Conditions: Cystinuria
Keywords: cystinuria D-penicillamine (Cuprimine®) tiopronin (Thiola®)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of escalating doses of cystine biding thiol drugs, including tiopronin and d-penicillamine, on the urinary cystine capacity, which is a measure of the amount of cystine in the urine, in patients with cystinuria. The overall goal will be to help guide therapy and ultimately minimize unnecessary side effects caused by larger doses.

Detailed description:
Cystinuria is a rare genetic cause of kidney stones that leads to significant morbidity due to the recurrent nature of the disease. As a result, a significant part of treatment is focused on prevention of stone formation. Current methods of prevention include increasing fluid intake, dietary modifications, alkali therapy, and cystine binding thiol drugs (CBTDs), which help increase the solubility of cystine in the urine. At present, the dosing of CBTDs is empiric, and not titrated to a specific measured effect. Our primary objective will be to measure the effect of increasing doses of CBTDs on cystine capacity. The investigators predict that higher dosages of these medications will lead to a more positive urinary cystine capacity, or the ability of urine to take up more cystine (and therefore decreased risk of stone formation). However, the dose at which increasing dosages of the medications cease to provide additional benefit is unknown. The investigators will directly measure the cystine capacity in the urine in response to increasing doses of medications to determine if there is a dose at which the maximum benefit of the drug exists.

This is a cross-over trial of escalating doses. There will be four parts to the study. In the first part, subjects will stop taking CBTDs for 7 days, and perform a 24-hour urine collection on day 7. In part 2, they will take their usual CBTD (either tiopronin or d-penicillamine) 1 gram per day for 7 days. They will perform another 24-hour urine collection on day 7 of this study period. In part 3, they will take their usual CBTD at 2 grams per day for 7 days and in part 4 they will take their CBTD at 3 grams per day for 7 days. Again, they will perform 24-hour urine collections on day 7 of each period. The order in which the parts of the study are performed will be randomized for each subject. The mean cystine capacities in each part of the study will be compared to determine the effect of drug dosage on urinary cystine capacity.

Arms:
arm 1: Part 1: patients will stop taking CBTDs for seven days and perform a 24-hour urine collection on day 7 Part 2: patients will take their usual CBTD, either tiopronin or d-penicillamine, 1g per day for 7 days, taken as 500 mg twice a day Part 3: patients will take a total of 2g of tiopronin or D-penicillamine daily for 7 days Part 4: patients will take a total of 3g/d of tiopronin or D-penicillamine, also for a 7 day period

Interventions: intervention 1: Tiopronin 1g per day intervention 2: Tiopronin 2g per day intervention 3: Tiopronin 3g per day
Intervention descriptions: intervention 1: 500mg PO BID x 7 days intervention 2: 1g PO BID x 7 days intervention 3: 1.5g PO BID x 7 days

Protocol document:
Prot_SAP_000.pdf: 
 
 
RDCRN Protocol # 
6413      CysCap Dose Response            Version Date: 17Feb2016 
 
 
 
 
 
 
 
Rare Diseases Clinical Research Network 
 
Effect of Increasing Doses of Cystine Binding Thiol Drugs on Cystine 
Capacity in Patients with Cystinuria 
 
Rare Kidney Stone Consortium 
 
 
 
 
Study Chair 
Principal Investigator: David S. Goldfarb, M.D. 
500 First Avenue – OBV 600 
New York, NY 10016 
212-263-0744 
 
This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose.  The procedures in this 
protocol are intended only for use by Consortium investigators in carefully 
controlled settings.  The Chair of this study should be consulted before 
using or attempting any procedure in this protocol. 


2 
 
iv. RDCRN Protocol Template 
 
Participating Institutions/Investigators Table (contact information) 
 
 
Principal Investigator: David S. Goldfarb, MD 
Contact:  David S. Goldfarb, MD 
Institution: 
New York University  
Address: 
550 First Avenue 
Phone: 
212-263-0744 
Fax: 
212-951-6842 
Email: 
david.goldfarb@nyumc.org 
Sub-
Investigators: 
 
;; Frank Modersitzki, MPH (Research Coordinator) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Management and Coordinating Center Principal Investigator: Jeffrey Krischer, Ph.D. 
Contact:  Carrie Light, Research Project Manager 
Statistician: 
 
Institution/ 
Department: 
Data Management and Coordinating Center (DMCC); Pediatrics Epidemiology Center; 
University of South Florida 
Address: 
3650 Spectrum Blvd; Suite 100; Tampa, Fl 33612 
Phone: 
(813) 396-9248 
Fax: 
(813) 910-1230 
Email: 
 Carrie.light@epi.usf.edu 
 
 
 


3 
 
Table of Contents 
Contents 
1. Protocol Synopsis .................................................................................................................... 4 
1.1 Overview ............................................................................................................................. 5 
2. Specific Aims (Hypothesis and Objectives) ......................................................................... 5 
3. Background ............................................................................................................................... 6 
4. Study Design and Methods .................................................................................................... 6 
4.1 Inclusion Criteria ................................................................................................................ 8 
4.2 Exclusion Criteria ............................................................................................................... 8 
4.3 Recruitment of Participants .............................................................................................. 8 
4.4 Retention Strategies.......................................................................................................... 8 
4.5 Schedule of Events ........................................................................................................... 9 
5. Data and Safety Monitoring Plan .......................................................................................... 9 
5.1 Study Oversight ................................................................................................................. 9 
5.2 Definitions and Standards .............................................................................................. 10 
5.3 Expected/Known Risks/Discomforts/Adverse Events Associated with Study 
Intervention and Procedures: Definition of Expected Adverse Events .......................... 10 
5.4 Reporting Timeline .......................................................................................................... 11 
5.5 RDCRN Adverse Event Data Management System (AEDAMS) ............................. 11 
5.6 Study Discontinuation ..................................................................................................... 12 
5.7 Subject Discontinuation .................................................................................................. 12 
5.8 Data Quality and Monitoring Measures ....................................................................... 12 
6. Statistical Considerations ..................................................................................................... 12 
7. Data Management ................................................................................................................. 12 
7.1 Registration ...................................................................................................................... 13 
8. Human Subjects ..................................................................................................................... 13 
8.1. GCP Statement ............................................................................................................... 13 
8.2. Benefits ............................................................................................................................ 13 
8.3. Risks ................................................................................................................................. 14 
8.4. Recruitment ..................................................................................................................... 14 
8.5. Written Informed Consent: ............................................................................................ 14 
8.6. Process of Consent: ....................................................................................................... 14 
8.7. Certificate of Confidentiality .......................................................................................... 15 
9. References .............................................................................................................................. 17 
10. Appendices ........................................................................................................................... 17 
 
 
 


4 
 
1. Protocol Synopsis 
Interventional Synopsis 
Protocol Number: 
6413 
Protocol Title: 
Effect of Increasing Doses of Cystine Binding Thiol Drugs on Cystine 
Capacity in Patients with Cystinuria 
Study Chair: 
Dr. David Goldfarb 
Statistician: 
 
Consortium: 
Rare Kidney Stone Consortium 
Participating Sites: 
New York University Medical Center, New York, NY 
 
Activation Date: 
 
Current Status: 
 
Sample Size: 
10-15 subjects 
Target Enrollment Period: 
1 year 
Study Design: 
Crossover trial of escalating doses 
Primary Study Objective: 
To evaluate the effect of escalating doses of cystine binding thiol drugs 
on the cystine capacity of the urine. The overall goal will be to help 
guide therapy and ultimately minimize unnecessary side effects caused 
by larger dosages. 
Secondary Study 
Objective(s): 
None. 
Study Population and Main 
Eligibility/ Exclusion Criteria: 
Eligilbilty: Patients between ages 18-80 with confirmed diagnosis of 
cystinuria with a medical regimen that includes tiopronin or D-
penicillamine. 
Exclusion Criteria: Patients who are unwilling or unable to provide 
informed consent, pregnancy, patients with renal colic or patients who 
are scheduled for a urological procedure. 
Treatment (if applicable) 
Agent- 
Tiopronin or D-Penicillamine 
Dosage, schedule, route of 
administration- 
500mg PO BID x 7 days, then 1g PO BID x 7 days, then 1.5g PO BID x 
7 days 
Safety Issues- 
Allergy or drug side effects 
Primary Outcome Measures: 
Urine cystine capacity 
Secondary Outcome 
Measures: 
Urine volume, pH, urea, sodium, creatinine, cystine concentration, and 
urinary  cystine supersaturation 
Statistical Considerations 
(sample size and analysis 
plan): 
 
Sponsors (federal, state, 
foundation and industry 
support): 
National Institutes of Health (NIH), NIDDK, ORDR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


5 
 
1.1 Overview 
 
The purpose of this study is to determine the effect of increasing doses of cystine binding thiol 
drugs, including tiopronin and D-penicillamine, on urinary cystine capacity, which is a measure 
of the amount of cystine in the urine, in patients with cystinuria.  
 
Cystinuria is a rare genetic disease that can lead to significant morbidity in affected patients due 
to the recurrent nature of the disease. As a result, a significant part of treatment is focused on 
prevention of stone formation. Current methods of prevention include increasing fluid intake, 
dietary modifications, alkali therapy, and cystine binding thiol drugs (CBTDs), which help 
increase the solubility of cystine in the urine (1). At present, the dosing of CBTDs is empiric, and 
the drugs are not titrated to a specific measured effect. We propose to measure the effect of 
increasing doses on urinary cystine capacity, in order to help guide treatment. Ultimately, we 
hope to minimize the amount of unnecessary larger dosages of the medications, which may 
decrease potential side effects as well as increase compliance with the medications by decreasing 
the burden of the large number of pills that need to be taken daily. 
 
THIOLA® is FDA approved for the prevention of cystine (kidney) stone formation in patients 
with severe homozygous cystinuria with urinary cystine greater than 500 mg/day, who are 
resistant to treatment with conservative measures of high fluid intake, alkali and diet 
modification, or who have adverse reactions to d-penicillamine. CUPRIMINE is FDA approved 
in the treatment of cystinuria. Both drugs are used within the approved indications. The usual 
dosage of CUPRIMINE in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to 4 
g/day. The average dose of Thiola in some studies was 1000 mg (1g) but the package insert does 
not specify a dose range; many clinicians use doses between 500 mg and 3g per day based on 
clinical stone activity and 24h urine collection results.  
2. Specific Aims (Hypothesis and Objectives) 
 
Our primary objective will be to measure the effect of increasing doses of CBTDs on urinary 
cystine capacity. We predict that higher dosages of these medications will lead to a more positive 
urinary cystine capacity, or the ability of the urine to take up more cystine (and therefore 
decrease risk of stone formation). However, the dose at which increasing dosages of the 
medications cease to provide additional benefit is unknown. We propose to directly measure the 
cystine capacity of urine in response to increasing doses of medications to determine if there is a 
dose at which the maximum benefit of the drugs exists.  
 
This protocol was previously conducted at Lenox Hill Hospital, New York, and approved by the 
Feinstein Institute IRB. The Feinstein Institute conducts research oversite for North Shore Long 
Island Jewish Health System.  
 
We plan to transfer 2 previously enrolled Lenox Hill participants to NYU. No further enrollment 
into this protocol will occur.  


6 
 
3. Background 
 
Cystinuria accounts for approximately 1% of kidney stones in adults and 6% to 8% in children 
(2). It is an autosomal recessive disorder that leads to an impairment in the renal and intestinal 
transport of cystine and dibasic amino acids. As a result of the poor solubility of cystine, the 
increased urinary excretion leads to precipitation of cystine in the renal tubules, resulting in 
nephrolithiasis. The recurrent nature of the stones in this disorder can lead to significant 
morbidity in these patients. 
Measurements of cystine excretion in the urine are inaccurate for several reasons. For one, the 
assays cannot reliably distinguish between the thiol groups of cystine and the drugs used to bind 
cystine (3). Prior studies also found that measurements of cystine solubility varied with pH, and 
therefore nomograms to determine cystine supersaturation could not accurately be made (4). A 
recent assay for cystine capacity is a promising new tool that directly measures the ability of the 
urine to take up additional cystine from a preformed solid phase (undersaturation, or positive 
cystine capacity) or give it up to the solid phase (supersaturation, or negative cystine capacity) 
(3). In contrast to previous assays, the cystine capacity assay accurately measures cystine 
solubility in the presence of CBTDs (5).  The test is widely used by clinicians throughout the 
USA and in standard care for patients with cystinuria under the care of Dr. Goldfarb. 
Current treatment strategies to prevent stone formation in patients with cystinuria include 
increasing fluid intake, alkalinizing urine with alkali therapy, and cystine-binding thiol drugs 
(CBTD) such as tiopronin (Thiola), D-penicillamine, and captopril. These medications have 
sulfhydryl groups that can reduce the disulfide bond in the cystine and produce mixed disulfides 
with cysteine that are more soluble than the homodimer itself. A study by Dolin, et al, showed 
that CBTDs significantly increased the cystine capacity of urine compared to the control period 
without CBTDs (1). However, this preliminary study did not include a dose-response algorithm 
so the minimum effective dosage of each drug is still unknown. We propose a study of CBTDs in 
patients with cystinuria to measure the change in cystine capacity in the urine in response to 
different dosages of the drugs currently used to treat the disorder, with a goal to help guide 
therapy and ultimately minimize unnecessary side effects caused by large dosages. 
4. Study Design and Methods 
Due to the low prevalence of cystinuria in the population, the number of patients available to 
participate in this study precludes the ability to conduct a randomized controlled trial with 
satisfactory probability to achieve a projected sample size. We plan to enroll 10-15 patients in 
the study and perform a crossover trial in which patients receive escalating dosages of cystine 
binding thiol drugs (CBTDs).  
All participants were recruited at Lenox Hill Hospital and enrollment is completed. Two 
remaining participants will be transferred to NYU to complete this protocol.  
 
Patients will be recruited from the clinical practice of the principle investigator at routine clinic 
visits at Lenox Hill Hospital.  After completing informed consent, the patient will have an initial 


7 
 
visit that will be a screening interview. During this interview, the patient will be screened for 
symptoms of renal colic, (which if present would exclude him/her from eligibility), as well as 
asked about any scheduled urologic procedures. A medication history will be taken at this time, 
and the subject’s most recent bloodwork (including a complete blood count) and most recent 
urinalysis will be reviewed. The total time for this visit should be approximately 20 minutes. The 
remainder of the study will be performed at home. 
 
There will be four parts to the study. In the first part, patients will stop taking CBTDs for seven 
days and perform a 24-hour urine collection on day 7. In part 2, patients will take their usual 
CBTD, either tiopronin or d-penicillamine, 1g per day for 7 days, taken as 500 mg twice a day. 
They will perform another 24-hour urine collection on day 7 of this study period. In part 3 of the 
study, patients will take a total of 2g of tiopronin or D-penicillamine daily for 7 days and in part 
4 they will take a total of 3g/d of tiopronin or D-penicillamine, also for a 7 day period. A 24-hour 
urine collection will be performed on day 7 of each study period. The order in which the four 
parts of the study are performed will be randomized for each subject, in order to prevent an order 
effect. After a subject is enrolled in the study, the order in which he/she will perform the study 
periods will be determined by a computer program that generates a random order of the numbers 
1-4. There will not be a specified wash-out period in between study periods due to the short half-
life of the CBTDs. With the exception of CBTDs, the patients will continue all of their regular 
medications including alkali therapy.  
 
Patients will on their self-selected ad-lib diets. They will keep a food diary during the day before 
the urine collection and during the urine collection. They will then replicate the diet during each 
of the subsequent parts of the study, repeating the same diet on the day before and the day of the 
urine collection. We will collect the food diaries at the end of the study to ensure compliance and 
to keep a record of what the subjects were eating. 
The urine will be collected with thymol and gentamicin as preservatives, and maintained at room 
temperature. The urine will be alkalinized at home with 10g of NaHCO3 as per the usual 
Litholink protocol for cystine measurement. Study participants will be asked to measure the 
volume of their urine and then mail an aliquot of their urine to a commercial laboratory, 
Litholink Corp (Chicago, IL), for analysis. 
The urine pH, sodium, urea, and creatinine will be measured. Additionally, the cystine 
supersaturation, 24h urine cystine excretion and cystine capacity of each urine sample will be 
measured by the following method, the “solid phase” cystine assay (3): Measured amounts of 
cystine crystals will be incubated in the urine at 37ᴼC for 48 hours with stirring. The residual 
solid phase will then be harvested by centrifugation at 3800 rpm for 20 minutes at room 
temperature and then dissolved in 25ml of high-pH buffer (0.1 M sodium carbonate; pH 9.9). 
The cystine concentration will be measured in both the supernatant liquid and the buffer to 
determine the change in solid phase, which is known as the cystine capacity. 
The mean cystine capacities in each part of the study (0 g/d of D-penicillamine, 1g/d, 2 g/d, and 
3 g/d) performed will be compared to determine the effect of drug dosage on urinary cystine 
capacity. Urine urea will be measured as a surrogate of protein intake to ensure diets are 


8 
 
replicated correctly, and urine pH will be measured to make sure similar amounts of alkali 
therapy are used in each part of the study. 
Subjects will be asked to undergo a blood test (for complete blood count, one 3 ml EDTA tube of 
blood) and urine test (urinalysis) within one month of completing the study to monitor for any 
potential adverse effects of changing the dosages of medication. The laboratory tests may either 
be performed at an outside lab at the patient’s convenience, or in a routine office visit at Kidney 
Stone Prevention Clinic at NYU. If laboratory tests are performed at an outside laboratory, 
subjects will be asked to send the results to Dr. Goldfarb for review. 
Subjects will be reimbursed for any additional medication costs that they incur as a result of 
participating in the study, but otherwise will not receive compensation for participation in the 
study. 
 
4.1 Inclusion Criteria 
- 
Age between 18 and 80 years 
- 
Patients with a confirmed laboratory diagnosis of cystinuria who meet the following 
criteria: (1) stone analysis demonstrating cystine as a component, or (2) increased urinary 
cystine excretion (>250mg/24hrs in adults) 
- 
A medical regimen that includes either tiopronin or D-penicillamine  
- 
Ability to reliably urinate in a collection vessel and measure urine volume 
- 
Ability to give informed consent 
- 
Documentation of a stable complete blood count (CBC) and urinalysis (UA) in the six 
month period prior to the date of enrollment 
- 
Enrollment in Protocol 6401 (Cystinuria Registry, NYU IRB #09-0425) 
4.2 Exclusion Criteria 
- 
Patients with renal colic 
- 
Patients who are scheduled to undergo a surgical procedure 
- 
Inability to give informed consent 
- 
Patients that are not enrolled in Protocol 6401 (Cystinuria Registry, NYU IRB # 09-0425) 
 
4.3 Recruitment of Participants 
No additional participants will be recruited into this protocol. Two remaining participants will be 
transferred from Lenox Hill to NYU. 
. 
 
4.4 Retention Strategies 
Due to the short duration of the study (4 weeks), we do not anticipate the need for extensive 
retention strategies. We will call patients periodically during the 4-week study period to answer 
any questions they may have, and to ask about any adverse effects they may be experiencing. 


9 
 
 
4.5 Schedule of Events 
 
Baseline 
(Visit 1) 
Day 7 
Day 14  
Day 21 
 
Day 28 
Day 29-60 
Demographics (sex, date of birth) 
x 
 
 
 
 
 
Baseline stone history (diagnosis date 
and method of diagnosis, review of 
current symptoms) 
x 
 
 
 
 
 
Medication history (Current 
medications including Alkali therapy, 
and history of CBTDs including side 
effects, allergic reactions) 
x 
 
 
 
 
 
Dietary history (fluid intake, low 
sodium, low protein, etc) 
x 
 
 
 
 
 
24-hour urine collection 
 
x 
x 
x 
x 
 
Blood test (CBC) and urinalysis 
 
 
 
 
 
x 
5. Data and Safety Monitoring Plan 
The study protocol will be reviewed and approved by the National Institutes of Health (NIH) 
before submission to individual center IRBs for approval.  Participant enrollment may only begin 
with IRB approved consent forms.  
 
This is an interventional pilot study that meets the federal definition of low risk. 
 
5.1 Study Oversight 
The Study Chair has primary oversight responsibility of this clinical trial. The NIH appointed 
Data (Observational) Safety Monitoring Board (D/OSMB) has oversight responsibility of the 
Data Safety Monitoring Plan (DSMP) for this clinical trial. The D/OSMB will review accrual, 
patterns and frequencies of all adverse events, and protocol compliance every 6 months. The 
D/OSMB makes recommendations to the NIH regarding the continuation status of the protocol. 
 
Each site’s Principal Investigator and their research team (co-Investigators, research nurses, 
clinical trial coordinators, and data managers) are responsible for identifying adverse events. 
Either the Principal Investigator or one of the co-Investigators will call each subject weekly 
during the study period to remind them to change the dose of medication, and to assess for any 
potential adverse events. All subjects will undergo a blood test for complete blood count and 
urine test for urinalysis within one month of completing the study to monitor for any adverse 
effects from the changes in medication dosages. The results of the blood and urine tests will be 
reviewed by the Principal Investigator. All adverse events will be reported to the D/OSMB. 
Aggregate report- detailed by severity, attribution (expected or unexpected), and relationship to 
the study drug/study procedures – will be available from the DMCC for site review.  A separate 
report detailing protocol compliance will also be available from the DMCC for site review on a 
monthly basis. The research team will then evaluate whether the protocol or informed consent 
document requires revision based on the reports. 
 


10 
 
5.2 Definitions and Standards 
The Rare Diseases Clinical Research Network defines an adverse event as:  “…an unfavorable 
and unintended sign, symptom or disease associated with a participant’s participation in a Rare 
Diseases Clinical Research Network study.” 
 
Serious adverse events include those events that:  “result in death; are life-threatening; require 
inpatient hospitalization or prolongation of existing hospitalization; create persistent or 
significant disability/incapacity, or a congenital anomaly/birth defects.”  
 
An unexpected adverse event is defined as any adverse experience…the specificity or severity of 
which is not consistent with the risks of information described in the protocol.  
 
Expected adverse events are those that are identified in the research protocol as having been 
previously associated with or having the potential to arise as a consequence of participation in 
the study 
 
All reported adverse events will be classified using the current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) developed and maintained by CTEP at 
National Cancer Institute. 
 
5.3 Expected/Known Risks/Discomforts/Adverse Events Associated with Study 
Intervention and Procedures: Definition of Expected Adverse Events 
 
It is not anticipated that randomization to taking “no CBTD” or doses greater or less than what 
was taken outside of the study will expose subjects to any risks greater than what is already 
encountered from routine use of CBTDs.   
The period off CBTDs is only a week. During that period, the patients will continue their alkali 
therapy, if prescribed, and their usual fluid intake and dietary restrictions. Therefore, the week 
off CBTD is extremely unlikely to lead to cystine stone formation. That is particularly true since 
dosing of CBTDs is completely empirical and not based on cystine supersaturation values; in 
other words, the doses have not been titrated to a particular level to achieve a particular 
therapeutic effect.  
CBTDs are associated with allergy and other side effects, most of which are considered 
idiosyncratic and not clearly dose-related. Patients will take 1-3g, which is likely to exceed their 
usual doses. The duration at each dose is a week and half-life is 12 hours. Since all patients are 
taking the drugs for inclusion, it is again very unlikely that patients will experience any 
important allergy or toxicity of the drugs in the short time they take doses different than their 
usual doses. In our practice, we have patients that take daily up to 3g of CBTDs without any 
reported AE. 
 
Patients will be closely monitored during the time in the study and will have frequent contact 
with the investigators in order to report any AEs in the course of the study. Patients will be 
contacted by phone at least weekly to be asked about any potential adverse effects. Within 


11 
 
four weeks after finishing this protocol, patients will undergo blood testing (CBC, 
comprehensive metabolic and urine protein) to monitor for adverse events. 
5.4 Reporting Timeline 
 
• Within 24 hours (of learning of the event), investigators must report any reportable Serious 
Adverse Event (SAE) that: 
o 
Is considered life-threatening/disabling or results in death of subject 
-OR- 
o 
Is Unexpected/Unanticipated  
• Investigators must report all other reportable SAEs within 5 working days (of learning of the 
event). 
• All other (suspected) reportable AEs must be reported to the RDCRN within 20 working days 
of the notification of the event or of the site becoming aware of the event. 
 
Local institutional reporting requirements to IRBs, any GCRC oversight committee and the 
FDA, if appropriate, remain the responsibility of the treating physician and the Study Chair. 
 
 
5.5 RDCRN Adverse Event Data Management System (AEDAMS) 
Upon entry of a serious adverse event, the DMCC created Adverse Event Data Management 
System (AEDAMS) will immediately notify the Study Chair, site PIs, the  Medical Review 
Officer, and any additional agencies (if applicable- industry sponsor, CTEP, etc) of any reported 
adverse events via email.  
 
Serious adverse events: The NIH appointed Medical Review Officer (MRO) determines 
causality (definitely not related, probably not related, possibly related, probably related, 
definitely related) of the adverse event. The MRO may request further information if necessary 
and possibly request changes to the protocol or consent form as a consequence of the adverse 
event. A back-up notification system is in place so that any delays in review by the MRO beyond 
a specified period of time are forwarded to a secondary reviewer. The Adverse Event Data 
Management System (AEDAMS) maintains audit trails and stores data (and data updated) and 
communication related to any adverse event in the study.  
 
Non-serious expected adverse events: Except those listed above as immediately reportable, non-
serious expected adverse events  that are reported to or observed by the investigator or a member 
of his/her research team will be submitted to the DMCC in a timely fashion (within 20 working 
days). The events will be presented in tabular form and given to the MRO and RDCRN DSMB 
on a bi-annual basis. Local site investigators are also required to fulfill all reporting requirements 
of their local institutions. 
 
The DMCC will post aggregate reports of all reported adverse events for site investigators and 
IRBs. 
 
 


12 
 
5.6 Study Discontinuation  
The NIH, RDCRN DSMB and local IRBs (at their local site) have the authority to stop or 
suspend this trial at any time. This study may be suspended or closed if: 
• Early stopping rules have been met. The early stopping rule will be that the study will 
end if any apparent toxic effect of the medications occurs. These toxic effects include 
allergic manifestations, including rash, and including nausea, vomiting, or other 
symptoms that lead a patient to not tolerate the medication.   
• Accrual has been met 
• The study objectives have been met 
• The Study Chair / Study Investigators believe it is not safe for the study to continue 
• The RDCRN DSMB suspends or closes the trial 
• The NIH suspends or closes the trial 
 
5.7 Subject Discontinuation 
An intent to treat approach will be used. All data acquired prior to termination for the 
reasons outlined below will be included in the primary analysis unless patient withdraws 
consent. Every effort will be made to conduct a final study visit with the participant and 
participants will be followed clinically until, if applicable, all adverse events resolve.  
 
• Withdrawal of consent 
• Withdrawal by the participant 
• Withdrawal by the investigator 
• Intercurrent illness or event that precludes further visits to the study site or ability to 
evaluate disease (e.g.-mental status change, large pleural effusion).  
 
5.8 Data Quality and Monitoring Measures 
As much as possible data quality is assessed at the data entry point using intelligent on-line data 
entry via visual basic designed screen forms. Data element constraints, whether independent 
range and/or format limitations or ‘relative’ referential integrity limitations, can be enforced by 
all methods employed for data input. QA reports assess data quality post-data entry. As we note, 
data quality begins with the design of the data collection forms and procedures and incorporates 
reasonable checks to minimize transcription and omission errors.  Of the more important quality 
assurance measures are the internal validity checks for reasonableness and consistency.  
 
6. Statistical Considerations 
 
The impact of CBTD dose on CysCap will be analyzed with a mixed effects model, with subject 
as a repeated factor, and including dose and period effects. 
7. Data Management 
 


13 
 
Collection of all study data will comply with all applicable guidelines regarding patient 
confidentiality and data integrity.   
 
All study data will be collected through REDCAP and will comply with all applicable guidelines 
regarding patient confidentiality and data integrity.  REDCAP is a secure, web-based application 
for building and managing online databases. On-line forms will be developed that contain the 
requisite data fields.   
 
7.1 Registration 
Registration of participants on this protocol will employ an interactive data system in which the 
clinical site will attest to the participant’s eligibility as per protocol criteria and obtain 
appropriate informed consent. IRB approval for the protocol must be on file at the DMCC before 
accrual can occur from the clinical site. 
 
The DMCC will use a system of coded identifiers to protect participant confidentiality and 
safety.  Each participant enrolled will be assigned a local identifier by the enrollment site.  This 
number can be a combination of the site identifier (location code) and a serial accession 
number.  Only the registering site will have access to the linkage between this number and the 
personal identifier of the subject.  When the participant is registered to participate in the study, 
using the DMCC provided web-based registration system, the system will assign a participant ID 
number.  Thus each participant will have two codes: the local one that can be used by the 
registering site to obtain personal identifiers and a second code assigned by the DMCC.  For all 
data transfers to the DMCC both numbers will be required to uniquely identify the subject.  In 
this fashion, it is possible to protect against data keying errors, digit transposition or other 
mistakes when identifying a participant for data entry since the numbers should match to 
properly identify the participant.  In this fashion, no personal identifiers would be accessible to 
the DMCC.  
8. Human Subjects 
8.1. GCP Statement 
 
This clinical trial will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and all 
applicable regulatory requirements. 
 
8.2. Benefits  
 
The potential benefits of this study are: 
 
There are no direct benefits to participating in this study. However, if there is a maximal 
beneficial dose of Cystine Binding Thiol Drugs, then physicians will be able to minimize 
potential side effects of the drugs by prescribing lower doses overall, and patients will not be 
burdened with taking extra unnecessary pills. The results of the study may help guide treatment 
of patients with cystinuria with CBTDs in the future. 


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8.3. Risks  
 
The potential risks of this study are: 
 
Performing multiple 24-hour urine collections over the course of four weeks may be 
burdensome, but it is non-invasive and should not cause any pain or discomfort. 
 
It is not anticipated that randomization to taking “no CBTD” or doses greater or less than what 
was taken outside of the study will expose subjects to any risks greater than what is already 
encountered from routine use of CBTDs.  Although it is possible that some doses in the study 
may exceed the usual dose of medication in subjects, the doses used in this study are within the 
range of recommended doses for the treatment of cystinuria, and not known to be associated with 
a higher risk of developing side effects. 
 
8.4. Recruitment  
 
 
Patients will primarily be recruited from the clinical practice of the principle investigator, Dr. 
David Goldfarb. There will be no restrictions on recruitment with regards to gender, 
socioeconomic background, educational level, or ethnicity. 
 
8.5. Written Informed Consent: 
 
Written informed consent will be obtained from each participant before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained.  The participant’s willingness to participate in the study will be 
documented in writing in a consent form, which will be signed by the participant with the date of 
that signature indicated.  The investigator will keep the original consent forms and signed copies 
will be given to the participants.  It will also be explained to the participants that they are free to 
refuse entry into the study and free to withdraw from the study at any time without prejudice to 
future treatment.  Written and/or oral information about the study in a language understandable 
by the participant will be given to all participants. 
8.6. Process of Consent:   
 
Each investigator is responsible for ensuring that informed consent is obtained from each 
participant using a current consent form according to the guidelines of its local Institutional 
Review Board (IRB) and in accordance with the Common Rule (45 CFR Part 46 subpart A 
Protection of Human Subjects). The informed consent form must be obtained and on file at the 
site responsible for informed consent (signed and dated by the participant) prior to initiation of 
any study related activity. 
 


15 
 
In all cases, an attempt will be made to obtain written informed consent in-person. In extenuating 
circumstances, informed consent may be obtained via a combination of the phone and mail. In 
these circumstances, the investigator will discuss the study in detail with the potential subject 
either in person or on the phone. After the discussion, the potential subject will be mailed a copy 
of the consent for review. The study investigator will then perform the informed consent process 
via telephone with the potential subject. If the subject desires to participate in the study, they will 
sign and date the consent form and send it back to the study investigator, who will then sign and 
date the document as well. In this situation, the requirement for a witness signature is waived. 
The investigator will send a copy of the signed form back to the subject and retain the original in 
the study records. The investigator will be sure to also properly document the entire process, 
including phone conversation, in the study records.  
 
Since the study also requires a review of the most recent blood work and medical record 
information to confirm eligibility, the study team will make attempts to have this information 
sent to them from the treating physician for all remotely consented subjects. In regards to the one 
month post-procedure visit that includes a blood test and urine test, subjects consented remotely 
will have the option to come into the study office for these tests or offered the ability to have the 
tests performed locally with the results being forwarded to the study investigators. In either case, 
there will be no additional costs to the subject. 
 
The Informed Consent form must provide the following information to each participant: 
• A statement that the study involves research, and explanation of the purposes of the 
research and expected duration of the participant’s involvement. 
• A description of any benefits to the participants or to others which may reasonably be 
expected from the research. 
• A description of any foreseeable risks or discomforts to the subject. 
• A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the subject. 
• A statement describing the extent, if any, to which confidentiality of records identifying 
the participant will be maintained. 
• An explanation of whom to contact for answers to pertinent questions about the research 
and research subjects’ rights. 
• A statement that participation is voluntary, refusal to participate will involve no penalty 
or loss of benefits to which the participant is otherwise entitled and the participant may 
discontinue participation at any time without penalty. 
• Written and/or oral information about the study in a language understandable by the 
participant will be given to all participants. 
 
8.7. Certificate of Confidentiality  
 
To help protect participant privacy, a Letter of Confidentiality has been obtained from the 
National Institutes of Health (NIH).  With this Certificate, the researchers cannot be forced to 
disclose information that may identify a study participant, even by a court subpoena, in any 


16 
 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings.  The 
researchers will use the Certificate to resist any demands for information that would identify a 
participant, except as explained below. 
 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of Federally funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). 
 
Even with the Certificate of Confidentiality, the investigators continue to have ethical and legal 
obligations to report child abuse or neglect and to prevent an individual from carrying out any 
threats to do serious harm to themselves or others.  If keeping information private would 
immediately put the study participant or someone else in danger, the investigators would release 
information to protect the participant or another person. 
 
Department of Health and Human Services (DHHS) personnel may request identifying 
information for purposes of performing audits, carrying out investigations of DHHS grant 
recipients, or evaluating DHHS funded research projects. 
 
 
 


17 
 
9. References 
1. Dolin DJ, et al. Effect of Cystine-Binding Thiol Drugs on Urinary Cystine Capacity in Patients 
with Cystinuria. J Endourol 2005; 19: 429-432. 
2. Chillaron J, Font-Llitjos M, Fort J, Zorzano A, Goldfarb D, Nunes V, Palacin M. 
Pathophysiology and Treatment of Cystinuria. Nat Rev Nephrol 2010; 6: 424-434. 
3. Goldfarb D, Coe F, Asplin J. Urinary Cystine Excretion and Capacity in Patients with Cystinuria. 
Kidney Int 2006; 69: 1041-1047. 
4. Nakagawa Y, Aspin J, Goldfarb D, Parks J, Coe F. Clinical Use of Cystine Supersaturation 
Measurements. The J Urol 2000; 164: 1481-1485. 
5. Coe F, Clark C, Parks J, Asplin J. Solid Phase Assay of Urine Cystine Supersaturation in the 
Presence of Cystine Binding Drugs. J Urol 2001; 166: 688-693. 
10. Appendices