Conditions: Cystinuria
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the minimum effective dose of the cysteine binding thiol drug (CBTD) Tiopronin on urine cystine capacity, which is a measure of cystine solubility in the urine, in patients with cystinuria 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.

Cystinuria is a rare genetic disease that can lead to significant morbidity in affected patients due to the recurrent nature of the disease. This study will follow the levels of urine cystine capacity in order to help guide treatment and to use lower than usually prescribed Tiopronin doses to decrease the potential side effects while maintaining therapeutic benefit. This will increase adherence with the medications by decreasing the burden of the large number of pills that need to be taken daily.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Tiopronin
Intervention descriptions: intervention 1: Phase 1: No medication, Phase 2: 500mg PO daily x 7 days (total 500mg), Phase 3: 500mg PO BID x 7 days (total 1g), Phase 4: 1g PO BID x 7 days (total 2g)

Protocol document:
Prot_SAP_000.pdf: 
 
1
RDCRN Protocol #6421 
Tiopronin on Cystine Capacity Version Date: 15May2019 
 
 
 
 
 
 
Rare Diseases Clinical Research Network 
(RDCRN) 
 
Effect of Increasing Doses of Tiopronin on Cystine Capacity in Patients with 
Cystinuria 
 
 
Rare Kidney Stone Consortium 
 
 
 
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
Effect of Increasing Doses of Tiopronin on Cystine Capacity in Patients with 
Cystinuria 
 
1. Synopsis 
Protocol Number: 
6421 
Protocol Title: 
Effect of Increasing Doses of Tiopronin on Cystine 
Capacity in Patients with Cystinuria 
Study Chair: 
Dr. David Goldfarb 
Statistician: 
Frank Modersitzki 
Consortium: 
Rare Kidney Stone Consortium 
Participating Sites: 
New York University Langone Health, New York, NY 
Activation Date: 
09/10/2018 
Sample Size: 
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: 
Eligibility: Patients between ages 18-80 with confirmed 
diagnosis of cystinuria with a medical regimen that includes 
Tiopronin who are willing to complete a 24h urine 
collection and food diary. Female patients at childbearing 
age who are willing to use a contraception method.  
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  
Agent- 
Tiopronin 
Dosage, schedule, route of 
administration- 
500mg PO daily x 7 days, then 500 mg PO BID x 7 days, 
then 1g 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): 
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. 


 
3
Sponsors (federal, state, 
foundation and industry 
support): 
National Institutes of Health (NIH), NIDDK, ORDR 
1.1 Overview: 
 
The purpose of this study is to determine the minimum effective dose of the cysteine binding 
thiol drug (CBTD) Tiopronin on urine cystine capacity, which is a measure of cystine solubility 
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 CBTDs, which help increase the solubility of cystine in 
the urine.1 At present, the dosing of Tiopronin is empiric, and the drug not titrated to a specific 
measured effect. We propose to follow the level of urine cystine capacity in order to help guide 
treatment and to use lower than usually prescribed Tiopronin doses to decrease the potential side 
effects while keeping the same therapeutic benefit. This will increase adherence with the 
medications by decreasing the burden of the large number of pills that need to be taken daily.  
 
 
2 Specific Aims (Hypothesis and Objectives) 
 
Our primary objective is to compare the effect of different Tiopronin doses on urinary cystine 
capacity (CysCap). A positive urinary cystine capacity reflects the ability of the urine to take up 
more cystine and therefore decrease the risk of stone formation. In a previous study, we 
demonstrated that Tiopronin improves cystine capacity and that the change in cystine capacity 
was minimal with doses above 1g. 
We propose comparing the effects of lower doses of Tiopronin on cystine capacity. 
 
 
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: ornithine, arginine, and lysine. 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. The assays cannot reliably 
distinguish between the thiol groups of cystine and the thiol groups of CBTDs either free or 
bound to cysteine.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, 


 
4
or positive cystine capacity) or give it up to the solid phase (supersaturation, or negative cystine 
capacity).3 In contrast to previous assays, the CysCap assay accurately measures cystine 
solubility in the presence of CBTDs.5  
Current treatment strategies to prevent stone formation in patients with cystinuria include 
increasing fluid intake, alkalinizing urine with alkali therapy, and CBTDs such as Tiopronin 
(Thiola), D-penicillamine, and Captopril. These medications have sulfhydryl groups that can 
reduce the disulfide bond in the dimer cystine and produce mixed disulfides with the monomer 
cysteine that are more soluble than the homodimer itself. 
 
Our study by Dolin, et al, showed that CBTDs significantly increased the cystine capacity of 
urine compared to the control period without CBTDs.1 We tested the effect of different doses of 
CBTDs used in clinical practice (1g, 2g, 3g) on cystine capacity in a previous study and 
concluded that there was no change in cystine capacity with doses above 1g. The higher doses 
were well tolerated but had little efficacy in changing CysCap. We also retrospectively realized 
that measuring Tiopronin in the urine would have been useful; in the current study, we will 
collect urine for that purpose.  
 
We propose testing the minimum effective dose of Tiopronin by comparing doses lower than 2g. 
Reducing Tiopronin doses will ultimately minimize unnecessary side effects while keeping the 
same benefit. 
 
 
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. As in our recently completed study, 
we plan to enroll 5-10 patients in the study and perform a crossover trial in which patients 
receive escalating dosages of CBTDs.  
 
Patients will be recruited from the clinical practice of the principle investigator at routine clinic 
visits at the Kidney Stone Prevention Clinic at NYU Langone Health. After completing informed 
consent, the patient will have an initial 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. Each part will be divided into a 7-day period in which 
patients will be taking different dosage of Tiopronin and will have a urine collection at the end of 
each period. Patients will stop taking their medications for one week in the first part. The dosage 
of Tiopronin in the following parts will be as follow: 500 mg for the second part, 1g for the third 
part and 2g for the third part. Unlike the previous study, there will not be a 3g dosage week. 
 


 
5
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 Tiopronin. With the exception of Tiopronin, the patients will continue all of 
their regular medications including alkali therapy.  
 
Patients will continue 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 Corporation (Chicago, IL), for analysis. Another specimen will be mailed to Mayo 
Clinic for liquid chromatography mass spectrometry (LC/MS) testing.  
 
The urine pH, sodium, urea, and creatinine will be measured by Litholink. 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 assay3. Measured amounts 
of cystine crystals will be incubated in the urine at 37°C 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 primary outcome of the study is to determine the effect of drug dosage on urinary cystine 
capacity. Thus, the mean cystine capacities in each part of the study (0 g/d, 500 mg/d, 1 g/d, and 
2 g/d) will be compared. Urine urea, a surrogate of protein intake and urine sodium will be 
measure and compared to ensure diets are replicated correctly throughout the study period. Urine 
pH will be also 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) and urine test 
(urinalysis) within one month of completing the study to monitor for any potential adverse 
effects of changing the dosages of medication. In our previous study of doses up to 3g no adverse 
effects were anticipated and none occurred. The laboratory tests may either be performed at an 
outside lab at the patient’s convenience, or in a routine office visit at the Kidney Stone 
Prevention Clinic at NYU Langone Health. If laboratory tests are performed at an outside 
laboratory, subjects will be asked to send the results to Dr. Goldfarb for review.  
 


 
6
As in the previous study, subjects will be reimbursed for any additional medication costs that 
they incur as a result of participating in the study. They will be compensated for the amount of 
$25 per week, a total of $100 only if they completed all 4 stages of the study. Litholink and 
Mayo Clinic testing will be performed at no cost to the patients and their insurance will not be 
billed.  
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 Tiopronin. 
- Female patients who are willing to use a birth control method. 
-  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 Rare Kidney Stone Consortium (RKSC) Protocol 6401 (Cystinuria Registry)  
 
4.1 Exclusion Criteria: 
 
- Pregnant patients.  
-  Patients with renal colic  
-  Patients who are scheduled to undergo a surgical procedure  
-  Inability to give informed consent  
 
4.2 Recruitment of Participants: 
 
Patients from Dr Goldfarb’s clinic and those who are enrolled in the RKSC protocol 6401 
(Cystinuria Registry) will be contacted either by phone, mail, or email and recruited.  
 
4.3 Retention Strategies: 
 
Due to the short duration of the study (4 weeks), we do not anticipate the need for extensive 
retention strategies. Patients will be called periodically at least once a week during the 4-week 
study period to answer any questions they may have, and to ask about any adverse effects they 
may be experiencing.  
 
 
 
 
 
 
 
 
 


 
7
 
 
 
4.4 Schedule of Events: 
 
 
 
 
 
 
5 Data and Safety Monitoring Plan  
 
The study protocol will be reviewed and approved by the National Institutes of Diabetes and  
Digestive and Kidney Diseases (NIDDK) before submission to NYU Langone Health IRB 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  Safety Monitoring Board (DSMB) has oversight responsibility of the Data Safety 
Monitoring Plan (DSMP) for this clinical trial. The DSMB 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 DSMB. 
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. The research 
Pregnancy Test                                       X 


 
8
team will then evaluate whether the protocol or informed consent document requires revision 
based on the reports.  
 
5.2 Adverse Event 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: 
 
The period off Tiopronin 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 Tiopronin is extremely unlikely to lead to cystine stone formation. That is particularly 
true since dosing of Tiopronin 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. In the previous study, no episodes of renal colic occurred during the 
week off Tiopronin.  
 
Tiopronin is associated with allergy and other side effects, most of which are considered 
idiosyncratic and not clearly dose-related. Patients will take 0.5-2g, which is less likely to exceed 
their usual doses. The duration at each dose is a week. 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.  
 
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.  
 
5.4 Reporting Timeline:  


 
9
 
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.  
 
5.6 Unanticipated Problem Reporting 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to subjects or others to include, in general, any incident, experience, or outcome that meets 
all of the following criteria: 
 unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 


 
10 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
 related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
 suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
Per the definition, only a subset of adverse events would be characterized as unanticipated 
problems. There are other types of incidents, experiences, and outcomes that are not considered 
adverse events, but are characterized as unanticipated problems (e.g., breach of confidentiality or 
other incidents involving social or economic harm). 
Incidents or events that meet the OHRP criteria for unanticipated problems are to be reported to 
the IRB, per local institutional reporting requirements. 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. 
 
5.7 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. 
 
5.8 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).  


 
11 
 
 
 
5.9 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.  
 
6421 Sample Size 
The primary endpoint is defined as a mean change in Cystine Capacity (CysCap). In a previous 
study, we saw the highest change in CysCap between dose 0mg/d vs. dose 1mg/d. With this 
large effect size, we would need 9 participants (P=0.05, power 85%) in this protocol. We plan to 
enroll 15 participants in this protocol. This should account for potential patient withdrawal or 
other unforeseen protocol issues.  
 
Statistical Considerations 
Standard descriptive, repeated-measure ANOVA (Friedman test), and GLS regression will be 
applied. 
 
 
 
7 Data Management 
 
Collection of all study data will comply with all applicable guidelines regarding patient 
confidentiality and data integrity. 
 
 7.1 Registration: 
 
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.  
  
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 


 
12 
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 accessionnumber. 
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 Subject 
 
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 Tiopronin in the future.  
 
8.3. Risks: 
  
The potential risks of this study are:  
 
CBTDs are associated with allergy and other side effects including fever, central nervous system 
depression, anorexia, nausea, vomiting, loss of taste, abdominal pain, and myalgia. More serious 
adverse effects include nephrotic syndrome, hypersensitivity reactions, transient blood 
dyscrasias, aplastic anemia, neutrophilic agranulocytosis, neutropenia, thrombocytopenia, 
bronchiolitis obliterans, rashes, dystonia and various autoimmune responses (polymyositis, 
myasthenia gravis, SLE, Goodpasture’s syndrome, thyroiditis). Although the side effects are 
considered idiosyncratic and not clearly dose related, there is a risk that a patient could develop a 


 
13 
new side effect at a drug dose that is higher than their usual dose. Since all patients are already 
taking the drugs for inclusion and demonstrated good tolerance, it is very unlikely that a patient 
will develop a significant new allergy.   
 
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.  
 
8.4. Recruitment: 
  
Patients who are enrolled in the RKSC protocol 6401 (Cystinuria Registry) as well as patients 
from Dr Goldfarb’s clinic will be recruited. They will be contacted by phone, mail or email or 
during their regular clinic visits. 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:  
 
The investigator is responsible for ensuring that informed consent is obtained from each 
participant using a current consent form according to the guidelines of NYU Langone Health 
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 (signed and dated by the participant) prior to initiation of any study related activity. In all 
cases, an attempt will be made to obtain written informed consent in-person. In extenuating 
circumstances, informed consent may be obtained over the phone or through the mail. In these 
circumstances, the investigator will discuss the study in detail with the subject either in person or 
on the phone. After the discussion, the subject will be mailed a copy of the consent to review and 
may sign and return the consent to the investigator via the mail. The investigator will then co-
sign the consent and return a copy of the signed consent 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.  


 
14 
- 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  
 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify the participant in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding, or be used as evidence, for 
example, if there is a court subpoena, unless the participant has consented for this use. 
Information, documents, or biospecimens protected by this Certificate cannot be disclosed to 
anyone else who is not connected with the research except, if there is a federal, state, or local law 
that requires disclosure (such as to report child abuse or communicable diseases but not for 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, see 
below); if the participant consents to the disclosure, including for their medical treatment; or if it 
is used for other scientific research, as allowed by federal regulations protecting research 
participants.  
 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the U.S. Department of Health and Human Services and/or the National 
Institutes of Health, which is funding this project or for information that must be disclosed in 
order to meet the requirements of the Federal Food and Drug Administration (FDA).  The 
Certificate of Confidentiality does not prevent a participant from voluntarily releasing 
information about themselves or their involvement in this research. If a participant wants 
research information released to an insurer, medical care provider, or any other person not 
connected with the research, the participant must provide consent to allow the researchers to 
release it. 
 
Even with the Certificate of Confidentiality, the investigators continue to have ethical 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.  The Certificate of Confidentiality will also not be used 


 
15 
to prevent disclosure as required by federal, state, or local law, such as reports of child abuse and 
neglect, or harm to self or others.  
 
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 
 
NYU Informed Consent Form