disease in humans.
Detailed description
Patients will be randomize to placebo or 15 mg pioglitazone for 12 months, and then be crossed over to the other arm. Patients will undergo MRI of the liver and kidney and MRspectroscopy of the lumbar spine (if they choose as this is ancillary study) three times during the study. Assessments will be every 3 months and include blood work, blood pressure, and body water assessments.
Interventions
DRUGPioglitazone
Pioglitazone
DRUGPlacebo
Placebo
Sponsors
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients with autosomal dominant polycystic kidney disease (ADPKD) aged 18-55 * estimate glomerular filtration rate (GFR) at or above ≥ 50 ml/min/1.73 m2 by any GFR formula * Normal liver enzymes (ALT/AST) * fasting blood glucose between 70 and120 * for female patients, a willingness to use double contraception to avoid pregnancy while in study * able to give informed consent * In the opinion of the investigator, high likelihood of progressive kidney disease
Exclusion criteria
* diabetes, defined as any of the following: fasting blood sugar \> 130 times two, HgbA1C \> 7, on any blood sugar lowering medication, or past diagnosis of diabetes not occurring during pregnancy * uncontrolled hypertension as determined by the examining physician * history of impaired systolic function (ejection fraction \< 50%) by previous echocardiogram or known ischemic cardiovascular disease * findings suggestive of a kidney disease other than ADPKD * systemic illness requiring immunosuppressive or anti-inflammatory agents * congenital absence of a kidney or history of a total nephrectomy * history of cyst reduction or partial nephrectomy * history of renal cyst aspiration within the previous year * History of bladder cancer, or gross hematuria * inability to undergo MRI due to implantable devices or foreign objects that preclude MRI * active renal transplant * allergy or sensitivity to any of the components of the test materials * institutionalized * currently pregnant or plans to become pregnant during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Total Body Water | average of 4 measures in each 12 month arm | Bioimpedance analysis (BIA)(Ohms); Increase in BIA in Ohms indicates a decrease in total body water |
| Efficacy: Percent Change in Total Kidney Volume | Baseline, end of year 1, and end of year 2 | Change in total kidney volume by Magnetic Resonance Imaging (MRI) from beginning to end of the 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Glomerular Filtration Rate | average of 4 values over 12 months | average estimated glomerular filtration rate by chronic kidney disease (CKD) epidemiologic (epi) formula measured quarterly |
| Safety: Hypoglycemia | measured quarterly for 12 months in pioglitazone and same in placebo | number of patients with blood sugar \< 70 mg/dl |
| Bone Marrow Fat | Baseline, end of year 1, and end of year 2 | We will assess change in bone marrow fat by MR spectroscopy as an ancillary study to be done at the same time as MRI; will not be done due to person leaving institution. |
| Efficacy Blood Pressure | average of 4 measures over 12 months | mean systolic and diastolic blood pressure |
| Safety: Elevated Liver Function Tests | measured quarterly over 12 months for each arm | Number of patients with elevated liver test (ALT or AST) \> 2 times upper limit of normal |
Countries
United States
Participant flow
Recruitment details
Age 18-55 years old, with known autosomal dominant polycystic kidney disease (ADPKD), estimated glomerular filtration rate (eGFR) \> 50 ml/min/m2 on recent labs, and no history of diabetes were identified using international disease codes (ICD-9) code for cystic kidney disease by search of electronic medical records or through advertisements and letters sent to Nephrologists.
Pre-assignment details
Patients who fulfilled the initial screening underwent further screening with a baseline magnetic resonance imaging (MRI) and randomized to pioglitazone or placebo providing the total kidney volume (TKV) was ≥675 ml (18-25 years old), ≥ 900 ml (26-35 years old), and ≥ 1350 ml (36-55 years old).
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants at randomization to sequence 1 (pioglitazone 15 mg) or placebo for cross over study | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 34.2 years STANDARD_DEVIATION 7.54 |
| estimated glomerular filtration rate (eGFR) by CKD-epi | 86 ml/min/m2 STANDARD_DEVIATION 27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| left kidney volume | 1078 ml STANDARD_DEVIATION 652 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 18 participants |
| right kidney volume | 965 ml STANDARD_DEVIATION 636 |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 13 / 18 | 15 / 18 |
| serious Total, serious adverse events | 0 / 18 | 3 / 18 |
Outcome results
Primary
Efficacy: Percent Change in Total Kidney Volume
Change in total kidney volume by Magnetic Resonance Imaging (MRI) from beginning to end of the 12 months
Time frame: Baseline, end of year 1, and end of year 2
Population: Those who completed both arms
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pioglitazone | Efficacy: Percent Change in Total Kidney Volume | 4.35 percentage of change |
| Placebo | Efficacy: Percent Change in Total Kidney Volume | 7.85 percentage of change |
p-value: 0.14Paired t-test
Primary
Safety: Total Body Water
Bioimpedance analysis (BIA)(Ohms); Increase in BIA in Ohms indicates a decrease in total body water
Time frame: average of 4 measures in each 12 month arm
Population: All patients randomized
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pioglitazone | Safety: Total Body Water | 45.78 Ohms |
| Placebo | Safety: Total Body Water | 44.17 Ohms |
p-value: 0.024Paired t-test
Secondary
Bone Marrow Fat
We will assess change in bone marrow fat by MR spectroscopy as an ancillary study to be done at the same time as MRI; will not be done due to person leaving institution.
Time frame: Baseline, end of year 1, and end of year 2
Population: The MRIs were done, but could not be analyzed as requires special expertise and software.
Secondary
Efficacy Blood Pressure
mean systolic and diastolic blood pressure
Time frame: average of 4 measures over 12 months
Population: All patients that completed both arms
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pioglitazone | Efficacy Blood Pressure | systolic blood pressure | 127 mmHg |
| Pioglitazone | Efficacy Blood Pressure | diastolic blood pressure | 83 mmHg |
| Placebo | Efficacy Blood Pressure | systolic blood pressure | 129 mmHg |
| Placebo | Efficacy Blood Pressure | diastolic blood pressure | 82 mmHg |
p-value: 0.4paired t test
Secondary
Efficacy: Glomerular Filtration Rate
average estimated glomerular filtration rate by chronic kidney disease (CKD) epidemiologic (epi) formula measured quarterly
Time frame: average of 4 values over 12 months
Population: All patients that completed both arms.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pioglitazone | Efficacy: Glomerular Filtration Rate | 75.5 ml/min/m2 |
| Placebo | Efficacy: Glomerular Filtration Rate | 78.1 ml/min/m2 |
p-value: 0.15Paired t-test
Secondary
Safety: Elevated Liver Function Tests
Number of patients with elevated liver test (ALT or AST) \> 2 times upper limit of normal
Time frame: measured quarterly over 12 months for each arm
Population: All patients who were randomized, regardless of whether they completed both arms
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pioglitazone | Safety: Elevated Liver Function Tests | 0 Participants |
| Placebo | Safety: Elevated Liver Function Tests | 1 Participants |
Secondary
Safety: Hypoglycemia
number of patients with blood sugar \< 70 mg/dl
Time frame: measured quarterly for 12 months in pioglitazone and same in placebo
Population: All randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pioglitazone | Safety: Hypoglycemia | 1 Participants |
| Placebo | Safety: Hypoglycemia | 1 Participants |