Clinical trial NCT02697617
Conditions: Polycystic Kidney Disease
Sponsor: Indiana University
Start date: 2016-01-26; Completion date: 2020-01-01
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: Subject will be on placebo arm 2: Subject will be on pioglitazone
Interventions: intervention 1: Pioglitazone intervention 2: Placebo
Intervention descriptions: intervention 1: Pioglitazone intervention 2: Placebo

Protocol documents:
Prot_SAP_001.pdf: 
D. Study Protocol v 5/31/17 (amended 8-20-18) 
 
Hypothesis:  Treatment with a low dose PPARγ agonist will slow cyst expansion in human ADPKD 
patients and delay the progression to renal complications and failure. 
 
Specific Aim 1: To provide pilot data on the safety of low dose pioglitazone (15 mg daily) treatment in human 
ADPKD patients over a one year period. Tests will be conducted to monitor the known side effects of PPARγ 
agonist treatment, including fluid retention and edema. In addition, liver enzyme tests and risk of hypoglycemia 
will be routinely assessed. 
 
Specific Aim 2: To provide pilot data on the efficacy of low dose pioglitazone therapy in human ADPKD 
patients over a one year period using MRI assessment of total kidney volume.  This will help with power 
calculations for a future multi-center trial. 
 
D.2.a. Study design: The proposed study is a double-blind, placebo controlled, cross-over trial of pioglitazone 
(15 mg/day) versus placebo therapy for the treatment of ADPKD. The study is a pilot study to test the safety 
and efficacy of pioglitazone to slow progression of PKD assessed by percent change in kidney volume by MRI 
compared to one year of placebo.  45 subjects will be enrolled.  A one year cross-over design provides the 
best opportunity to obtain meaningful efficacy and safety data in a short term protocol by allowing each patient 
to serve as his/her own control. This will allow an assessment of effect size and adverse events thereby 
facilitating the design of a future multi center randomized trial. Our protocol will be modeled on two previous 
studies using similar populations of ADPKD patients: One study examined safety and efficacy of long acting 
somatostatin in 12 patients [1] while the other examined the use of sirolimus in 10 patients [2] and both 
obtained statistically meaningful data. 
 
D.2.b. End points: 
 
Safety End Points: 
1) Measures of volume overload/fluid retention: 
a) Net change (decrease) in resistance (which converts to increase in total body water (TBW)) 
assessed by bio impedance analysis (BIA) over the course of each arm. 
b) Episodes of congestive heart failure:  New onset of pulmonary symptoms together with either 
increased interstitial edema on chest X-ray, or changes by echocardiogram (increase in end diastolic 
ventricular volume or new/increase pericardial effusion). 
c) Edema: Number of episodes of edema, classified as either 1) sustained > 1 week of edema despite 
adjustment of diet or 2) unresponsive to diuretic therapy. 
d) Change in echocardiography parameters consistent with coronary artery disease (reduction in 
systolic ejection fraction and/or wall motion abnormalities). 
e) Any doctors’ visit or hospitalization for new cardiac symptoms. 
 
2) Hypoglycemia:  Number of episodes of hypoglycemia (defined as blood glucose < 70 on routine labs). 
 
3) Liver function: Number of episodes of elevated ALT or AST to > 2 times the upper limit of normal. 
 
Efficacy End Points: 
1) The primary efficacy outcome will be percent change in total kidney volume by MRI from baseline to 12 
months for pioglitazone compared to placebo. 
 
2)Measures of kidney function: 
a) Change in the estimated GFR (eGFR) by CKDepi  formula, 
b) Change in the urine micro albumin/creatinine ratio, 
c) Average MAP from both blood pressure reading taken at each visit over the 12 months.  
 
3) Other PKD parameters: 
a) Percent change in liver size by MRI, 
b) Cumulative pain score (on 0 to 10 scale) as average area under the concentration time curve between 
baseline and last trial visit or last visit before requirement of surgical or medical therapy for pain. 
 
 


D.2.c. Setting and Participants: This pilot study that will enroll 45 patients with a diagnosis of ADPKD by 
standard clinical criteria.  All patients will be screened and, if eligible, enrolled at the Indiana University Health 
Clinics under the supervision of Dr. Sharon Moe (PI) and PKD Clinic under the supervision of Dr. Robert 
Bacallao (Co-I). Dr. Blazer-Yost, (Co-PI) will assist in recruitment, especially with outreach, and help Dr. Moe 
and the Research Coordinator with other aspects of the study. 
 
D.2. d: Inclusion/Exclusion Criteria: 
Screening: 
Patients will be initially assessed based on historical data available in the medical record or through discussion 
with patient/primary Nephrologist in the previous 3 months. 
Inclusion criteria: 
• 
Male or female ADPKD patients aged 18-55 
• 
eGFR at or above ≥ 50 ml/min/1.73 m2   by 4 parameter MDRD,CKD-Epi formula, or any other eGFR 
formula or urine creatinine clearance  
• 
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 ECHO 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 
 
Step 2 inclusion criteria:  patients who fulfill these screening criteria will be asked to undergo further 
screening with a baseline MRI of the kidney ≤30 days prior to day 0. Patients with kidney volumes estimated 
to be in the following ranges on MRI imaging: 18-25 years old with TKV >750 ml, 26-35 years old with TKV > 
1000 ml, 36-50years old with TKV >1500 ml define a high likelihood of rapid progression based on the CRISP 
study [3, 4]. For consistency with other studies, the MRI images from IUSM will be sent to the Mayo Clinic for 
analysis. The investigators at the Mayo Clinic are internationally known and some of the most experienced in 
interpretation of MRI results from ADPKD patients.  The baseline scans will be re-read at the end of the study 
by the same observer.  Thus the actual values for this step of inclusion will not be in the final analyses. In a 
study of 40 patients, the inter-observer variation had a confidence interval of roughly +/-10%.  Thus, as 
discussed with our DSMB, in order to maximize inclusion, the minimum TKV criteria for randomization will be 
the above published criteria minus 10% as detailed below:   
 
1:  18-25 years old with TKV ≥675 ml; 
2.   26-35 years old with TKV ≥ 900 ml; 
3.  36-50 years old with TKV ≥1350 ml 
 
Depending on logistics and distance traveled for potential subjects, the MRI and baseline visit will occur the same day 
and drug overnight expressed to the patient if patient eligible.   
 
 


D2.e.  Interventions:  Once all of the inclusion-exclusion criteria are met (including the kidney volume by MRI), 
patients will be randomized by an investigational pharmacist to placebo or pioglitazone  (15 mg) as a tablet 
taken once a day.  After one year, the patient will be transitioned to the opposite therapy (pioglitazone or 
placebo) for one year after a 2 week wash out.  Study investigators will remain blinded to the study intervention 
and results until the end of the trial. 
 
The Investigational Pharmacist will distribute the study medication to research coordinator and the research 
coordinator will give  study medication to the patients. Patients will return study medication to research 
coordinator at which time compliance will be performed via pill count, prior to returning to IDS. IDS will also 
conduct compliance upon return to the pharmacy. Placebo and drug pills will appear identical.  The Indiana 
Clinical and Translational Sciences Institute (CTSI) Accessing Technology Program (ATP) assists 
investigators in identifying pharmaceutical manufacturing sites for clinical trial materials. The site selected for 
manufacture of product for this study is The Foundation of The University of Iowa Pharmaceuticals (UIP). The 
UIP has been audited by a R.Ph. contracted by the ATP to ensure compliance with current Good 
Manufacturing Practices (cGMP) per 21CFR210,211.  All manufacturing documents are approved by the 
investigator prior to manufacture and all release documents are approved by the investigator prior to 
acceptance of the product. The active material for this study includes over- encapsulation of Actos 
(pioglitazone) tablet purchased from a pharmaceutical company with microcrystalline cellulose as a filler. The 
placebo consists entirely of microcrystalline cellulose in a capsule identical to that used for the active 
ingredient. The PKD foundation has agreed to pay for costs of drug and over- encapsulation.  See budget 
justification for University of Iowa quote and letter of support from the PKD foundation. 
 
Study subjects will be contacted by phone and/or email once a month in between visits to encourage 
compliance by study coordinator and will be asked to return all unused pills to the research coordinator at the 
time of refill.  Compliance will be defined as greater than 80% prescribed pill intake.  Study visits will be done 
at baseline 1,3, 6, 9, and 12 months of each arm. At each visit standardized blood pressure and assessment 
of edema will be done by study research coordinator under the direct supervision of Drs. Moe or Bacallao. 


Table for schedule of events for each arm: 
Screen 
#1 
Screen 
#2 
Treatment period 1 
Wash out 
Protocol 
Activity 
≤30 days 
from day 
0 
day 0 
Month 1 
Day 30 
(+/- 10 
days) 
month 3 
Day 91 
(+/- 10 
days) 
month 6 
Day 182 
(+/- 10 
days) 
month 9 *** 
Day 274 
(+/- 10 days) 
VISIT 9 IS 
OPTIONAL
month 12 
Day 365 
(+/- 10 
days) 
2 weeks 
Medical History 
X 
X 
X 
Physical/ vital 
signs/standardi 
zed blood 
pressure 
(temperature 
will be 
captured only if 
subject reports 
symptoms/illne
ss in which a 
change in 
temperature 
would be 
expected) 
X** 
X (no PE at 
day 0) 
 
X 
X 
X** 
X 
X** 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Pill Count 
X 
X 
X 
X 
X 
X 
Laboratory 
and other 
testing 
CMP 
X* 
X 
X 
X 
X 
X 
X 
Urine 
Alb/creatinine 
ratio/HCG 
X* 
X 
X 
X 
MRI 
X 
X 
Cardiac Echo 
X 
(completed 
at V1 Arm 1 
only) 
X 
BIA 
X 
X 
X 
X 
X 
X 
* If not done in previous 3 months; CMP = comprehensive metabolic profile (includes liver enzymes and 
glucose); BIA = bioelectrical impedance analysis 
** Physical exam will be completed by MD at screening, month 6, and month 12 visits. All other visits 
coordinator will assess subject and if any issues, subject will be seen by MD.  


*** Visit 9 is optional if subject is unable to make visit due to logistic issues (i.e., cost, time to travel etc…) 
 
 
Detailed Methods: 
1) MR imaging without gadolinium enhancement will be conducted at the initiation, at the 1 year cross-over  
time and end of the study (total 3 per study participant) for determination of total kidney volume and total liver 
volume following the protocol developed by the Consortium for Radiologic Imaging Studies of Polycystic  
Kidney Disease (CRISP)[4, 5]. MR images will be reviewed locally to ensure adequate imaging, and made 
available after anonymization to the Imaging Core of the Mayo Translational PKD Center using the National 
Biomedical Imaging Archive.  At the Imaging Core, the images will be stored in a Radiology secured server 
and transferred to local PKD workstations for assessment of image quality and further processing. Kidneys 
or liver volumes will be measured from coronal T1-weighted images from MR or axial CT images, using a 
stereologic method with ANALYZE™ software (standard method used in multiple clinical, NIH and industry 
trials). Ten percent of the images from randomly selected patients will be routinely measured on two 
separate occasions (by at least 30 days) to assure reliable volumes.  Initial measurements for screening will 
be done by one of three available radiologists, but actual study results will be read by a single radiologist 
blinded to study intervention. 
 
2) Blood will be drawn for routine analysis (comprehensive metabolic panel) at the time of screening (if not 
available in medical history), at baseline (time of randomization), then month 1, 3, 6, 9, and 12 (all treatment 
visits will have a visit window of +/- 10 days) during the first treatment period (Year 1) and again at the same 
time points after the cross over during the second treatment period (Year 2). The comprehensive metabolic 
panel consists of 14 blood tests that include Albumin, Alkaline phosphatase, ALT (alanine aminotransferase), 
AST (aspartate aminotransferase), Urea Nitrogen (BUN), Calcium, Chloride, Carbon Dioxide, Creatinine, 
Glucose, Potassium, Sodium, Total Bilirubin, Total Protein and a calculation of the eGFR using the CKD-epi 
formula. At each visit up to 30ml of blood will be drawn for storage and future research studies. 
 
3) Standardized blood pressure measurements will be taken at time of step 1 screening, and at each study 
visit and again at the same time points after the cross-over for the second treatment period. Blood 
pressure will be taken once when the patient has been sitting for 5 minutes, and then again, ≥5 minutes 
later. 
 
4) Urine will be taken on first urine sample of the day (patient may bring to clinic) for urine albumin and 
creatinine ratio at baseline, and at months 6 and 12.  For female patients of reproductive age, a urine 
pregnancy test (point of care) will be performed as well. 
 
5) A cardiac echo will be performed on each patient at the beginning of Arm 1 and end of each arm, or in any 
patients with complaints of new dyspnea.  The cardiac echo will be reviewed by clinical cardiologist with 
standard echocardiographic end points assessed (including left ventricular hypertrophy, ejection fraction, left 
atrial enlargement, and wall motion abnormalities) 
 
6) Bioelectrical impedance analysis (BIA) will be done at baseline and every 3 months of each arm. This will 
be done using the RJL systems segmental BIA machine (RJL Sciences, Inc.  Clinton Township, MI). The BIA 
will be conducted by the Research Coordinator who has been tried on the device.  Segmental bio impedance 
(opposition to the flow of an electric current through body tissues) can be used to calculate total body water. 
The resistance in ohms (Ω) decreases with increased total body water.  Patients with CKD have reduced 
resistance and increased TBW compared to normal controls[6].  In a randomized trial of amlodipine versus 
placebo in patients with hypertension, Schoeller et al found that such an assessment was comparable to the 
gold standard of water displacement and ankle circumference and more sensitive than clinical assessment of 
edema[7]. Total body water can then be derived by standardized formulas and can differentiate between 
intracellular and extracellular water[8, 9]. (In red as more information provided than in previous submission). 
 
D.2.f. Recruitment: 
Indiana University Health is a statewide hospital network integrated with a common electronic medical record 
(EMR).  The patients will be recruited from the following sites: 
1) PKD clinic run by Dr. Robert Bacallao (Co-PI).  Currently 35 patients are seen in this clinic per year.  Of 
the 35 patient, 2 are African American (5.7%), 0 are Asian, 1 is American/Indian/Alaska Native (2.8%). The 


remaining patients are Caucasian.  Of the 35, 20 are female and 15 are male. 
2) All clinics where patients are seen by IU Health Physicians Nephrology group (the common practice plan of 
IU  School of Medicine Nephrology division). Importantly, all of the 28 Nephrologists (including Dr. Moe) see 
PKD patients. A review of billing records from our Nephrology group using the 753.12, 753.19 and 753.13 
ICD-9 codes identified over 390 unique patients with cystic disease in our data base seen in the last 5 years. 
 
D.2.g. Compliance 
a) Good Clinical Practices: The investigators and research coordinators are all trained in Good Clinical 
Practices. The individuals who will have clinical interactions have conducted or been involved in several clinical 
research projects. Compliance with regulatory bodies including the Indiana University IRB is mandatory for the 
conduction of this study and will be continuously assessed by the investigators and on an annual basis or more 
frequently by the IRB if needed based on established criteria.  A Data Safety Monitoring Board (DSMB) will 
monitor the ethical, medical and scientific conduct of the study (please see more details below).  No members 
of the panel will be directly involved in the clinical grant. 
 
b) Informed Consent: Potential candidates meeting eligibility criteria will be informed about the study, including 
potential risks and benefits. When patients are deemed clinically stable and cognitively able to give consent, 
an approved investigator and/or research coordinator will review the project and the informed consent with the 
patient providing ample time for the patients to ask questions and have them answered. Those who are 
interested will be asked to voluntarily participate and give written informed consent. Documentation of 
informed consent process will include not only the signed and dated informed consent forms, but also 
appropriate notes to file, per institutional requirements.  Subjects must be given a copy of the informed 
consent. Subjects will be consented prior to any study interventions, including any additional blood tests (if not 
done in the requisite time period prior) or the MRI to assess kidney volume. 
 
c) HIPAA authorization: Subjects must also sign a HIPAA authorization form and they will be provided with a 
copy of the form.  Respect for patient confidentiality will be strictly maintained.  Access to individually 
identifiable private information will be restricted to the IRB-approved investigators and/or research 
coordinators. 
Publications resulting from this research will not identify patients.  No data containing private 
patient information will ever be transmitted to other institutions.  Data sharing will occur in a HIPAA-compliant, 
de-identified manner supervised closely by the Data Safety Monitoring Board at Indiana University (see 
composition below). Study data maintained in paper format will be stored in locked cabinets and/or restricted- 
access areas.  Research material includes the inpatient and outpatient source paper and electronic medical 
records at each site, including results of study tests and procedures, medical history, baseline laboratory 
results, physical examinations, coordinator assessments, vital signs, heart rate, concomitant medications, and 
baseline demographics.   In addition, information will be collected regarding study drug accountability and 
adverse events.  MRI data sets will be collected electronically and transmitted via a secured web site. 
 
d) ClinicalTrials.gov Requirements: This application includes a clinical trial for which registration and results 
reporting in ClinicalTrials.gov will be required, pursuant to Public Law 110-85. 
 
D.2.h.  Statistical analyses: 
 
Hypothesis: Treatment with a low dose PPARγ agonist will slow cyst expansion in human ADPKD patients 
and delay the progression to renal complications and failure. Therefore, the overall objective of this study is to 
conduct a pilot study to obtain information on safety and feasibility that will be needed to design a larger, 
appropriately powered clinical trial. 
 
Specific Aim 1: To provide pilot data on the safety of low dose pioglitazone (15 mg daily) treatment in 
human ADPKD patients over a one year period. Tests will be conducted to monitor the known side 
effects of PPARγ agonist treatment, including fluid retention and edema. In addition, liver enzyme 
profiles, renal function and risk of hypoglycemia will be assessed routinely. 
 
Patients’ characteristics including, demographics, kidney function at baseline will be summarized by treatment 
and placebo groups and compared using t-test or Chi-square test as appropriate. Nonparametric Wilcoxon test 
or transformation will be used if a continuous variable appears to be non-normal. All analysis will be performed 
using SAS 9.3 (Cary, NC). 
 


Safety end points: The following safety end points will be summarized by group for all subjects at both 
periods and compared by t-test or Chi-square test as appropriate: 
 
1) Measures of volume overload/fluid retention: 
a) Net change (decrease) in resistance (which converts to increase in total body water (TBW)) 
assessed by bio impedance analysis (BIA) over the course of each arm. 
b) Episodes of congestive heart failure:  New onset of pulmonary symptoms together with either 
increased interstitial edema on chest X-ray, or changes by echocardiogram (increase in end diastolic ventricular 
volume or new/increase pericardial effusion). 
c) Edema: Number of episodes of edema, classified as either 1) sustained > 1 week of edema despite 
adjustment of diet or 2) unresponsive to diuretic therapy. 
d) Change in echocardiography parameters consistent with coronary artery disease (reduction in 
systolic ejection fraction and/or wall motion abnormalities). 
e) Any doctors’ visit or hospitalization for cardiac symptoms. 
 
2) Hypoglycemia: 
a) Number of episodes of hypoglycemia (defined as blood glucose < 70 on non-fasting labs, or <70 on 
fasting labs with symptoms or if reviewing physician suspects symptoms based on patient’s description 
b) Average blood glucose level.  . 
3) Liver function: Number of episodes of elevated ALT or AST to > 2 times the upper limit of normal. 
 
4) Other adverse events noted in previous trials will be assessed:  Episodes of gross hematuria, 
gastrointestinal symptoms (nausea/vomiting, diarrhea). 
 
Specific Aim 2: To provide pilot data on the efficacy of low dose pioglitazone therapy in human ADPKD 
patients over a one year period using MRI assessment of total kidney volume. 
 
1) The percent change in total kidney volume (TKV) by MRI is the primary efficacy end point. We will use the 
paired t-test to compare the difference of percent change of TKV between the two study periods. With the 
cross-over design, the paired t-test allows us to use the subjects as their own controls as has been done with 
other therapies in PKD at this stage of development[10]. A p-value of 0.05 will be considered as significant. We 
will evaluate the carry-over effect by comparing the total change in both periods in the two different treatment 
sequences[11]. 
 
The following end points will be summarized by group for all subjects at both periods and compared by paired 
t-test or Chi-square test as appropriate: 
 
2)Measures of kidney function: 
a) Change in the estimated GFR (eGFR) by CKD-epiformula, 
b) Change in the urine micro albumin/creatinine ratio, 
c) Average MAP over the 12 months for each blood pressure measurement.  It is expected that there may be 
adjustments to medication dosage as part of standard of care.  However, if a new medication is started for 
any reason this will be considered an adverse event. .. 
d) Change in volume of 4 individual cysts (2 large and 2 small) over time in each kidney 
 
 
3)Other PKD parameters: 
a) Percent change in liver size by MRI, 
b) Cumulative pain score (on 0 to 10 scale) as average area under the concentration time curve between 
baseline and last trial visit or last visit before requirement of surgical or medical therapy for pain. Since 
day-to-day fluctuations in pain normally occur with PKD due to the enlarged kidneys, pain events will not 
be called adverse events unless the pain is severe enough to require new analgesic treatment or 
doctor/ER/hospitalization. 
 
Sample size: We calculated the power based on a paired t-test for comparison of the primary end point, 
change in total kidney volume (TKV) by MRI.  With the paired t-test, power calculations take into account the 
difference between treatment groups (treatment effect), the Standard Deviation (SD) and the correlation 


between the change in TKVs between two treatment periods.  With SAS our power calculations using 
paired mean t-test, mean difference of 2%, standard deviation of 4, correlation of 0.69, 5% Type I error, 
and power of 80% we need 22 subjects to complete the trial.   If we assume a 20% drop out rate, we 
need to enroll 28 subjects.  The rationale is detailed below: 
 
1) For the treatment effect, we assumed an annual 6% increase in TKV while on placebo and 4% while on drug 
(treatment effect of 2%). We feel that an annual growth of 6 %/year is a reasonable estimate based on  
controls of multiple clinical trials. Examples are: SUISSE study of sirolimus[12], 6.8-9.5%; everolimus study[13], 
8.4%; SIRENA sirolimus study[14], 7.4%; Bergamo octreotide study[15],11.8%; the LOCKCYST of 
Lanreotide[16], 6.8%; Mayo octreotide study[10], 8.6%. This estimate is also consistent with the annualized 
rates of growth observed in the CRISP study in patients with baseline age and kidney volumes similar to those 
pre-specified by our inclusion criteria. The difference between the placebo and treatment arms is a conservative 
estimate based on our pre-clinical data; the purpose of this study is to identify the true difference for future 
trials. 
 
2) We assumed a SD of 4% based on the inter-reviewer SD for MRI readings in the CRIC study. 
 
3) As demonstrated in the CRIC study, those with higher TKV at baseline have faster progression with a 
correlation of 0.69[17]. We expect that the correlation between the percent change from the same subject 
under the two treatment conditions will be greater or equal to 0.69. In calculating the sample size, we took this 
correlation into account when calculating the power calculation for the paired t-test (versus an independent 
unpaired t test when the correlation is not taken into account). 
 
D.3.  DATA MANAGEMENT: 
 
a. Clinical Trial Management: The study will be managed by the PIs and study coordinator using the OnCore 
CTMS.  OnCore® is a Clinical Trial Management System (CTMS) developed by Forte Research Systems, Inc., 
and has been licensed by Indiana University to support the operations and study data capture of clinical 
research trials. The system has been installed and configured within a HIPAA aligned IT operations center 
supported by Indiana University’s IT organization (UITS). OnCore® is web-based and provides users secure 
access from any location to record, manage, and report on data associated with the operation and conduct of 
clinical trials.  The system is comprised of three specific applications—Clinical Research Management (CRM), 
Biospecimen Management (BSM), and Unified Registries Management (URM).  Indiana University leverages 
OnCore® to support clinical research trials specifically as it relates to the following  functions and 
processes:  protocol and subject life cycle management, subject safety monitoring, coverage analysis, 
electronic data management, study financials management, subject visit management, correlative study 
sample management, annotation management, requisition and distribution management, inventory 
management, and reporting. 
 
 
The software allows the investigative team to develop case report forms with real time validation rules 
(automated data type and range checks) that are integrated with a study schedule calendar. The central IU 
laboratory is integrated with the system allowing auto-population of laboratory tests for the chemistry and urine 
study results. The system can also be accessed by the Investigational pharmacy.  Finally the output reports 
include summary reports for the DSMB (e.g. recruitment/retention) and SAS output. 
 
b. Data Access: Only study investigators and coordinators will have access to the patient data.  Advanced IT 
Core (AITC) staff, because they maintain the software, will have access to the data, but are trained to observe 
HIPAA rules. 
 
c. Disposition of the Data 
There are two secure means of access to the study data for study members who are granted access:  1) via 
the application by use of IU’s Central Authentication Service (CAS) and project database specific permissions; 
and, 2) via direct access to the database by use of secure database authentication. In each case, the PI will 
identify who has relevant access to the study data and what permissions each individual shall have. 
The deidentified MRI data will be shared with the Mayo Clinic using CDs. 
Data will be stored for at least 7 years after the completion of the study. 


 
d. Sharing Study Results 
The volunteers in this study will have access to their own study results at the end of the study.  It is anticipated 
that the results of this study will be published in scientific journals and at that point the de-identified data are 
publically available.  If the outcome of the study is positive, organizations such as the PKD Foundation will 
likely interpret the peer-reviewed journal articles in lay language for their constituents. 
 
e.  Data integrity and quality 
1. Quality Assurance procedures to a) ensure the validity and integrity of the data, b) ensure the accuracy 
and completeness of the data, and c) completeness, quality, and analysis of measurements. – to be 
completed periodically by other nephrology research staff 
2. Site Monitoring Plan – The study records will be periodically reviewed by Indiana University Clinical and 
Translational Science Institute. 
 
D.4 SAFETY: 
 
The primary concern with respect to subject safety is the development of edema/volume overload and 
hypoglycemia from the pioglitazone. 
 
D.4.1 Potential Risks 
 
Edema: Some reports have indicated an increase in the incidence of edema in pioglitazone compared  to 
control treatments. The specific risks from the pioglitazone based on interventional trials are summarized in the 
FDA Physician Desk Reference (PDR). Specifically, the following data were noted:  “In pooled data of 16 to 26 
week placebo controlled trials of actos monotherapy, edema did not reach > 5% of subjects or differences 
between drug and placebo.  However, in combination trials of Actos plus sulfonylurea edema was observed in 
2.1% of placebo + sulfonylurea, 1.6% of Actos 15 mg plus sulfonylurea and 12.7% in Actos 30 mg + sulfonylurea 
(n = 187, 184, and 189 subjects, respectively). In studies with insulin, the addition of placebo, Actos 15 mg, or 
Actos 30 mg reported 7, 12.6 and 17.6% of subjects with edema in 187, 191, and 188  subjects, respectively.  
In an additional summary table (Table 12) of the PDR, a recorded AE of edema was 1.2% in placebo patients (n 
= 259), 2.5% (n = 81) in Actos 15 mg, 4.7% (n= 275) in 30 mg Actos, and 6.5% (n 
= 169) in Actos 45 mg.” Thus, edema appears to be dose related and increases with other diabetic therapies. 
In the present study, we will use only a 15 mg dose of pioglitazone and the patients will not be diabetic (and 
thus no other medications). Thus, the risk is relatively small. 
 
2. Cardiovascular toxicity:   There has been some controversy regarding the overall effects of PPARγ 
agonists on cardiovascular function. A beneficial drug-induced decrease in blood pressure is well established 
and a recent case report has suggested that pioglitazone can suppress primary aldosteronism and resistant 
hypertension[18].  However, the propensity towards fluid retention has had adverse clinical outcomes.  A study 
showing a statistically significant increase in the incidence of ischemic cardiovascular events in patients treated 
with rosiglitazone[19] has caused a decrease in the use of this drug in the US and a suspension of marketing 
authorization in Europe[7]. In addition, PPARγ agonist-induced fluid retention, that is exacerbated by 
concomitant insulin treatment in diabetic patients, can lead to edema formation and heart failure[20] thus 
overshadowing any potential beneficial effects such as the trend toward reduced risk of cardiovascular events 
that was demonstrated in the PROActive (prospective pioglitazone clinical trial in macrovascular events) 
study[21]. 
Phase III studies and post marketing results revealed a measureable incidence of edema, congestive 
heart failure, and myocardial infarction/ischemic events in diabetics using pioglitazone. A meta analyses 
commissioned by the FDA to evaluate toxicities related to pioglitazone was published in 2009 
(http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm  
226071.pdf). The following is a summary of this special report: “Dose-response analyses based on information 
from 24 of the 40 studies including over 9,000 patients show that there are visible dose-response trends of 
increased risk of myocardial ischemic symptoms, myocardial infarction, and congestive heart failure in 
pioglitazone. Among the 24 studies, the planned treatment duration of 23 studies was 6 months and under. 
The dose-response trends for myocardial ischemia (MIS) and Myocardial Infarction (MI) events were primarily 
driven by the differences between pioglitazone 30 and 45 mg. The risk increase in MIS in pioglitazone 45 mg 
from 30 mg was statistically significant. The incidence rate of MIS for pioglitazone 45 mg was 4.19 per 100 


patient-years, while the incidence rate for pioglitazone 30 mg was 1.98 per 100 patient-years (similar to the 
placebo rate). The incidence rate of MI for pioglitazone 45 mg was 1.60 per 100 patient-years, while the rate 
for 30 mg was 0.69 per 100 patient-years (also close to the placebo rate). The risk of CHF increased as the 
dose levels of pioglitazone increased.”…. “No overwhelming evidence suggests that pioglitazone 30 mg or 
under had higher risk in MIS and MI.” 
In the present study we are using doses of 15 mg daily and thus the risk of these cardiovascular 
events is small. 
 
3. Bladder cancer:  Long term risks of pioglitazone include bladder cancer. 
An analysis of data retrieved 
from the FDA Adverse Events Reporting System between 2004-2009 found an association between 
pioglitazone and bladder cancer[12].  Both the FDA and the European Medicines Agency recommended new 
contra-indications and warnings for pioglitazone and advised prescribers to carefully select patients. However 
they also concluded that the increased risk of bladder cancer was very small and in patients responding to the 
anti-diabetic treatment, the benefits outweigh the risks.  A recent news release revealed completion of a 10 
year post marketing study which found no significant increase risk of bladder cancer in patients ever exposed 
to pioglitazone (http://www.prnewswire.com/news-releases/takeda-announces-completion-of-the-post-  
marketing-commitment-to-submit-data-to-the-fda-the-ema-and-the-pmda-for-pioglitazone-containing-  
medicines-including-actos-273044811.html) In accordance with agency recommendations, we will not enroll 
patients who have current, or a history of, bladder cancer or patients with uninvestigated macroscopic 
hematuria. Any subject developing gross hematuria will be promptly evaluated by a urologist. 
4. Hypoglycemia: Given the intended use of this drug is for the treatment of diabetes related hyperglycemia, 
hypoglycemia is a potential risk. The drug has not been previously given in a non-diabetic population and thus 
the risk is unknown. 
 
Elevated liver function tests: In phase 3 trials of Tolvaptan, there was a slight increase in the risk of elevated 
liver function tests.  Adverse changes in hepatic function are not a common side effect of the PPARγ agonists 
that are currently approved for treatment of diabetes.  In the PDR for pioglitazone, it was noted that there were 
post marketing reports of fatal and nonfatal hepatic failure in patients taking Actos, but probable cause could 
not be determined.  In the controlled clinical trial database, there was no evidence of drug induced 
hepatoxicity.   In addition, troglitazone, another drug in this class of compounds, was taken off the market due 
to liver toxicity in certain patients. Although liver function is generally normal in ADPKD despite the presence  
of liver cysts, we plan to closely monitor liver enzyme levels in the patients during therapy to avoid any potential 
problems.  Monitoring of liver enzymes will take place as part of the serum comprehensive metabolic         
panel which will done quarterly on all volunteers. 
 
6. Risk to pregnant women: Pioglitazone is a class C drug – risk unknown.  No teratogenicity has been 
shown in animal studies but some embryo loss and delayed development of fetus has been reported in 
animals at 10X normal dose. 
 
7. Risk of loss of Confidentiality: 
The review of medical records carries potential risk of loss of privacy:  There is a minimal risk of loss of privacy; 
however, appropriate methods will be implemented to maintain confidentiality (see above for additional details). 
 
8. Risk of bleeding or infection at site of blood draw: There is minimal risk due to phlebotomy. 
 
9. Risk of gastrointestinal symptoms (nausea/vomiting/diarrhea) 
 
10. Fracture:  Risk of fracture may be lower than in other studies because of the subject population’s younger 
age, lower dose, and shorter time on the drug, but the precise risk is currently unknown. 
 
 
D.4.2 Adequacy of Protection Against Risks: 
 
1. Recruitment and Consent 
Subjects will be recruited from the adult patients seen in CKD clinics.  Potential candidates meeting eligibility 
criteria will be informed about the study, including its potential risks and benefits.  When patients are deemed 


clinically stable and cognitively able to give consent, an approved investigator and/or research coordinator will 
review the project and the informed consent with the patient, providing ample time for the patients to ask 
questions and have them answered. Those who are interested will be asked to voluntarily participate and give 
written informed consent.  Documentation of informed consent will include not only the signed and dated 
informed consent forms, but also appropriate notes to file, per institutional requirements.  Subjects will be given 
a copy of the informed consent and HIPAA authorization forms. 
 
2:  Protection Against Risks 
The laboratory tests will be monitored by the site coordinator and PI. The protections (corresponding to risks 
noted above) are: 
 
1. Edema: The subjects will be assessed for edema at each visit, and undergo BIA testing to detect subtle 
differences. If subjects develop edema they will be counseled by a dietician on a 2 gm sodium diet. If this 
fails to improve symptoms, they will be given low dose (20 mg) of furosemide until symptoms resolve.  If 
the edema fails to resolve on Lasix, results in congestive heart failure or pericardial effusion, or is 
considered bothersome by the patient despite diet and furosemide they will be discontinued from 
the study. 
2.  Cardiovascular disease: The subjects will be excluded if they have known cardiovascular disease and will 
undergo an echocardiogram at baseline, 12 and 24 months. If subjects develop new wall motion 
abnormalities or a significant (10%) change in ejection fracture or shows evidence of new 
significant diastolic dysfunction, they will be discontinued from the study. 
3. Bladder Cancer: Subjects will be excluded if they have bladder cancer, and any subject developing 
gross hematuria will be promptly evaluated by a urologist. 
4. Hypoglycemia: Given the intended use of this drug is for the treatment of diabetes related hyperglycemia, 
hypoglycemia is a potential risk.  However, diabetics are excluded and thus this risk is very small as there 
should be adequate insulin response.  Blood glucose levels will be monitored at each visit.  At the 
physician’s discretion, subjects with a glucose level <70, who show other hypoglycemic like 
symptoms (e/g dizziness, sweating, altered concentration) may be given a glucose monitor to 
assess blood glucose randomly.   
5.  Abnormal Liver Function Tests: Patients will have monitoring of liver tests at each visit.  Any subject with 
elevated ALT or AST > 2 X ULN will have the blood test repeated within 48-72 hrs. If abnormal, the 
tests will be repeated one week later.  Persistently elevated LFTs on two occasions at least one 
week apart will be discontinued from the study. 
6. Pregnancy: A urine pregnancy test will be performed, as point of care, each month and at each visit.  
Tests will be provided to subjects to take home for months in between visits. Subjects of child bearing 
potential will be questioned at each visit regarding any irregularities in menses or amenorrhea.    
Adequate birth control will be discussed at each visit. If a woman becomes pregnant, she will be 
discontinued from the study. 
7. Loss of Confidentiality: Subject names will not be used in publications and access to private health 
information collected as a part of this project will be restricted to IRB-approved investigators and 
coordinators only and will never be made part of the central study data repository.  Paper records will be 
stored in locked cabinets and/or in restricted-access areas at each site.  Access to databases will be 
controlled through password protection and granted to approved personnel only. 
8. Bleeding or infection due to blood draw:  Blood will be drawn by an experienced technician. 
9. Gastrointestinal symptoms: If these develop, patients will be instructed to take medication with meals and 
or symptoms treated conservatively. 
10. 10.  Fractures:  Risk is limited given age of participants but this risk in included in the informed consent.  
 
The Principal Investigator and Study Coordinator will review each subject’s clinical course for immediate 
adverse events using medical records and subject observation.  Serious adverse events meeting the criteria 
for prompt reporting will be reported to the local IRB within 5 business days.  The HHS regulations (46.103) 
and Indiana University (IUPUI) Standard Operating Procedures for prompt reporting of unanticipated problems 
to the IRB, appropriate institutional officials, and OHRP will be followed. Adverse events will be graded 
according the system described below.  In general, unanticipated serious adverse events attributable to the 
intervention will be promptly reported to the IRB within 5 days of date of discovery.  Non-serious adverse 
events will be reported to the IRB at the time of continuing review. 
 


This research will not involve pregnant women, human fetuses, prisoners, or those known to be cognitively 
impaired. Women of child bearing potential will be asked to use double contraceptive methods and complete 
urinary pregnancy tests as above. 
 
D.4.d. Potential benefits of the proposed research to human subjects and others 
A potential benefit to human subjects is that the treatment strategies being studied in this application may lead 
to treatments for slowing the progression of PKD. The dose is very low and thus it is expected that there will 
be minimal side effects. The risk is reasonable because the drug used in clinical practice for the treatment of 
hyperglycemia has minimal side effects and is usually used at doses higher than the proposed dose of 15 mg. 
 
D.4.e. Importance of the knowledge to be gained 
There is currently no FDA approved therapy for the treatment of PKD. Because this is an FDA-approved drug 
the risk to subjects participating in the study is small. On the other hand, the benefit in knowledge gain related 
to appropriate treatment of PKD is significant. We propose that the risk to subjects are reasonable compared 
to the anticipated knowledge to be gained. 
 
D.4.f Prompt reporting of unanticipated problems: 
All members of the research team are expected to comply with the highest standards of ethical and 
professional conduct in accordance with federal and state regulations and institutional policies. This project 
will be conducted in compliance with HHS regulations 46.103(b)(5) and 21 CFR 56.108 requiring “prompt 
reporting” of unanticipated problems involving risk to human subjects and/or any serious or continuing 
noncompliance with federal or local requirements (Guidance for Clinical Investigators, Sponsors and IRBs, 
January 2009; http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf ). 
 
Generally, the PIs and research coordinator will review study results for each subject as they are collected.  
The PIs and/or research coordinator will monitor subject recruitment, eligibility criteria, collected data, subjects’ 
clinical course and adverse events. Given the nature of this project, adverse events are not anticipated beyond 
those which subjects might otherwise experience during routine clinical care.  Nonetheless, the Principal 
Investigators and Study Coordinator will review each subject’s clinical course for adverse events using medical 
records and subject observation. Unanticipated problems which are serious and require changes to the protocol 
or informed consent will be reported to the local IRB.   All adverse events will be reported to the DSMB as 
detailed below. 
All non-
serious adverse events that are not considered “unanticipated” will be reported in writing to the IRB at the time 
of continuing review. 
 
All adverse events will be evaluated for grade and attribution to the study intervention using the following 
system: 
 
Adverse event grading 
a. Mild - Awareness of sign or symptom, but easily tolerated 
b. Moderate - Interference with normal daily activities 
c. Severe - Inability to perform normal daily activities 
d. Serious/Life Threatening – any event that results in death or places subject at immediate risk of 
death from the reaction as it occurred; results in hospitalization or prolonged hospitalization, causes 
disability, results in a congenital anomaly, or may jeopardize the subject’s health sufficiently to 
require medical or surgical intervention to prevent one of the other outcomes listed in this category. 
Scale for determining the attribution/relationship of adverse events: 
• 
Definite: 
Adverse event clearly related to study intervention 
• 
Probable: 
Adverse event(s) likely related to study intervention 
• 
Possible: 
Adverse event(s) may be related to study intervention 
• 
Unrelated: 
Adverse event(s) clearly not related to study intervention 
 
Plan for reporting serious adverse events 
Serious adverse events that meet ALL of the following criteria will be reported to the DSMB in 24 hours and 
IRB within five business days. 
a. caused harm to one or more subjects, or placed one or more subjects at increased risk of harm, 
b. were unexpected (the frequency or severity of the event is not accurately reflected in the informed 


consent document or is inconsistent with available literature), 
c. were related to the research procedures, 
d. require revision to the protocol or informed consent document. 
 
D.5. Data Safety Monitoring Plan 
 
D.5.a Membership: 
A Data Safety Monitoring Board (DSMB) will be utilized to provide monitoring of the study. The board will 
include four members who have been chosen for their expertise in various important components of the study 
protocol.  Their biosketches are found in the appendix. The Chair will be a PKD expert, Dr. Bennett. The 
local members who have agreed to serve are: 
 
William Bennett, M.D., Legacy Good Samaritan Medical Center, Oregon will chair the DSMB. Dr. Bennett is a 
recognized expert in PKD and has substantial clinical trial experience. Dr. Bennett has agreed to serve as the 
chair of the DSMB. 
 
Kieren Mather, M.D.   Dr. Mather is an Associate Professor at the Indiana University School of Medicine 
(IUSM), in the Division of Endocrinology.  He is a clinical investigator with expertise in clinical trials in diabetes 
and pre-diabetes. He is, therefore, very knowledgeable about the PPARγ agonists, their metabolic actions and 
potential side effects. 
 
Rajiv Agarwal, M.D.  Dr. Agarwal is a Professor of Medicine at IUSM in the Division of Nephrology. He is an 
expert in hypertension and chronic kidney disease.  His knowledge in both renal and cardiovascular issues will 
be valuable to the committee. 
 
Dr. Richard Kovacs, M.D.  Dr. Kovacs is an Associate Dean for Clinical Research at IUSM.  Dr. Kovacs has substantial 
experience in clinical trials and in drug induced cardiovascular changes. The DSMB will meet after the third patient is 
enrolled and every 6 months thereafter, by conference call. A report of serious adverse events (those which are felt possibly 
related or probably related to the study drug) and enrollment will be sent to the DSMB between meetings. Data from this 
study will be prepared by the statistical team and will be presented to the DSMB for review every 6 months. The DSMB will 
monitor the data quality, rate of subject recruitment, results of related studies, any adverse event data and procedures for 
protecting privacy.  Information about all adverse events, whether volunteered by the subject, discovered by the 
investigator questioning, or detected through physical examination, laboratory test or other means, will be collected and 
recorded.  Data may be reviewed in the aggregate and individual cases will be reviewed, as appropriate. Unanticipated 
problems requiring prompt reporting to the IRB will be reviewed by the DSMB. The DSMB may make recommendations 
regarding protocol changes to enhance safety. Written documentation of DSMB reviews, including recommendations 
regarding continuation or discontinuation of each of the treatment arms, will be based upon review of cases and adverse 
events and will be forwarded to the Study PI and the IRB. 
 
D.5.b. Authority 
 
The Data Safety Monitoring Board is an advisory committee and will review those aspects of the trial that are 
discussed in the Responsibilities section below. When the Board determines that changes should be made to 
the ongoing trial, it will make recommendations to the Study PI as outlined in the Recommendations section 
below. 
D.5.c. Responsibilities 
 
The DSMB will be responsible for: 
 
1. Reviewing interim safety data for the trial and proposing corrective actions when the side effects for one 
or more treatments in the trial are unexpectedly severe. These corrective actions may include 
modification to one or more treatments, early closing or suspension of the trial, or limiting participation  
in the trial to a subset of the original subject population. This review of toxicity by the DSMB is in 
addition to that of the study chair and study team, who have primary responsibility for monitoring  
toxicity. 
 


2. Reviewing end point data categorized by treatment A and B so that blinding is maintained and 
recommending changes in the study status on the basis of these analyses. These changes may include 
early termination of accrual, increases to the accrual goal or major changes to the eligibility criteria for 
the trial. 
 
3. Assessing the impact of independent scientific investigations, especially other trials, on the trial being 
monitored and recommending changes based on those external results. 
 
4. Reviewing and approving or disapproving requests for data from any other party. These responsibilities 
end after the unblinding of the trial. The DSMB would usually not be involved in further review of the 
trial after unblinding, but the Study Chair (Principal Investigator) may consult the DSMB on other 
issues, such as appropriate action for late toxicities, at any time. The scientific responsibilities for 
publishing or presenting the results of a trial to the scientific community and for using the results of a 
trial for planning future studies will continue to rest with the Study Chair and the protocol team. 
 
 
D.5.d. Data and Safety Monitoring Plan 
 
The Elements of the Data Safety Monitoring Plan which will be developed by the DSMB will include: 
1. Summary of the protocol focusing on a) information on benefit/risk ratio of procedures and participant 
burden and b) the selection, recruitment, and retention of participants 
2. Trial Management, organization and participating clinics/investigators. 
3. Data Management and Analysis:  Data acquisition and transmission, data entry methods, and data analysis 
plan. 
4. Regulatory Issues:  a) SAE reporting to the IRB, and FDA, b) reporting of IRB actions to the FDA, c) 
reporting of amendments to protocol, d) conflict of interest disclosures reporting and management 
5. Protocol:  Adherence to protocol requirements and amendments to the study protocol and consent forms. 
6. Trial Safety:  a) Risks and benefits for participants and informed consent procedures, b) AE reporting, c) 
management of risks, d) stopping rules, e) notification of and referral for abnormal findings. 
 
D.5.e. Reports 
A number of reports will be generated during the implementation of the study. These reports will be used for 
the assurance of subject safety and will be reviewed monthly by the co-Principal Investigators. A compilation 
of these monthly reports will be sent to the DSMB for review. 
 
These reports will include:  recruitment information; modified participation (withdrawn consent, drop in, etc.); 
visit completion, forms and protocol violations by site; adverse events with causality determinations and SAEs. 
The Study Statistician will also generate reports to the DSMB including recruitment information, protocol 
violations and dose modifications with reasons. 
 
These reports will be circulated to the DSMB approximately three weeks before the meeting. Any member of 
the committee may request additional data after seeing the report. 
 
1. At the DSMB meeting, there will be an open session, which will include a presentation on clinical issues, 
accrual, compliance, and toxicity by the Statisticians and Study Chair.  Data presented in the open session 
will be aggregated across treatment arms. 
2. The protocol statisticians will present outcome and safety data by blinded treatment code to the core 
DSMB in a closed session. 
3. An executive session, which formulates recommendations, will include only voting members of the DSMB. 
 
Any recommendations regarding the study must be approved by a majority vote of the DSMB members 
present at any executive session meeting. While all recommendations must be transmitted in writing to the PI, 
electronic mail or facsimile may be used in special circumstances requiring immediate decisions. 
 
All deliberations of the DSMB are confidential, and all recommendations transmitted to the Study Chair must 
be considered confidential until implemented by the Study Chair.  Any member who violates the confidentiality 
of the committee will be removed. 
 


D.5.f. Recommendations 
 
The DSMB will be responsible for sending recommendations to the Study Chair no later than one week 
following the meeting. 
 
1. In the event that the DSMB recommends a study change for subject safety reasons (including early 
stopping of inferior therapy), the Study Chair will act to implement the change as expeditiously as possible. 
An amendment will be prepared and submitted to participating member institutions, which will reflect the 
recommendations of the DSMB and will provide the rationale for the changes. 
2. In the event that the DSMB recommends the study be closed early due to slow accrual, then the 
recommendation of the DSMB would be processed as in (1) above. 
3. In the event that the DSMB recommends a change in the study for reasons other than either subject safety 
(e.g., to extend accrual because of an event rate lower than expected) or study closure due to slow 
accrual, the DSMB will provide an adequate rationale to the Study Chair, then the recommendation of the 
DSMB would be processed as in (1) above. 
 
E. Expected Results/Outcomes 
 
Outcome 1: To provide information on the safety of pioglitazone therapy in human ADPKD patients over a one 
year period. The major side effects of drug treatment are expected to be manifested rather early during 
treatment. Thus, after one year of drug treatment we can use this moderate sample size to determine if there 
are any safety issues that frequently appear in PKD patients as opposed to the lack of such side effects in the 
normal population. 
Outcome 2: To provide information on the efficacy of pioglitazone therapy in human ADPKD patients over a 
one year period using MRI monitoring of total kidney volume. The results obtained in this study, whether 
significant or not, will inform future deliberation on whether to pursue a larger and more prolonged clinical trial 
which can be scaled for additional outcomes such as a change in the decline of kidney function, changes in 
degree of hypertension and amelioration of pain. 
 
F. Investigators: The team that has been assembled to carry out a proposed clinical trial has the expertise to 
accomplish the stated goals within the time-frame of the proposed studies. 
Dr. Sharon Moe (Corresponding PI) is the Chief of the Nephrology Division at IU School of Medicine. She 
has substantial clinical research and clinical trial experience. Dr. Moe will oversee all patient procedures, will 
supervise the clinical study coordinator and will be responsible for responding to the FDA, IRB and DSMB. 
Dr. Bonnie Blazer-Yost (Co-PI) was the senior investigator in all the published basic research and pre- 
clinical trials that showed the effectiveness of pioglitazone in decreasing the driving forces for cyst expansion 
by inhibiting the synthesis of the CFTR Cl- channel.  Dr. Blazer-Yost will also communicate with the PKD 
Foundation and others to champion external recruitment and engagement for the study. Drs. Moe and Blazer- 
Yost will jointly be responsible for communicating the findings of the study. 
Dr. Robert Bacallao (Co-I) is the Director of the Polycystic Kidney Disease Clinic at the Indiana University 
School of Medicine.  He will also recruit patients and will help with patient procedures. 
Kristen Ponsler-Sipes, an experienced (over 6 year) clinical study coordinator at Indiana University School 
of Medicine in the Division of Nephrology, will be responsible to managing patient recruitment, testing and 
completion of case report forms.  She will work with the PIs and Co-I to ensure IRB and FDA compliance. 
Dr. Vicente Torres (Consultant) is a leader in the PKD field who will provide critical advice and oversight of 
the project. Dr. Bernard King (Consultant)), a radiologist and Director of the Human Imaging Core at the Mayo 
Clinic will oversee the MRI analyses at the Mayo Clinic.  He will interface with the Radiology Department, 
specifically Dr. Lin Chen (Consultant), at the IU School of Medicine to optimize the local protocol and ensure 
high quality imaging necessary for the final volumetric analyses.  Please see letters of confirmation from Drs. 
King and Chen who have already been in contact to discuss the IU/Mayo interaction. 
Susan Perkins, PhD (consultant) is a Professor of Medicine in the Department of Biostatics and will be the 
statistician responsible for the study. Drs. Moe and Perkins will also oversee a Data Manager from the 
Department of Biostatistics who will be responsible for setting up the OnCore data capture system, 
preparation of initial case report forms in collaboration with the PIs, importing data from the laboratory system, 
performing data cleaning and checking and preparing data for DSMB report and final data analysis in this 
project. Dr. Perkins will also oversee a MS statistician who will help generate reports and conduct analyses. 
 
G. SUMMARY STATEMENT 


In summary, the proposed clinical trial will test the safety and efficacy of low dose pioglitazone (15 mg daily) for 
the treatment of ADPKD. The drug is already FDA approved for the treatment of diabetes and has been 
s h o wn  to have long-term safety profile that is better than any of the other pharmaceutical agents in clinical 
studies for PKD.  If the proposed clinical trial shows positive results, the investigators will immediately seek 
funding for a long-term, multi-center phase III trial designed to move the drug to market. 
Based on basic 
research and pre-clinical studies, we have found that the effect of the drug is to inhibit the growth of cysts 
thereby delaying the progression of the disease. It is highly likely that decreased cyst growth will alleviate much 
of the pain that patients experience in mid-life. It is also anticipated that the drug treatment will delay or prevent 
the progression to end-stage renal failure that usually occurs in patients in their 5th decade. 
In addition, the PKD Foundation has been made aware of the studies and strongly supports this clinical trial. 
They have agreed to pay for the drug encapsulation to create a placebo pill.  If the proposed proof-of-concept 
study has a positive outcome, the PKD Foundation has agreed to be a partner in the development of future 
funding and FDA approval process for the repurposing of this commercially available drug. 


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kidney disease. N Engl J Med, 2010. 363(9): p. 820-9,PMID:20581391. 
13. 
Walz, G., K. Budde, M. Mannaa, J. Nurnberger, C. Wanner, C. Sommerer, U. Kunzendorf, B. Banas, W.H. Horl, N. 
Obermuller, W. Arns, H. Pavenstadt, J. Gaedeke, M. Buchert, C. May, H. Gschaidmeier, S. Kramer, and K.U. 
Eckardt, Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med, 2010. 363(9): 
p. 830-40,PMID:20581392. 
14. 
Perico, N., L. Antiga, A. Caroli, P. Ruggenenti, G. Fasolini, M. Cafaro, P. Ondei, N. Rubis, O. Diadei, G. Gherardi, S. 
Prandini, A. Panozo, R.F. Bravo, S. Carminati, F.R. De Leon, F. Gaspari, M. Cortinovis, N. Motterlini, B. Ene- 
Iordache, A. Remuzzi, and G. Remuzzi, Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol, 
2010. 21(6): p. 1031-40,PMID:20466742. 
15. 
Ruggenenti, P., A. Remuzzi, P. Ondei, G. Fasolini, L. Antiga, B. Ene-Iordache, G. Remuzzi, and F.H. Epstein, Safety 
and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int, 
2005. 68(1): p. 206-16,PMID:15954910. 
16. 
Dai, B., Y. Liu, C. Mei, L. Fu, X. Xiong, Y. Zhang, X. Shen, and Z. Hua, Rosiglitazone attenuates development of 
polycystic kidney disease and prolongs survival in Han:SPRD rats. Clin Sci (Lond), 2010. 119(8): p. 323- 
33,PMID:20507283. 
17. 
Torres, V.E., B.F. King, A.B. Chapman, M.E. Brummer, K.T. Bae, J.F. Glockner, K. Arya, D. Risk, J.P. Felmlee, J.J. 
Grantham, L.M. Guay-Woodford, W.M. Bennett, S. Klahr, C.M. Meyers, X. Zhang, P.A. Thompson, J.P. Miller, and 
D. Consortium for Radiologic Imaging Studies of Polycystic Kidney, Magnetic resonance measurements of renal 
blood flow and disease progression in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol, 
2007. 2(1): p. 112-20,PMID:17699395. 


18. 
Covic, A. and M. Onofriescu, Time to improve fluid management in hemodialysis: should we abandon clinical 
assessment and routinely use bio impedance? Clin J Am Soc Nephrol, 2013. 8(9): p. 1474-5,PMID:23949234. 
19. 
Moissl, U., M. Arias-Guillen, P. Wabel, N. Fontsere, M. Carrera, J.M. Campistol, and F. Maduell, Bioimpedance- 
guided fluid management in hemodialysis patients. Clin J Am Soc Nephrol, 2013. 8(9): p. 1575- 
82,PMID:23949235. 
20. 
Kashiwagi, Y., Y. Mizuno, E. Harada, M. Shono, S. Morita, M. Yoshimura, M. Yano, and H. Yasue, Suppression of 
primary aldosteronism and resistant hypertension by the peroxisome proliferator-activated receptor gamma 
agonist pioglitazone. Am J Med Sci, 2013. 345(6): p. 497-500,PMID:23313950. 
21. 
Nissen, S.E. and K. Wolski, Effect of rosiglitazone on the risk of myocardial infarction and death from 
cardiovascular causes. N Engl J Med, 2007. 356(24): p. 2457-71,PMID:17517853. 


PIOPKD 
Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease 
 
 
Page 1 of 2 
 
 
 
Participant ID (MRN) 
Study ID (SEQ) 
Visit # 
 
 
 
Date of Visit 
/ 
/ 
Participant Initials (first/ middle/ last) 
 
Pain Scoring Questionnaire 
 
1.) In the past 12 months have you 
experienced pain that you believe 
was caused by your PKD? 
Yes 
No 
If Yes: 
A. Was your pain associated with an 
infection? 
 
B. Which side was your pain on? 
 
 
 
 
C. On a scale of 1 to 10, one being the 
least pain you have ever experienced , 
and 10 being the worst pain you have 
experienced how bad was that painful 
episode? 
Yes 
 
 
Left 
 
 
Front 
 
 
 
1 
2 
(least) 
3 
No 
Right 
Back 
4 
5 
6 
(cicle one) 
Both Left and Right 
Both Front and Back 
7 
8 
9 
10 
(most) 
2.) Do you have a history of kidney stones? 
Yes 
No 
 
3.) Since you have enrolled in the study, or since you 
were last seen for the purpose of the study, have you had 
an episode of pain that you believe was caused by your 
PKD? 
 
Yes 
No 
If Yes: 
A. Was your pain associated with an 
infection? 
 
B. Which side was your pain on? 
 
 
 
 
C. On a scale of 1 to 10, one being the 
least pain you have ever experienced , 
and 10 being the worst pain you have 
experienced how bad was that painful 
episode? 
 
D.) Was your pain caused by a urinary 
tract infection? 
Yes 
 
 
Left 
Front 
1 
2 
(least) 
 
 
 
 
 
Yes 
3 
No 
Right 
Back 
4 
5 
6 
(cicle one) 
No 
Both Left and Right 
Both Front and Back 
7 
8 
9 
10 
(most) 
 
2 0 


1830057576 


PIOPKD 
Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease 
 
 
Page 2 of 2 
 
 
 
Participant ID (MRN) 
Study ID (SEQ) 
Visit # 
 
 
 
Date of Visit 
/ 
/ 
Participant Initials (first/ middle/ last) 
 
 
 
Pain Scoring Questionnaire 
 
 
4.) Have you had a kidney stone since you have 
enrolled in the study or were seen in clinic for the 
purpose of the study? 
Yes 
No 
 
5. Have you had a urinary tract infection since you 
have enrolled in the study or were seen in clinic for 
the purpose of the study? 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
 
Completed by signature 
/ 
/ 
Date of Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 0 
2 0 


 
 
3881057574 


 
PIOPKD 
Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease 
 
 
 
Page 1 of 1 
 
 
 
Participant ID (MRN) 
Study ID (SEQ) 
Visit # 
 
 
 
Date of Visit 
/ 
/ 
Participant Initials (first/ middle/ last) 
 
 
Patient Self-Report of Clinical 
 
 
 
 
1.) Experienced shortness of breath that lasted more than two hours? 
Yes 
No 
2.) Been to the emergency room or a doctor's office because of new 
chest pain or shortness of breath? 
Yes 
No 
3.) Developed swelling of your lower extremities that last for more than 
24 hours? 
Yes 
No 
4.) Been told by a physician or nurse that you have edema or worsening 
swelling? 
Yes 
No 
5.) Had your water pill (diuretic) dose increased? 
Yes 
No 
6.) Gained more than 5 pounds? 
Yes 
No 
7.) Had recurrent episodes (more than 2 times) of dizziness, shakiness, 
sweats, or nightmares? 
Yes 
No 
8.) Noticed blood in your urine? 
Yes 
No 
9.) Had diarrhea that lasted more than 2 days or recurred at least twice 
since you were last seen for a study visit? 
Yes 
No 
10.) Had nausea or vomiting that lasted for more than 2 days or 
recurred at least twice since you were last seen for a study visit? 
Yes 
No 
11.) Are you a female of child bearing potential? 
11a.) If Yes, are you actively using birth control? 
Yes 
 
 
Yes 
No 
No 
 
Not sexually active 
 
 
 
 
 
 
Completed by 
signature 
/
Since your last study visit have you: 
2 0 


 
/ 
Date of Signature 
 
 
 
0529429641 
2 0 

ICF_000.pdf: 
Protocol # 1308084213
Version Date 5.31.17
1
 
 
INDIANA UNIVERSITY INFORMED CONSENT STATEMENT FOR
Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease
You are invited to participate in a research study testing the use of a low dose of pioglitazone (Actos) to
treat polycystic kidney disease. 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. You were selected as a possible subject because you have been diagnosed with
autosomal dominant polycystic kidney disease and you are in an early stage of the disease. We ask that
you read this form and ask any questions you may have before agreeing to be in the study.
The study is being conducted by Drs. Sharon Moe and Robert Bacallao of Indiana University School of
Medicine (IUSM) and Dr. Bonnie Blazer-Yost of Indiana University Purdue University Indianapolis
(IUPUI).
STUDY PURPOSE
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 (animal) models of
polycystic kidney disease have shown that low dose treatment with pioglitazone decreases the growth of
the cysts and may delay progression in animals. The dosage used in the animal 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. This drug has not
previously been tested in humans with cystic kidney disease.
NUMBER OF PEOPLE TAKING PART IN THE STUDY:
If you agree to participate, you will be one of up to 45 subjects who will be participating in this research.
PROCEDURES FOR THE STUDY:
This is a placebo controlled study. This means for half of the study you will get the active drug and for
the other half of the study you will get a fake pill. This study involves the following visits and tests:
Screening Visits:
This visit is to determine if you are eligible to participate in the study. This visit will be at Indiana
University and you may be asked to bring previous medical records documenting your polycystic kidney
disease.
During this visit you will have the following tests and procedures:
x
Review and sign consent (if you agree to participate)
x
A review of your medical history
x
Physical exam
x
Pregnancy test
x
Collect a blood sample from a vein in your arm (this will be about 2 Tablespoons) if you have
not had the same blood tests done in the last 3 months.
x
If the above indicate eligibility, you will be scheduled to come back and undergo a magnetic
resonance imaging (MRI) procedure to determine the size of your kidney and liver.
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Protocol # 1308084213
 
 
If the investigators determine that you are eligible for the study, you will be assigned by chance (like a coin
toss) to the pioglitazone group or the placebo (a capsule that looks like the drug but has no active ingredients)
group for the first part of the study. You and/or your doctor cannot choose the study group to which you are
assigned. You will have 1 in 2 chance of being assigned to the pioglitazone group in the first year.
This is a cross-over study which means that all participants who complete the first half of the study on their
assigned treatment will then cross over to the other treatment arm. You will be in the pioglitazone group for
one year and the placebo group for one year. Again, you and your doctor will not know which one you are in
for either year.
The study medication (pioglitazone or placebo) will be given to you by the pharmacy at Indiana University
Hospital. Each time you get new medication, you will be asked to return the containers and any leftover pills 
to the pharmacist.
Visit 1:
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Perform a cardiac echocardiogram (heart ultrasound picture) to examine heart function
x
Conduct a bioelectrical impedance analysis (BIA) to determine your body water content For this you
lie flat on a table and have sticky pads (like for a heart electrocardiogram test) placed on both ankles
and wrists for up to 10 minutes.
x
Ask you about any medical problems or side effects you may have had in the last month
x
Review your medications.
x
Have 2 Tablespoons blood and urine collected.
x
Pregnancy Test
x
Get study drug from investigational pharmacy
Visit 2  (Month 1)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Conduct a BIA to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container (and any remaining drug) and get new drug from investigational
pharmacy
Visit 3 (Month 3)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Conduct a BIA to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container (and any remaining drug) and get new drug from investigational
pharmacy
Visit 4 (Month 6)
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Protocol # 1308084213
 
 
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Collect a urine sample, or bring a urine sample to the clinic
x
Conduct a BIA to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container (and any remaining drug) and get new drug from investigational
pharmacy
Visit 5 (Month 9)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Conduct a BIA to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container (and any remaining drug) and get new drug from investigational
pharmacy
Visit 6 (Month 12)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Collect a urine sample or bring a urine sample to the clinic
x
Perform an MRI to determine kidney and liver size
x
Perform a cardiac echocardiogram (ultrasound of your heart)
x
Conduct a BIA test to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
After visit 6 (Month 12) you will have what is called a “washout period”, at this time you will not take any
study medication. You will have two weeks of not taking study medication before proceeding to the opposite 
treatment that you were on during year one of the study. All of the previous studies will be repeated. This is 
called Arm 2 of the study
Visit 7 (Baseline Arm 2)
During this visit you will have the following tests and procedures:
x
A medical history
x
A physical exam
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (this will be about 2 Tablespoons)
x
Pregnancy Test
x
Collect a urine sample or bring a urine sample to clinic.
x
Conduct a BIA to determine your body water content
x
Ask you about any medical problems or side effects you may have had in the last month
x
Get new drug from investigational pharmacy
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Protocol # 1308084213
 
 
Visit 8 (Arm 2 Month 1)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Collect a urine sample or bring urine sample to the clinic
x
Conduct a BIA to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container and get new drug from investigational pharmacy
Visit 9 (Arm 2 Month 3)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Collect a urine sample or bring urine sample to the clinic
x
Conduct an impedance analysis to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container and get new drug from investigational pharmacy
Visit 10 (Arm 2 Month 6)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test
x
Collect a urine sample or bring urine sample to the clinic.
x
Conduct an impedance analysis to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container and get new drug from investigational pharmacy
Visit 11 (Arm 2 Month 9)
During this visit you will have the following tests and procedures:
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (about 2 Tablespoons)
x
Pregnancy Test 
x
Conduct a BIA to determine your body water content
x
Ask you about any medical problems or side effects you may have had since your last visit.
x
Return study drug pill container and get new drug from investigational pharmacy
Visit 12 (Arm 2, Month 12 – last study visit)
During this time you will have the following tests and procedures;
x
A review of your medical history
x
A physical exam
x
Collect your vital signs (including blood pressure, heart rate, height, weight and temperature)
x
Collect a blood sample from a vein in your arm (this will be about 2 Tablespoons)
x
Pregnancy Test
x
Collect a urine sample
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Protocol # 1308084213
 
 
x
Conduct a BIA to determine your body water content
x
Perform an MRI
x
Perform a cardiac echocardiogram
x
Ask you about any medical problems or side effects you may have had in the last month
RISKS OF TAKING PART IN THE STUDY:
While on the study, the risks, side effects and/or discomforts are:
BLOOD DRAW:
The risks of drawing blood include pain, bruising, lightheadedness, and/or fainting, or rarely, infection
at the site of the needle stick.
ECHOCARDIOGRAM:
This test uses sound waves to look at your heart. The person doing the test will press on your chest with a
machine to obtain the pictures. The pressure may be uncomfortable.
BIOELECTRIAL IMPEDANCE ANALYSIS:
This is a test to measure your body water content to determine if the drug is causing you to retain fluid. It is 
performed by putting sticky pads on each of your wrists and ankles and taking a measurement.
There is no sensation or pain associated with this procedure. Patients with amputated limbs cannot
participate in this test. The test takes less than 10 minutes
MRI:
There is no radiation associated with MRI, but people who have metal devices like pacemakers cannot have 
an MRI and will not be able to participate in the study. Some people with claustrophobia (fear of being
closed in small spaces) may feel too closed in and may not tolerate MRI scanning. If you feel too confined in 
the MRI scanner you can inform the technologist and the MRI scan will be stopped. The MRI machine 
makes loud knocking sounds when it is scanning. Because of this you will be asked to wear earplugs while
getting your MRI scan.  The earplugs minimize discomfort from noise and keep the MRI noise within the
safety range.
PIOGLITAZONE:
Pioglitazone may cause or worsen some types of heart failure and is not indicated for patients with certain
types of heart disease. Subjects will be monitored for signs and symptoms of heart failure after initiation and
if heart failure occurs the drug will be discontinued.
Common side effects of Pioglitazone are as follows:
x
Fluid retention including swelling of the ankles (edema)
x
Increased weight
x
Headache
x
Gastrointestinal: Diarrhea, Flatulence, Indigestion, Malabsorption syndrome (when the body
cannot fully absorb nutrients from the intestines), Nausea and Vomiting
x
Respiratory symptoms such as sore throat, sinus infection and upper respiratory infection.
x
Hypoglycemia or low blood sugar. The symptoms include dizziness, sweating and decreased
ability to concentrate.
Less common but serious side effects include:
x
Congestive heart failure or inability to breath due to fluid in the lungs
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Protocol # 1308084213
 
 
x
Elevation in liver enzymes (0.3%)
x
Malignant tumor of urinary bladder (0.16% to 0.44% )
x
Pneumonia
x
Diabetic macular edema (swelling and fluid retention in the eyes)
x
Fracture: Your risk of fracture may be lower than in other studies because of your younger age, lower 
dose, and shorter time on the drug, but the precise risk is currently unknown.
As with all drugs, it is possible that pioglitazone may cause allergic reactions, although this has not been seen
so far. Tell your doctor immediately if you have symptoms of an allergic reaction which include:
x
itching
x
rash
x
swelling in the mouth, tongue, face, or throat.
UNKNOWN RISKS:
During the study, tell your study doctor if you get any side effect, whether it is listed here or not. If you are
worried, contact your study doctor immediately. Pioglitazone is used to lower blood sugar in patients who 
have diabetes. It is unknown if it will lower blood sugar levels in individuals who do not have diabetes.
BREAST FEEDING:
Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk
when used during breastfeeding. Women who wish to breast feed will be excluded from the study.
PREGNANCY:
The effect of pioglitazone on a fetus (developing baby still in the womb), or on a breastfeeding infant, is
unknown and may be harmful. Because of these risks, women of child bearing age may take part in this study
if they agree to use birth control and take a urine pregnancy test each month while participating in this study.
Urine pregnancy tests will be given to women at each visit for them to take home and use for months in between 
each visit. If a woman becomes pregnant during the study, she will be removed from the study.
If you learn you are pregnant between study visits, you must notify the study staff immediately.
If you are a female and sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below and take a monthly UPT:

Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants
 Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel
that kills sperm)

Intrauterine device (IUD)

Abstinence (no sex)
If you are a male and sexually active and able to father a child, you must agree to use one of the birth control
methods listed below:

Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel
that kills sperm)

Hormonal methods used by your partner, such as birth control pills, patches, injections, vaginal ring,
or implants

Intrauterine device (IUD) used by your partner

Abstinence (no sex)
You must use birth control for the entire study and for at least one month after your last dose of study drug.
PROTECTION AGAINST RISKS
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Protocol # 1308084213
 
 
Blood will be drawn by experienced technicians.
Heart echo will be done by experienced technician.
Earplugs minimize discomfort from noise and keep the MRI noise within the safety range.
Patients will be monitored for signs and symptoms of fluid retention and heart failure after initiation and if 
heart failure occurs the drug will be discontinued. If edema or swelling of the legs is observed, you will be
asked to follow a low salt diet, and possibly take a water pill.  If you become short of breath on the study,
you will be asked to get an additional heart echo study. This will require 1 to 2 additional visits.
If you have abnormal blood tests of your liver, you will be asked to come back for another visit and repeat the 
blood tests. If the tests remain elevated to greater than two times the upper limit of normal, you will be
removed from the study. This will require an additional visit.
If you are found to have a blood sugar level below the normal limits on your study visits and or have low 
blood sugar symptoms (eg. dizziness, nauseated, or confused)) , you will be given a glucometer to test your
blood by a finger stick (using a lance, or small needle) at various time points and when you feel dizzy,
nauseated or confused. You will be asked to keep a log of these symptoms and check the blood sugar for one
month. If the blood sugars are found to be repeatedly low then you will be dropped from the study. This may
require an additional visit.
While you are receiving pioglitazone or placebo, you will be questioned at each visit about possible side
effects and you will be monitored by the blood tests we are obtaining.
Records will be stored in a locked cabinet in a locked office and subjects will be identified by a study number
and not a name.
BENEFITS OF TAKING PART IN THE STUDY:
You may not receive any benefit from participation in the study. However, you will have laboratory tests,
MRIs and cardiac echocardiograms that you may give to your own physician to help him/her with your care at
the end of the study, and the blood tests will be given to you throughout the study.
ALTERNATIVES TO TAKING PART IN THE STUDY:
Instead of being in the study, you can continue to be treated by your doctor and not participate.
CONFIDENTIALITY
Efforts will be made to keep your personal information confidential. We cannot guarantee absolute
confidentiality. Your personal information may be disclosed if required by law. Your identity will be held in 
confidence in reports in which the study may be published and databases in which results may be stored.
Organizations that may inspect and/or copy your research records for quality assurance and data analysis
include groups such as the study investigators and their research associates, the Indiana University
Institutional Review Board or its designees, the study sponsor, the FDA, the Indiana Clinical Research Center
(ICRC), and (as allowed by law) state or federal agencies, specifically the Office for Human Research
Protections (OHRP) and the Food and Drug Administration (FDA) who may need to access your medical
and/or research records.
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. Law. This Web 
site will not include information that can identify you. At most, the Web site will include a summary of the
results. You can search this Web site at any time.
GENETIC INFORMATION
This research follows the Genetic Information Nondiscrimination Act (GINA), a federal law which generally
makes it illegal for health insurance companies, group health plans, and most employers to request the genetic 
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Protocol # 1308084213
 
 
information we get from this research and discriminate against you based on your genetic information.
COSTS
The study drug will be provide to you free of charge. Taking part in this study may lead to added costs to you
or your insurance company. You or your insurance company will be responsible for testing done for medical
problems that may arise during the course of the study but were not directly related to the study. You will not
be responsible for these study-specific costs: laboratory testing, MRIs or cardiac echocardiograms.
PAYMENT
You will receive a $10 payment in cash at each visit in the study to pay for parking and gas to get to the
visits. If you travel more than 100 miles, round trip, you will receive an additional $40 to equal $50 total per 
visit.
COMPENSATION FOR INJURY
In the event of physical injury resulting from your participation in this research, necessary medical treatment
will be provided to you and billed as part of your medical expenses.  Costs not covered by your health care
insurer will be your responsibility. Also, it is your responsibility to determine the extent of your health care
coverage. There is no program in place for other monetary compensation for such injuries. However, you
are not giving up any legal rights or benefits to which you are otherwise entitled.
FINANCIAL INTEREST DISCLOSURE
While funding is being provided for the investigators and their staff to conduct the study, there is no financial
gain anticipated.  The Institutional Review Board (an ethics committee which helps protect people involved 
in research) has reviewed the possibility of financial benefit.  The Board believes that the possible financial
benefit is not likely to affect your safety and/or the scientific integrity of the study. If you would like more
information, please ask the researchers or study staff.
CONTACTS FOR QUESTIONS OR PROBLEMS
For questions about the study or a research-related injury, contact the researcher, Dr. Sharon Moe, at 317-
278- 2868. If you cannot reach the researcher during regular business hours (i.e. 8:00AM- 5:00PM), please 
call the IU Human Subjects Office at (317) 278-3458 [for Indianapolis] or (812) 856- 4242 [for
Bloomington] or (800) 696-2949. After business hours, please call (317) 274-5000 and ask for the 
nephrology physician on-call.
If you are unable to reach the investigator at the above number, in an emergency you may contact the Indiana 
University Hospital Pharmacy at (317) 944-0362 (or at Methodist Hospital, (317) 963-5697).
For questions about your rights as a research participant or to discuss problems, complaints or concerns about
a research study, or to obtain information, or offer input, contact the IU Human Subjects Office at (317) 278-
3458 or (800) 696-2949.
VOLUNTARY NATURE OF STUDY
Taking part in this study is voluntary. You may choose not to take part or may leave the study at any
time. Leaving the study will not result in any penalty or loss of benefits to which you are entitled. Your
decision whether or not to participate in this study will not affect your current or future relations with
your doctor. If you decide to leave the study before it is done, please contact Dr. Moe so we can arrange
for basic safety testing.
Your participation may be terminated by the investigator without regard to your consent in the following
circumstances: an abnormality in liver function as determined by the blood analyses, edema or abnormal
findings in the cardiac echocardiogram, if you have fluid retention that is not treatable, persistent liver
test elevation, repeated low blood sugars, or miss a study visit despite reasonable efforts to reschedule to
accommodate your schedule.
You will be told about new information that may affect your health, welfare, or willingness to stay in the
Protocol 1308084213 IRB Approved


Version Date 5.31.17
9
Protocol # 1308084213
 
 
study.
If you leave the study due to side effects from the treatment, you may still chose to participate in the
study and undergo the same tests.  You may also choose not to continue to undergo these tests.
USE OF SPECIMENS 
Some of your blood samples will be kept by Dr. Sharon Moe for both genetic and non-genetic laboratory assays 
in the future to examine the factors that influence the cause or treatment of heart and kidney disease.  These 
samples may be used so far in the future, that it may even be after your death.  
I agree to allow my blood to be stored and possibly used in the future to look at factors that cause or treat 
heart and kidney disease.  I understand that these samples may be used at any time and may not be available for 
destruction if I decide to withdraw from the study.
Yes      
No       Initials ________     Date ____________ 
SUBJECT’S CONSENT
In consideration of all of the above, I give my consent to participate in this research study.
I will be given a copy of this informed consent document to keep for my records. I agree to take part in
this study.
Subject’s Printed Name: ____________________________________
Subject’s Signature:
Date:
(must be dated by the subject)
Printed Name of Person Obtaining Consent:
Signature of Person Obtaining Consent:
Date:
Protocol 1308084213 IRB Approved