PIOPKD: Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02697617
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arms: 2
• Actual Duration (Months): 47.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Kidney Disease	Drug: Pioglitazone; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney
• Actual Study Start Date: Jan 26, 2016
• Actual Primary Completion Date: Oct 1, 2019
• Actual Study Completion Date: Jan 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Arm Subject will be on placebo	Drug: Placebo; Placebo
Active Comparator: Pioglitazone Arm Subject will be on pioglitazone	Drug: Pioglitazone; Pioglitazone; Other Names: Actos

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. Safety: Hypoglycemia [measured quarterly for 12 months in pioglitazone and same in placebo]

   number of patients with blood sugar < 70 mg/dl

2. 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

3. 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

4. Efficacy Blood Pressure [average of 4 measures over 12 months]

   mean systolic and diastolic blood pressure

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University Health	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Indiana University

Investigators

• Principal Investigator: Sharon Moe, 317-944-7580, Indiana University

Study Documents (Full-Text)

• Informed Consent Form - May 31, 2017
• Study Protocol and Statistical Analysis Plan - Aug 20, 2018

More Information

Publications

None provided.

• Responsible Party: Sharon Moe, MD, Stuart A. Kleit Professor of Medicine, Director, Division of Nephrology, Indiana University
• ClinicalTrials.gov Identifier: NCT02697617
• Other Study ID Numbers: IndianaU 1308084213; FD-R-004826-01-A2
• First Posted: Mar 3, 2016
• Last Update Posted: Jan 15, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Pioglitazone

Study Results

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 Detail	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).

Arm/Group Title	PIO Then PLACEBO	Placebo Then PIO
Arm/Group Description	Sequence Pioglitazone then Placebo	sequence placebo then pioglitazone
Period Title: Overall Study
STARTED	9	9
COMPLETED	8	7
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	at randomization to sequence 1 (pioglitazone 15 mg) or placebo for cross over study
Overall Participants	18
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	18 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.2 (7.54)
Sex: Female, Male (Count of Participants)
Female	11 61.1%
Male	7 38.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	13 72.2%
Unknown or Not Reported	5 27.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	13 72.2%
More than one race	0 0%
Unknown or Not Reported	5 27.8%
Region of Enrollment (participants) [Number]
United States	18 100%
estimated glomerular filtration rate (eGFR) by CKD-epi (ml/min/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/m2]	86 (27)
right kidney volume (ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml]	965 (636)
left kidney volume (ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml]	1078 (652)

Outcome Measures

1. Primary Outcome

Title	Safety: Total Body Water
Description	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

Outcome Measure Data

Analysis Population Description

All patients randomized

Arm/Group Title	Pioglitazone	Placebo
Arm/Group Description	Total body water	Total Body Water
Measure Participants	18	18
Mean (95% Confidence Interval) [Ohms]	45.78	44.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments	First analyzed using a Linear Mixed Model to assess if there were carryover effects and then subsequently analyzed using paired t-tests to compare the mean differences between treatments.
	Method	Paired t-test
	Comments

2. Primary Outcome

Title	Efficacy: Percent Change in Total Kidney Volume
Description	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

Outcome Measure Data

Analysis Population Description

Those who completed both arms

Arm/Group Title	Pioglitazone 15 mg Daily	Placebo po Daily
Arm/Group Description	Patients who completed both arms, data from the 12 months of pioglitazone treatment	of patients who finished both arms, the results from the placebo arm
Measure Participants	15	15
Mean (95% Confidence Interval) [percentage of change]	4.35	7.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments	First analyzed using a Linear Mixed Model to assess if there were carryover effects and then subsequently analyzed using paired t-tests to compare the mean differences between treatments.
	Method	Paired t-test
	Comments

3. Secondary Outcome

Title	Safety: Hypoglycemia
Description	number of patients with blood sugar < 70 mg/dl
Time Frame	measured quarterly for 12 months in pioglitazone and same in placebo

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Pioglitazone 15 mg	Placebo
Arm/Group Description	All patients taking pioglitazone	all patients taking placebo
Measure Participants	18	18
Count of Participants [Participants]	1 5.6%	1 NaN

4. Secondary Outcome

Title	Safety: Elevated Liver Function Tests
Description	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

Outcome Measure Data

Analysis Population Description

All patients who were randomized, regardless of whether they completed both arms

Arm/Group Title	Pioglitazone 15 mg	Placebo
Arm/Group Description	All patients taking pioglitazone	all patients taking placebo
Measure Participants	18	18
Count of Participants [Participants]	0 0%	1 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		comparison by paired t-test

5. Secondary Outcome

Title	Efficacy: Glomerular Filtration Rate
Description	average estimated glomerular filtration rate by chronic kidney disease (CKD) epidemiologic (epi) formula measured quarterly
Time Frame	average of 4 values over 12 months

Outcome Measure Data

Analysis Population Description

All patients that completed both arms.

Arm/Group Title	Pioglitazone 15 mg	Placebo
Arm/Group Description	All patients taking pioglitazone	all patients taking placebo
Measure Participants	15	15
Mean (95% Confidence Interval) [ml/min/m2]	75.5	78.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments	First analyzed using a Linear Mixed Model to assess if there were carryover effects and then subsequently analyzed using paired t-tests to compare the mean differences between treatments.
	Method	Paired t-test
	Comments

6. Secondary Outcome

Title	Efficacy Blood Pressure
Description	mean systolic and diastolic blood pressure
Time Frame	average of 4 measures over 12 months

Outcome Measure Data

Analysis Population Description

All patients that completed both arms

Arm/Group Title	Pioglitazone 15 mg	Placebo
Arm/Group Description	All patients taking pioglitazone	all patients taking placebo
Measure Participants	15	15
systolic blood pressure	127	129
diastolic blood pressure	83	82

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4
	Comments	First analyzed using a Linear Mixed Model to assess if there were carryover effects and then subsequently analyzed using paired t-tests to compare the mean differences between treatments.
	Method	paired t test
	Comments

7. Secondary Outcome

Title	Bone Marrow Fat
Description	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

Outcome Measure Data

Analysis Population Description

The MRIs were done, but could not be analyzed as requires special expertise and software.

Arm/Group Title	Pioglitazone 15 mg Daily	Placebo po Daily
Arm/Group Description	Patients who completed both arms, data from the 12 months of pioglitazone treatment	of patients who finished both arms, the results from the placebo arm
Measure Participants	0	0

Adverse Events

Time Frame	2 years
Arm/Group Title	Pioglitazone		Placebo
Arm/Group Description	15 mg po daily		Over encapsulated (identical appearing) placebo
All Cause Mortality
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)
Serious Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		3/18 (16.7%)
Gastrointestinal disorders
surgery	0/18 (0%)	0	1/18 (5.6%)	1
Hepatobiliary disorders
hospitalization	0/18 (0%)	0	1/18 (5.6%)	1
Infections and infestations
pyelonephritis	0/18 (0%)	0	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Pioglitazone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)		15/18 (83.3%)
Gastrointestinal disorders
gastrointestinal symptom	6/18 (33.3%)	9	5/18 (27.8%)	10
General disorders
urinary tract infection or pain	7/18 (38.9%)	12	9/18 (50%)	18
Infections and infestations
infection	13/18 (72.2%)	38	15/18 (83.3%)	30
Musculoskeletal and connective tissue disorders
musculoskeletal pain	7/18 (38.9%)	17	9/18 (50%)	23
Nervous system disorders
headache	8/18 (44.4%)	12	9/18 (50%)	11
dizziness	4/18 (22.2%)	6	3/18 (16.7%)	6

Limitations/Caveats

The major limitation is the small sample size.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.