The Effect of Lipoic Acid Natural Supplement on Cystine Stone Formation
Phase: PHASE2
Conditions: Cystinuria
Sponsor: Thomas Chi, MD

 
 
 
 
The effect of lipoic acid natural supplement on 
cystine stone formation 
NCT#:NCT02910531 
Version date: 26JUL2017 

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THOMAS CHI, MD
Clinical Research Protocol
The effect of lipoic acid natural supplement on cystine stone formation
Protocol Number:
16-20523
Version Date:
JUL 26 2017
Investigational Product:
Alpha Lipoic Acid
IND Number:
Development Phase:
Phase 2
Sponsor:
Thomas Chi, MD 
Department of Urology
University of California, San Francisco 
400 Parnassus Ave, 6th floor A632
San Francisco, CA 94143
Funding Organization:
Food and Drug Administration (FDA)
Principal Investigator:
Name: Thomas Chi, MD 
Telephone:
415-206-2934
Fax:
415-476-8849
E-mail:
Tom.Chi@ucsf.edu
Medical Monitor:
Name: Thomas Chi, MD 
Telephone:
415-206-2934
Fax:
415-476-8849
E-mail:
Tom.Chi@ucsf.edu
Coordinating Center:
Single center
Approval:
Thomas Chi, MD
Assistant Professor of Urology, UCSF
July 26th, 2017 
Date

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This confidential information about an investigational product is provided for the 
exclusive use of investigators of this product and is subject to recall at any time. The 
information in this document may not be disclosed unless federal or state law or 
regulations require such disclosure. Subject to the foregoing, this information may 
be disclosed only to those persons involved in the study who have a need to know, 
with the obligation not to further disseminate this information.

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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision and 
providing the FDA with complete and timely information, as outlined in the protocol. It is 
understood that all information pertaining to the study will be held strictly confidential and 
that this confidentiality requirement applies to all study staff at this site. Furthermore,       
on behalf of the study staff and myself, I agree to maintain the procedures required to carry 
out the study in accordance with accepted GCP principles and to abide by the terms          
of this protocol.
Protocol Number: 16-20523
Protocol Title: The effect of lipoic acid natural supplement on cystine stone formation 
Protocol Date: AUG 24 2016
July 26, 2017
Investigator Signature
Date
Thomas Chi, MD
Assistant Professor of Urology 
University of California, San Francisco
400 Parnassus Avenue, Suite A610 Box 0330 
San Francisco, CA 94143
Print Name and Title
Site #
Single center
Site Name
Department of Urology, University of California, San Francisco
Address
400 Parnassus Ave, 6th floor A632
San Francisco, CA 94143
Phone Number
415-476-0331

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TABLE OF CONTENT
1 BACKGROUND........................................................................................................10
2 STUDY RATIONALE...............................................................................................10
2.1
Risk / Benefit Assessment..................................................................................11
3 STUDY OBJECTIVES .............................................................................................12
3.1
Primary Objective...............................................................................................12
3.2
Secondary Objectives .........................................................................................12
4 STUDY DESIGN........................................................................................................12
4.1
Study Overview ..................................................................................................12
5 CRITERIA FOR EVALUATION............................................................................14
5.1
Primary Efficacy Endpoint .................................................................................14
5.2
Safety Evaluations ..............................................................................................14
6 PARTICIPANT SELECTION.................................................................................14
6.1
Study Population.................................................................................................14
6.2
Inclusion Criteria ................................................................................................15
6.3
Exclusion Criteria ...............................................................................................15
7 CONCURRENT MEDICATIONS ..........................................................................15
7.1
Allowed...............................................................................................................15
7.2
Prohibited............................................................................................................15
8 STUDY TREATMENTS...........................................................................................15
8.1
Method of Assigning Participants to Treatment Groups....................................15
8.2
Blinding ..............................................................................................................15
8.3
Test and Control Formulation.............................................................................16
8.4
Supply of Study Medication at the Site..............................................................17
8.5
Study Medication Accountability.......................................................................18
8.6
Measures of Treatment Compliance...................................................................18
9 STUDY PROCEDURES AND GUIDELINES.......................................................18
9.1
Clinical Assessments ..........................................................................................18
9.2
Clinical Laboratory Measurements (include sections as appropriate) ...............19
9.3
Pharmacokinetic Measurements.........................................................................19
9.4
Research Laboratory Measurements (include sections as appropriate) .............19
10 EVALUATIONS BY VISIT...................................................................................20
10.1 Visit 1 (Initial Visit) ...........................................................................................20
10.2 Visit 2-9 (4, 8, 12, 16, 20, 24, 28, 32 months)...................................................21
10.3 Visit 3 (36 months).............................................................................................21
10.4 Visits 11-16 (40, 44, 48, 52, 56, 60 months)......................................................22
10.5 Early Withdrawal Visit.......................................................................................22

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11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION .............23
11.1 Adverse Events ...................................................................................................23
11.2 Serious Adverse Experiences (SAE).................................................................24
11.3 Medical Monitoring ............................................................................................25
12 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS...............25
12.1 Early Discontinuation of Study Drugs................................................................25
12.2 Withdrawal of Participants .................................................................................25
12.3 Replacement of Participants ...............................................................................25
13 PROTOCOL VIOLATIONS....................................................................................24
14 DATA SAFETY MONITORING (OPTIONAL SECTION .................................24
15 STATISTICAL METHODS AND CONSIDERATIONS .....................................27
15.1 Data Sets Analyzed.............................................................................................27
15.2 Demographic and Baseline Characteristics.........................................................27
15.3 Analysis of Primary Endpoint.............................................................................28
15.4 Analysis of Secondary Endpoints.......................................................................28
15.5 Interim Analysis..................................................................................................28
15.6 Sample Size and Randomization.........................................................................28
16 DATA COLLECTION, RETENTION AND MONITORING.............................28
16.1 Data Collection Instruments..............................................................................28
16.2 Data Management Procedures ............................................................................28
16.3 Data Quality Control and Reporting...................................................................29
16.4 Archival of Data..................................................................................................29
16.5 Availability and Retention of Investigational Records.......................................29
16.6 Monitoring.................................................................................................................29
16.7 Participant Confidentiality ..................................................................................30
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS       30
17.1 Protocol Amendments.........................................................................................30
17.2 Institutional Review Boards and Independent Ethics Committees ....................30
17.3 Informed Consent Form......................................................................................31
17.4 Publications ...............................................................................................................31
17.5 Investigator Responsibilities...............................................................................31
Appendix 1: Schedule of Study Visits………………………………………………...33 
Appendix 2: Package insert of alpha lipoic acid……………………………………..34 
References…………………………………………………………………………….  35

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LIST OF ABBREVIATIONS
AE
adverse event
ALA 
BUN 
CBC
alpha lipoic acid 
blood urea nitrogen 
complete blood count
CFR
Code of Federal Regulations
CRF 
CT 
DSMB 
EDC
case report form 
computed tomography
Data Safety Monitoring Board 
electronic data capture
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB 
KUB
institutional review board kidney 
ureter bladder radiograph
MG
milligrams
PI
QoL
principal investigator 
quality of life
SAE
serious adverse experience

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PROTOCOL SYNOPSIS
TITLE
The effect of lipoic acid natural supplement on cystine stone 
formation
SPONSOR
Thomas Chi, MD
FUNDING 
ORGANIZATION
FDA
NUMBER OF SITES
1 site
RATIONALE
Cystinuria is an inherited autosomal recessive disorder of the kidney 
that is the result of an inability to reabsorb cystine from the urine.
Supersaturation of cystine in the urine produces crystals that 
precipitate and form stones in the kidney, which can be a cause of 
obstruction, infection, and chronic kidney disease. Cystine stones 
constitute a major health challenge for affected individuals with 
cystinuria because of the frequent recurrence of painful symptoms 
and the current absence of effective, patient-accepting treatment.
The naturally occurring oral supplement alpha lipoic acid (ALA) has 
been shown in a mouse model of cystinuria to dramatically slow   
the initiation of cystine stone formation as well as the growth of 
existing stones. To date, there have been no published studies on the 
effect of ALA in individuals with cystinuria.
STUDY DESIGN
This study will be a single center, randomized double-blind placebo- 
controlled trial designed to assess how daily 1200 mg ALA 
supplementation for three years affects kidney stone recurrence, 
quantitative urinary cystine, and stone, blood and urinary 
metabolomic and metallomic profiles.
PRIMARY 
OBJECTIVE
Determine the effect of ALA on kidney stone recurrence in participants 
with cystinuria.
SECONDARY 
OBJECTIVES
Determine the effect of ALA on quantitative urinary cystine, and 
metallomic and metabolomics profiles in participants with cystinuria.
NUMBER OF 
PARTICIPANTS
50
PARTICIPANT 
SELECTION
CRITERIA
Inclusion criteria: males and females age 18 or older; documented 
cystinuria on prior 24-hour urine collection and/or stone analysis; 
history of previous cystine kidney stones; and being able and willing to 
provide consent.
Exclusion criteria: poorly controlled diabetes mellitus (hemoglobin A1C
> 8.0% for more than 1 year); current ALA administration at the time of 
screening; ALA administration within the last year prior to screening; 
vulnerable populations including incarceration status; anticipation of

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pregnancy during the study duration; unable to give informed consent; 
non-English primary language; pregnancy, lactation, or child- bearing 
age without birth control devices; and serious illness likely to cause 
death within the next 5 years.
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
The test product is 600 mg of ALA administered orally twice a day 
for three years.
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION
The control product is a sucrose tablet containing 10 mg of sucrose, 
given orally twice a day for three years.
DURATION OF 
PARTICIPATION 
AND DURATION OF 
STUDY
Screening:
1 week to determine eligibility 
Treatment:  3 years with visits every 4 months 
Follow-up:
2 years with visits every 4 months

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CONCOMMITANT 
MEDICATIONS
Allowed: The participants will be allowed to continue any 
medications they are currently taking. 
Prohibited:  No medications will be strictly prohibited.  However, 
alpha-mercaptopropionylglycione and D-penicillamine, two medications 
currently used to treat cystinuria, are both thought to bind the sulfhydryl 
groups of cysteine preventing the molecules from binding together and 
resulting in the insoluble cystine molecule. Both medications are not 
used with great frequency and both are not very effective.  As they may 
interfere with the mechanism of action of ALA, participants of this study 
who take alpha- mercaptopropionylglycione and/or D-penicillamine will 
be asked to stop these medications 12 weeks prior to starting the treatment 
portion of the study as a washout period to ensure no harmful effects 
result from stopping these therapies.  If they chose not to stop, at the 
discretion of the Principal Investigator, the participant will be allowed 
to participate and the study will simply document the use of Thiola 
throughout the course of the study and may look at these participants 
separately in the final analysis. 
EFFICACY 
EVALUATIONS
Efficacy evaluations will include determination of stone recurrences 
on clinical history, exam, and radiographic review; quantitative 24- 
hour urinary cystine; and urinary, blood, and stone metallomic and 
metabolomic profiling.
PRIMARY ENDPOINT
The primary efficacy endpoint will be assessed in two ways over the 
course of the 3-year treatment period:
1) symptomatic stone recurrences, defined as renal colic, stone 
passage, or surgical removal of a stone;
2) silent stone recurrences, classified as stone growth or new stones,

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diagnosed on the basis of renal ultrasound, plain KUB x-ray, or if 
clinically indicated, computed tomography.
SAFETY 
EVALUATIONS
After participants are enrolled at 3-4 weeks during the treatment 
period, a study coordinator will contact each participant to check 
compliance, tolerability, and side effects with ALA 
supplementation. Any concern for a potential adverse event will 
be reviewed by the study investigators. Patient clinical care will 
continue as per the current standard for the duration of this study. 
Tolerability and side effects will be reviewed at each scheduled 
clinic visit which normally occur every four months. All reported 
adverse events will be reviewed by the study investigators.
Depending on the severity of the adverse event, the study 
investigator may determine the need for un-blinding, and the 
participant may be advised to stop ALA intake if it is determined 
that ALA is the cause.
PLANNED INTERIM 
ANALYSES
When 50% of target participants have been enrolled and on the 
study protocol for 6 months, an interim analysis will be 
performed by an un-blinded statistician to evaluate for ALA 
clinical effects.
STATISTICS
Primary Analysis Plan
The analysis will be performed on the intention-to-treat principle in 
the treatment and placebo groups. The primary efficacy endpoint will 
be assessed by comparing the rates of symptomatic and silent stone 
recurrences using the t-test with a two-sided p-values and calculated 
95% confidence intervals. In addition, the analysis of secondary 
endpoints will compare quantitative urinary cystine, and metallomic 
and metabolomics profiles using repeated measures of analysis of 
variance.
Rationale for Number 
of Participants
The target enrollment for this study is 50 participants, based on a 
conservative approach to determine the sample size needed to evaluate 
the effect of ALA supplementation. Two recent studies evaluating the 
medical management of cystinuric individuals have reported that 
among individuals who are compliant in taking medications, the 
average number of stone events per person is approximately 1 per year 
(Reference #'s 5, 9). The current study design will be powered at 90% 
to detect a clinically meaningful reduction of stone events at 50% (0.5 
stone events per year) with two-tailed alpha = 0.05. Based on a two- 
sided t-test, the following scenarios were considered for the standard 
deviation (SD) for the sample and sample size (n): SD 0.5, n=11; SD 
0.75, n=24; SD 1, n=42. To account for a small dropout rate over the 
study duration, the enrollment goal of 50 participants was proposed.

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1
BACKGROUND
Cystinuria is an inherited autosomal recessive disorder of the kidney that is the result of  
a defect in the dibasic amino acid transporter in the apical membrane of the renal 
proximal tubule and small intestine. The disease causes hyperexcretion of cystine, lysine, 
arginine, and ornithine into the urine. Of these amino acids, only cystine is              
poorly soluble in urine. Supersaturation of cystine in the urine produces crystals that 
precipitate and form calculi, which can be a cause of obstruction, infection, and chronic 
kidney disease.1  Cystine stone disease has an estimated prevalence of up to 1 in 1,000 in 
some parts of Europe and 1 in 17,000 in the United States,2 and comprises up to 2% of  
all kidney stone disease overall and up to 10% of stone disease in children.3  As it is a 
rare disease, pharmaceutical treatments for cystinuria are considered “orphan drugs” 
based on the U.S. Orphan Drug Act of 1983, which was passed to encourage 
pharmaceutical companies to develop treatments for diseases with a small market.4 
However, cystine stones constitute a major health challenge for affected individuals 
because of the frequent recurrence of painful symptoms and the current absence of 
effective, patient-accepting treatment.5, 6
Two primary factors known to affect the solubility of cystine include are cystine 
concentration and pH.7 Therefore, the current mainstays of therapy include aggressive 
hydration to 2.5 to 3 liters of fluid intake daily, lowering of dietary sodium intake,  
urinary alkalinization to pH >7.0, and thiol derivative medications to bind urinary  
cystine to reduce urinary cystine concentrations to less than 250 mg/l, the level above 
which cystine becomes insoluble in urine.8  Thiol derivatives in current use including D- 
penicillamine and alpha-mercaptopropionylglycione increase the solubility of cystine by 
forming more soluble mixed amino acid-disulfide products. However, these medications 
are difficult to tolerate due to their side effect profiles and, therefore, compliance              
is poor.9   Furthermore, the medications require regular monitoring of                  
complete blood count, liver enzymes, and urinary protein excretion. In our own kidney 
stone clinic population, even when compliance is high, cystinuric patients taking D- 
penicillamine and alpha-mercaptopropionylglycione often continue to form recurrent 
cystine stones. It is not surprising that because cystinuria is a lifelong disease and current 
medical management is difficult to achieve and not very effective, these individuals have 
frequent stone recurrences and a higher risk of kidney loss compared to the average 
calcium oxalate stone former.10 Therefore, additional well-tolerated and effective medical 
therapies to treat cystinuria are desperately needed.
2
STUDY RATIONALE
One potential therapeutic is the thiol-containing compound alpha-lipoic acid (thioctic 
acid, 5-(1,2-dithiolan-3- yl) pentanoic acid, ALA). ALA is an over-the-counter 
supplement and antioxidant found in nutrition supplement stores. ALA is a naturally 
occurring compound involved with mitochondrial energy metabolism as an enzymatic 
cofactor. ALA is both synthesized in the body as well as absorbed in the diet. Once 
ALA is transported into the cell, it is reduced to dihydrolipoic acid (DHLA). Both 
ALA and DHLA have direct antioxidant activity, and they can regenerate endogenous

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antioxidants including ascorbic acid and vitamin E.11 ALA can also increase 
intracellular coenzyme Q1012 and glutathione levels.13 ALA and DHLA also have 
additional biochemical effects as metal chelators, reactive oxygen species scavengers, 
and modulators of signaling transduction of several pathways.11
While the potential therapeutic effects of ALA have been studied in a number of diseases 
including, including Alzheimer’s disease, obesity, cardiovascular disease, hypertension, 
and several cancers,11 the efficacy of ALA has been best studied in type 2 diabetic 
peripheral neuropathy.14,15  Safety of long-term administration of once- daily 600mg 
ALA over 4 years was established in the NATHAN 1 trial.15  Doses up to 1200 mg daily 
have also been used and appear well tolerated.16-19  Given this history safe use in clinical 
medicine and, most importantly, based upon our positive findings of ALA effectiveness 
in a mouse model of cystinuria (described below), we propose a pilot study on the use of 
this supplement in cystinuric participants.
At present we can only hypothesize on the possible mechanism(s) of action of ALA. First, 
ALA may modulate intracellular cysteine levels through its effects on the cystine/glutamate 
exchanger and thereby increase glutathione production.20, 21   Second,                             
ALA may counteract oxidative stress by induction of nuclear factor erythroid related factor 
2 (Nrf2), which is involved in cellular cystine uptake.22 Third, ALA may directly reduce 
insoluble cystine to form a mixed-disulfide compound to increase urinary solubility of 
cystine. Fourth, ALA may reduce zinc levels in the kidney,23 which has been identified as  
a cofactor in stone formation.24, 25 No matter which mechanism(s) ultimately emerge(s) as 
the appropriate explanation, we believe that oral administration of lipoic acid will decrease 
the amount of quantitative urinary cystine and, most critically, slow the rate of stone 
formation and growth, thereby reducing the frequency of stone events in cystine stone 
formers.
In our lab, a mouse model of cystinuria lacking the Slc3a1 gene was employed to study the 
formation and growth of urinary cystine stones. Slc3a1-/- male mice develop cystine  
stones at about 2-3 months of age and accumulate stone volume at an approximate rate of 1 
mm3/day, measured by micro-computed tomography. In initial work, 1-month old Slc3a1-
/- mice were treated with ALA administered through supplementation in the diet (0.5% by 
weight). By day 45, 1 of 8 mice on the ALA-supplemented diet had developed stones, in 
contrast to 7 of 7 control mice fed a regular chow diet. In addition, 3-month old untreated 
stone-forming mice that were then fed ALA grew cystine stones at a dramatically slower 
rate (stone volume accumulation 10% of controls, n=9) over 120 days. In summary, these 
initial results show that ALA markedly slows the initiation of cystine stone formation as 
well as the growth of existing stones. Moreover, based upon body weight, feeding 
behavior and activity level ALA appears to be very well tolerated in the mouse.
To date, there have been no published studies on the effect of ALA in human stone 
formers.
2.1
Risk / Benefit Assessment
ALA is an over-the-counter supplement and naturally occurring antioxidant. Safety and 
tolerability of ALA has been demonstrated in several large randomized, placebo-controlled

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trials for the treatment of diabetic polyneuropathy. In the SYDNEY 2 trial, diabetic 
participants received once-daily oral ALA at 600mg, 1,200 mg, or 1,800 ALA over 5 
weeks. Rates of adverse events compared to placebo were higher with higher dosing but 
primarily isolated to minor gastrointestinal side effects.16 Other large, placebo-controlled 
randomized trials reported no severe adverse events at 1,200 mg daily dosing.17, 19, 26 In the 
longest prospective trial (NATHAN 1) currently published, 600mg ALA daily was 
administered in 230 diabetic participants in the treatment arm over 4 years.15 Rates of 
noncompliance (<10%) and discontinuation due to treatment tolerability (<1%) were 
similar in both groups. No statistically significant differences were seen in serious adverse 
events between the two groups. Furthermore, dose-adjustment is not necessary in 
individuals with chronic renal insufficiency, which is relevant in a population of chronic 
kidney stone formers, as it does not affect the pharmacokinetics of ALA.27 Therefore, we 
do not anticipate a significant number of adverse side effects from administration based on 
prior studies at the same dose
3
STUDY OBJECTIVES
3.1
Primary Objective
The primary objective of this study is to determine the effect of ALA on kidney stone 
recurrence in participants with cystinuria. Stone recurrence in this study will be assessed in 
two ways:
1) symptomatic stone recurrences, defined as renal colic, stone passage, or surgical 
removal of a stone.
2) silent stone recurrences classified as stone growth or new stones, diagnosed on the 
basis of renal ultrasound, plain KUB x-ray, or, if clinically indicated, computed 
tomography.
3.2
Secondary Objectives
The secondary objectives of this study are to determine the effect of ALA on quantitative 
urinary cystine, cystine solubility, and metallomic and metabolomics profiles in 
participants with cystinuria. Quantitative urinary cystine is determined by 24-hour urine 
collection. The metallomic and metabolomics profiles of urine and stone samples will be 
compared in our lab as a new set of markers to understand how ALA has an effect on the 
stone-forming process and how its efficacy can be followed during treatment.
4
STUDY DESIGN
4.1
Study Overview
This study will be a single center, randomized double-blind placebo-controlled trial 
designed to assess the effect of daily 1200 mg ALA supplementation for three years on 
kidney stone recurrence in participants with cystinuria. Participants will be computer 
sequence-randomized to receive either oral daily dosing of 1200 mg ALA or placebo. 
Participants will be allowed to continue potassium citrate treatment, the currently mainstay 
of cysturia treatment, so as to avoid inducing worsened clinical events. If participants are 
taking D-penicillamine and alpha-mercaptopropionylglycione at the time of study 
enrollment, they will be asked to stop these medications 12 weeks prior to starting the 
treatment portion of the study as a washout period to ensure no harmful effects result 

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from stopping these therapies.  If they chose not to stop, at the discretion of the 
Principal Investigator, the participant will be allowed to participate and the study will 
simply document the use of Thiola throughout the course of the study. A minority of 
cystinuric stone formers take D-penicillamine and alpha- mercaptopropionylglycione 
and our clinical experience reflects that these medications do not demonstrate a high 
efficacy for stone prevention. We therefore do not think that  stopping these drugs will 
worsen clinical stone outcomes, but to ensure this is the case, participants who are on these 
medications and choose to stop, will be observed for a 12-week washout period after stopping 
D-penicillamine and alpha-mercaptopropionylglycione and prior to starting ALA. We 
anticipate participant enrollment to last 6-8 months. The secondary objectives of this 
study are to determine the effect of ALA on quantitative urinary cystine, cystine 
solubility, and metallomic and metabolomics profiles in participants with cystinuria to 
help determine the mechanism(s) of action of ALA in cystinuric individuals. Both 
study participants and study team members will be blinded to the treatment.
Clinical data including medical history, plain KUB x-ray and renal ultrasound, routine 
blood work, and 24-hour urine collections for all participants will be collected as part 
of normal clinical care at routine clinical visit intervals, which currently occur every 4 
months. Routine clinical care for participants will not be altered in any way outside of 
administration of the supplement or placebo. Routine clinical care generally consists  
of office visits every 4 months at which time, as medically necessary as determined 
by the study investigator, an imaging study is performed (plain KUB x-ray, 
ultrasound, or CT scan if clinically indicated), a 24-hour urine collection is done to 
check quantitative urinary cystine levels, and blood is drawn to evaluate electrolyte 
levels as well as renal function. During routine visits for blood and urine tests, any 
discarded blood and urine specimens will be collected for research testing. No 
additional blood draw or urine collection will be performed for this study. From 
discarded routine specimens provided during these clinic visits, metallomic and 
metabolomics profiling will be performed for all participants using discarded samples 
material. This is comprised of mass spectrometry and elemental analysis of samples 
performed in our research lab. Quality of life measurement, as recorded by the 
Wisconsin Stone-quality of life questionnaire (Wisconsin Stone-QoL), will also be 
evaluated.
Recurrent stone events, defined by symptomatic or silent stone recurrence, is the 
primary endpoint in this study. It will be documented in this study cohort, and compared   
between treatment and placebo groups to determine treatment effect. If stones are 
removed for surgery or spontaneously passed by participants, any discarded stone 
specimens not needed for clinical care will also be subjected to metabolomic and 
metallomic analysis.
At the end of the three years of study drug treatment, all participants will undergo a 
low dose non-contrast CT scan to look for a silent change in stone size. As this is a 
pilot study, recruitment will be limited to target enrollment of 50 participants (25 for 
each treatment arm). Treatment will continue for a total of 3 years and after treatment 
completion, participants will be followed for an additional 2 years to evaluate for change in 
clinical status or adverse events resultant from ALA administration.

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5
CRITERIA FOR EVALUATION
5.1
Primary Efficacy Endpoint
The primary efficacy endpoint will be assessed in two ways over the course of the 3-year 
treatment period:
1) Symptomatic stone recurrences, defined as renal colic, stone passage, or surgical 
removal of a stone
2) Silent stone recurrences, classified as stone growth or new stones, diagnosed on 
the basis of renal ultrasound, abdominal flat-plate examinations, or if clinically indicated, 
computed tomography.
These clinical endpoints are already collected as a part of the participants’ routine clinical 
care and exist as part of their medical record. Data will simply be abstracted from clinical 
encounters.
5.2
Safety Evaluations
After participants are enrolled at 3-4 weeks during the treatment period, a study 
coordinator will contact each participant to check compliance, tolerability, and side 
effects with ALA supplementation. Any concern for a potential adverse event will be 
reviewed by the study investigators. In addition, tolerability and side effects will be 
reviewed at each scheduled, four-month clinic visit. All adverse events will be 
reviewed by the study investigators. Depending on the severity of the adverse event, 
the study investigator may determine the need for un-blinding, and the participant 
may be advised to stop ALA intake if it is determined that ALA is the cause.
In addition, during the informed consent process, all potential side effects and drug 
interactions will be discussed. Enrolled participants will be provided the email  
address of the study coordinator and a 24-hour contact phone number of a physician if 
any adverse events occur during the study period.
When 50% of participants have been in the study for 6 months, an interim analysis will 
be performed. If it is found that clinical outcomes for ALA-treated participants         
are significantly improved compared to the placebo arm, study investigators may elect 
to complete the trial early and provide all participants with ALA.
6
PARTICIPANT SELECTION
6.1
Study Population
Participants with a diagnosis of cystinuria who meet the inclusion and exclusion criteria 
will be eligible for participation in this study.

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6.2
Inclusion Criteria
Inclusion criteria will include: males and females age 18 or older; documented cystinuria on 
prior 24-hour urine collection and/or stone analysis; history of previous cystine kidney 
stones; and being able and willing to provide consent.
6.3
Exclusion Criteria
Exclusion criteria will include: poorly controlled diabetes mellitus (hemoglobin A1C > 8.0% 
for more than 1 year); current ALA administration at the time of screening; ALA 
administration within the last year prior to screening; vulnerable populations including 
incarceration status; anticipation of pregnancy during the study duration; unable to give 
informed consent; non-English primary language; pregnancy, lactation, or child- bearing 
age without birth control devices; and serious illness likely to cause death within the next 
5 years.
7
CONCURRENT MEDICATIONS
All participants should be maintained on the same medications throughout the entire study 
period with no introduction of new chronic therapies, as medically feasible.  
7.1
Allowed Medications and Treatments
No medications will be strictly prohibited.  However, alpha-mercaptopropionylglycione 
and D-penicillamine, two medications currently used to treat cystinuria, are both thought 
to bind the sulfhydryl groups of cysteine preventing the molecules from binding together 
resulting in the insoluble cystine molecule. Both medications are not used with great 
frequency and both are not very effective.  As they may interfere with the mechanism of 
action of ALA, participants of this study who take alpha- mercaptopropionylglycione 
and/or D-penicillamine will be asked to stop these medications 12 weeks prior to starting 
the treatment portion of the study as a washout period to ensure no harmful effects result 
from stopping these therapies.  If they choose not to, at the discretion of the Principal 
Investigator, the participant will be allowed to participate and the study will simply 
document the use of Thiola throughout the course of the study and may look at these 
participants separately in the final analysis. .
8
STUDY TREATMENTS
8.1
Method of Assigning Participants to Treatment Groups
Participants will be computer sequence-randomized to receive either oral daily dosing of 
1200 mg ALA or placebo.
8.2
Blinding
Both participants and study team members will be blinded to treatment arm. The following 
study procedures will be in place to ensure double-blind administration of study 
treatments:

Randomization will occur at time of first screening visit and results will be 

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provided to the UCSF Pharmacy compounding services

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
Randomization will be controlled by the UCSF Pharmacy compounding service 
who will provide treatment packages to the study coordinator who will provide 
them to the study participant. Treatment packages will contain insert materials but 
no markings that will allow participants to know which study arm they have been 
randomized to.

Access to randomized code will be strictly controlled; study investigators and 
clinical coordinators will not have access to the randomized code unless a need for 
un-blinding arises.

Packaging and labeling of test and control treatments will be identical.
The study blind will be broken on completion of the clinical study and after the study 
database has been locked. In the event of an adverse event, the study investigator may 
decide to un-blind himself to determine if ALA is the cause. In addition, when 50% of 
target participants have been enrolled and on the study protocol for 6 months, an interim 
analysis will be performed by an un-blinded statistician to evaluate for ALA clinical 
effects. At that point, if it is found that clinical outcomes for ALA-treated participants are 
significantly improved compared to the placebo arm, study investigators may elect to 
complete the trial early and provide all participants with ALA.
8.3
Formulation of Test and Control Products
8.3.1
Formulation of Test Product
The test product will be comprised of 1200mg alpha-lipoic acid formulated for oral 
administration with no identifiable markings. ALA is currently commercially available 
from a variety of manufacturers and suppliers. For our mouse experiments, we used alpha 
lipoic acid sold by GNC. In our lab, purity testing with mass spectrometry revealed that 
this ALA contained no significant additional materials outside of ALA. Since this is a 
commercially available product with tablet markings on it, we will obtain our alpha lipoic 
acid from the Wellspring Pharmacy. (https://wellspringrx.com/). Wellspring Pharmacy 
maintains strict adherence to all regulations set by the California Board of Pharmacy. The 
requested formulation of ALA for this study will be two tablets
containing 600 mg ALA. Wellspring Pharmacy will maintain control of the test product 
and provide it to the study team in packaging identical to placebo packaging.
8.3.2
Formulation of Control Product
The control product will be designed to appear identical as the test product to serve as the 
placebo. It will contain 10 mg sucrose and be obtained from Wellspring Pharmacy 
(https://wellspringrx.com). Wellspring  Pharmacy maintains strict adherence to all 
regulations set by the California Board of Pharmacy.

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8.3.3
Packaging and Labeling
Because both participants and study team members will be blinded to treatment arm, the test 
product and control products will appear identical.
Packaging: Study supplement or placebo is supplied in cartons containing 240 tablets (a 
four- month supply). The tablets will be packaged in sets of 60 enclosed within a plastic 
bottle. Four bottles will be contained in each carton.
Labeling: Each carton of study supplement or placebo will be labeled with the required FDA 
warning statement, the protocol number, a treatment number, the name of the sponsors, and 
directions for patient use and storage. Each tablet will be labeled with the study protocol 
number.
8.4
Supply of Study Drug at the Site
The Test Product and Control Product will be stored in a locked cabinet in a locked office 
at the Compounding and Research Support Pharmacy at UCSF. There will only be one 
study site. After participants are randomized, treatment packages will be provided to the 
study coordinator who will provide them to study participants. Pill counts will be 
performed during each clinical visit and extra study drugs will be discarded. During 
clinical visits, if more study treatment packages are needed, they will be requested from 
the Compounding and Research Support Pharmacy at UCSF and provided to participants.
8.4.1
Dosage/Dosage Regimen
600 mg of the ALA supplement or placebo will be taken orally twice daily for three  
years. The pharmacology of ALA is such that bioavailability should be highest three  
hours after administration. Participants will be encouraged to take the study tablet at night 
prior to bed to facilitate consistent bioavailability between participants.
8.4.2
Dispensing
The ALA supplement or placebo will be given to the participant with sufficient quantity 
for administration at home, with a 4-month supply (240 tablets) to be given at each interval 
visit. At subsequent visits, remaining pills will be counted and counts recorded to     
reflect compliance for participants.
8.4.3
Administration Instructions
The ALA supplement or placebo is to be taken orally twice daily.
8.4.4
Storage
The ALA supplement will be stored under dry conditions and at room temperature in a 
locked cabinet in a locked office within the Compounding and Research Support 
Pharmacy at UCSF.

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8.5
Study Drug Accountability
An accurate and current accounting of the dispensing and return of study drug for each 
participant will be maintained on an ongoing basis by a member of the study team. The 
number of study drug dispensed and returned by the participant will be recorded on the 
Investigational Drug Accountability Record. A member of the study team will verify 
these documents throughout the course of the study. After participants are enrolled at 3-4 
weeks, a study coordinator will contact each participant to check compliance, tolerability, 
and side effects with ALA supplementation.
8.6
Measures of Treatment Compliance
Participants will be asked to keep a diary noting the day and date they take their study 
drug and any adverse events. They will be asked to bring their participant diary to each 
study visit along with all used and unused study drug containers.
9
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the participant or participant’s legal representative. If appropriate, assent must 
also be obtained prior to conducting any study-related activities.
9.1
Clinical Assessments
9.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at 
baseline/screening initial visit and at all Study Visits (as is the current standard for clinical 
care), and at early termination when applicable. Dose, route, unit frequency of 
administration, and indication for administration and dates of medication will be captured.
9.1.2
Demographics
Demographic information (date of birth, gender, race) will be recorded at the initial visit.
9.1.3
Medical History
Relevant medical history, including history of current disease, other pertinent family and 
social history, and information regarding underlying diseases will be recorded at the initial 
visit. The determination of symptomatic stone recurrences, defined as renal colic, stone 
passage, or surgical removal of a stone will be performed.
9.1.4
Physical Examination
A complete physical examination will be performed by either the investigator or a sub 
investigator who is a physician at the initial visit. Qualified staff (MD, NP, RN, and PA) 
may complete the abbreviated physical exam at all other visits. New abnormal physical

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exam findings must be documented and will be followed by a physician or other qualified 
staff at the next scheduled visit.
9.1.5
Vital Signs
Body temperature, blood pressure, pulse and respirations will be performed every 4 
months as part of their routine normally scheduled visits.
9.1.6
Other Clinical Procedures
Imaging studies will be performed at scheduled clinic visits as medically needed 
and at the discretion of the investigator. The imaging studies may include plain 
KUB x-ray and renal ultrasound, or CT scan if medically necessary (see below). 
This information will allow determination of silent stone recurrences classified as 
stone growth or new stones compared to prior radiologic exams. All participants 
will undergo low dose non-contrast CT scans at the end of the three years of study 
drug treatment (Visit10). This non-contrast CT scan at the end of the three-year 
study period will be considered a research imaging study (not a part of routine 
clinical care) and paid for by study funding.
In addition, quality of life surveys with Wisconsin Stone-QoL will be administered 
during regularly scheduled clinic visits.
If participants collect stones that pass during the course of the study, these will also 
be collected and analyzed for composition.
All of these clinical procedures are part of the current standard of care for patients with 
cystinuria undergoing management at UCSF with the exception of the CT scan 
performed at the completion of the study. With the exception of this radiographic 
study, the current study will not alter standard clinical care for participants.
9.1.7
Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation  
to study drug will be recorded on the case report form (CRF).
9.2
Clinical Laboratory Measurements
9.2.1
Blood Chemistry Profile
Blood tests will include CBC, chemistries, BUN, and creatinine that will be collected at 
regularly scheduled clinic visits as medically needed and at the discretion of the 
investigator. During routine visits for blood tests, any discarded blood will be collected 
for research testing. No additional blood will be taken outside of their normal routine 
medical care.
9.2.2
Pregnancy Test
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per the exclusion criteria.

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9.2.3
Urinalysis
Routine urinalysis (glucose, protein, blood, nitrite, pH) and 24-hour urine collections for 
quantitative urinary cystine (Litholink, Chicago, IL) will be performed at regularly 
scheduled clinic visits as medically needed and at the discretion of the investigator. 
Urinary metabolomic and metallomic profiles will be performed on urine collected at 
regularly scheduled clinic visits. No additional urinalysis studies will be collected outside 
of their normal routine medical care.
10 EVALUATIONS BY VISIT
After enrollment into the study, during the initial visit (Visit 1), participants will undergo 
a complete medical history and physical exam by either the investigator or a sub 
investigator who is a physician. Blood and urine will be collected if medically necessary 
as determined by the study investigator to perform blood chemistry profiling, urinalysis, 
and quantitative urinary cystine, as part of routine management for cystine stone patients. 
Leftover blood and urine specimens will be collected for further analysis in this study. 
Additionally, quality of life survey with the Wisconsin Stone-QoL will be performed for 
research purposes.
As per normal clinical care, at subsequent visits, study participants will be seen every 4 
months to obtain serum labs (CBC, chemistries, BUN, creatinine) if medically necessary 
as determined by the study investigator and 24-hour urine studies (quantitative urinary 
cystine level). Routine medical management will be continued in all participants, 
which includes hydration, lowering of dietary sodium intake, and urinary 
alkalinization. 
Plain KUB x-ray with renal ultrasound will be performed on a routine basis if 
medically necessary as determined by the study investigator.CT scans will also be 
performed only if medically necessary. These imaging studies will document stone 
size, location, and any interval changes in stone burden between study visits. No 
additional visits will be scheduled outside their normal clinical care. These are part of 
routine evaluation for patients with cystinuria that has been undertaken at UCSF for 
over 20 years.
At the 36-month visit, in addition to the routine surveillance information collected as 
noted above, a low-dose non-contrast CT scan of the abdomen will be performed to 
obtain the data of silent stone recurrence which is one of the primary endpoints in this 
study.
After the 36-month treatment period, study participants will stop administration of 
ALA or placebo. They will be seen an additional 24 months at a 4-month interval to 
obtain routine studies, including serum labs, imaging (plain KUB x-ray and renal 
ultrasound), and 24-hour urine if medically necessary as determined by the study 
investigator.
10.1 Visit 1 (Initial Visit)

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1.
Review the study with the participant (participant’s legal representative) and obtain 
written informed consent and HIPAA authorization.
2.
Assign the participant a unique study ID number.

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3.
Record demographics data.
4.
Record medical history, including a history of stone disease and family history of 
stone disease, date of first diagnosis, and prior surgical interventions.
5.
Record concomitant medications.
6.
Perform a complete physical examination and record vital signs if possible
7.
Administer the Wisconsin Stone-QoL survey.
8.
Collect routine blood for clinical laboratory tests (CBCs, chemistries, BUN, 
creatinine) if medically necessary as determined by the study investigator
9.
Perform routine 24hr urine testing.
10.
Collect passed stone specimens, if presented.
11.
Collect discarded blood and urine specimens for research purposes if presented.
10.2 Visit 2-9 (every 4th month)
1.
Record any Adverse Experiences and/or Review participant diary for adverse 
experiences and dosing compliance.
2.
Concomitant medications review.
3.
Perform pill count.
4.
Perform abbreviated physical examination and record vital signs if possible
5.
Administer the Wisconsin Stone-QoL survey.
6.
Collect routine blood for clinical laboratory tests (CBCs, chemistries, BUN, 
creatinine) if medically necessary as determined by the study investigator.
7.
Perform routine 24hr urine testing.
8.
Perform routine KUB x-ray and renal ultrasound if medically necessary as determined 
by the study investigator.
9.
Perform CT scan if medically necessary as determined by the study investigator.
10.
Collect passed stone specimens, if presented.
11.
Collect discarded blood and urine specimens for research purposes if presented.
10.3 Visit 10 (month 36)
1.
Record any Adverse Experiences and/or Review participant diary for adverse 
experiences and dosing compliance.
2.
Concomitant medications review.
3.
Perform pill count.
4.
Perform abbreviated physical examination and record vital signs if possible
5.
Administer the Wisconsin Stone-QoL survey

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6.
Collect routine blood for clinical laboratory tests (CBCs, chemistries, BUN, 
creatinine) if medically necessary as determined by the study investigator
7.
Perform routine 24hr urine testing.
8.
Perform low-dose CT scan for research purposes.
9.
Collect passed stone specimens, if presented.
10.
Collect discarded blood and urine specimens for research purposes if presented
10.4 Visit 11-16 (every 4th month to 5 years mark)
1.
Record any Adverse Experiences and/or Review participant diary for adverse 
experiences.
2.
Concomitant medications review.
3.
Perform abbreviated physical examination and record vital signs if possible
4.
Administer the Wisconsin Stone-QoL survey.
5.
Collect routine blood for clinical laboratory tests (CBCs, chemistries, BUN, 
creatinine) if medically necessary as determined by the study investigator
6.
Perform routine 24hr urine testing.
7.
Perform routine KUB x-ray and renal ultrasound if medically necessary as determined 
by the study investigator
8.
Perform CT scan if medically necessary as determined by the study investigator.
9.
Collect passed stone specimens, if presented.
10.
Collect discarded blood and urine specimens for research purposes if presented.
10.5 Early Withdrawal Visit
1.
Record any Adverse Experiences and/or Review participant diary for adverse 
experiences and exclusionary medication use.
2.
Concomitant medications review.
3.
Perform pill count.
4.
Perform abbreviated physical examination and record vital signs if possible
5.
Administer the Wisconsin Stone-QoL survey.
6.
Collect routine blood for clinical laboratory tests (CBCs, chemistries, BUN, 
creatinine) if medically necessary as determined by the study investigator
7.
Perform routine 24hr urine testing.
8.
Perform routine KUB x-ray and renal ultrasound if medically necessary as determined 
by the study investigator
9.
Perform CT scan if medically necessary as determined by the study investigator.
10.
Collect passed stone specimens, if presented.
11.
Collect discarded blood and urine specimens for research purposes if presented.

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11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
11.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
participant administered a pharmaceutical product and that does not necessarily have a 
causal relationship with the treatment. An AE is therefore any unfavorable and   
unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the administration of an investigational product, whether or not 
related to that investigational product. An unexpected AE is one of a type not identified in 
nature, severity, or frequency in the current Investigator’s Brochure or of greater severity 
or frequency than expected based on the information in the Investigator’s Brochure.
The Investigator will probe, via discussion with the participant, for the occurrence of AEs 
during each participant visit and record the information in the site’s source documents.
Adverse events will be recorded in the participant CRF. Adverse events will be described 
by duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause.
AE Severity
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual. If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity. It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious.
Table 1. AE Severity Grading
Severity (Toxicity Grade)
Description
Mild (1)
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The participant may be 
aware of the sign or symptom but tolerates it reasonably well.
Moderate (2)
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required.
Severe (3)
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible.
Life-threatening (4)
The participant is at risk of death due to the adverse experience 
as it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more severe.
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2.

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Table 2. AE Relationship to Study Drug
Relationship 
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis.
Probably
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the 
participant’s clinical state or by other interventions.
Possibly
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no relationship to the 
study drug.
11.2 Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:
●
death
●
a life-threatening adverse experience
●
inpatient hospitalization or prolongation of existing hospitalization
●
a persistent or significant disability/incapacity
●
a congenital anomaly/birth defect
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the participant or require intervention to 
prevent one of the outcomes listed.
11.2.1 Serious Adverse Experience Reporting
Study sites will document all SAEs that occur (whether or not related to study drug) per  
UCSF CHR Guidelines. The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed.
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.

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11.3 Medical Monitoring
Thomas Chi, MD should be contacted directly at these numbers to report medical 
concerns or questions regarding safety.
Phone : (415) 699-0617
Pager : (415) 443-1475
12 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS
12.1 Early Discontinuation of Study Drug
A participant may be discontinued from study treatment at any time if the participant, the 
investigator, or the Sponsor/Investigator feels that it is not in the participant’s best interest 
to continue. The following is a list of possible reasons for study treatment  
discontinuation:
●
Participant withdrawal of consent (or assent)
●
Participant is not compliant with study procedures
●
Adverse event that in the opinion of the investigator would be in the best interest of 
the participant to discontinue study treatment
●
Protocol violation requiring discontinuation of study treatment
●
Lost to follow-up
●
Sponsor request for early termination of study
●
Positive pregnancy test (females)
If a participant is withdrawn from treatment due to an adverse event, the participant will 
be followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.
All participants who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible and then should be encouraged to complete all 
remaining scheduled visits and procedures.
All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for participant 
withdrawals. The reason for the participant’s withdrawal from the study will be specified 
in the participant’s source documents (Refer to Section 10) for early termination 
procedures.
12.3
Withdrawal of Participants from the Study
A participant may be withdrawn from the study at any time if the participant, the 
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All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for participant 
withdrawals. The reason for the participant’s withdrawal from the study will be specified 
in the participant’s source documents. As noted above, participants who discontinue  
study treatment early (i.e., they withdraw prior to Visit 4) should have an early 
discontinuation visit. Refer to Section 10 for early termination procedures. Participants 
who withdraw after Visit 1 but prior to Visit 4 should be encouraged to come in for a final 
visit (and the procedures to be followed would include those for their next scheduled  
visit).
12.4
Replacement of Participants
Participants who withdraw from the study treatment will not be replaced. 
Participants who withdraw from the study will not be replaced.
13 PROTOCOL VIOLATIONS
A protocol violation occurs when the participant, investigator, or FDA fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, participant safety and 
primary endpoint criteria. Protocol violations for this study include, but are not limited to, 
the following:
●
Failure to meet inclusion/exclusion criteria
●
Use of a prohibited concomitant medication
●
Failure to orally intake prescribed dosage on a daily basis
●
Intake of ALA supplement exceeds the prescribed daily dosage
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The FDA will determine if a protocol violation will result in 
withdrawal of a participant.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files.
14 DATA SAFETY MONITORING
The study investigator will work with the study team to ensure that participants’ privacy 
and information is protected. They both have access to experienced clinical trials   
offices and expertise in conducting clinical research similar to the one proposed in this 
application, ensuring that safe and ethical practices will be followed. Physical risk     
will be minimized by the study design since routine clinical care will not be altered with 
inclusion in this study. All health-system source/legacy data files will be stored at the 
UCSF local health system and will be accessed only by the programmers/analysts 
working on this study. Since confidential information will be collected from the medical 
charts, we will not directly link personal identifiers with the data collected nor will we

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use personal identifiers in any reports, materials, or presentations that emanate from this 
work. All electronic files containing personal identifiers will be stored only on the  
UCSF site file servers located behind a firewall. Information transferred to the server  
for backup purposes will be done via secure ftp. Files may be transferred to other 
computers temporarily via the Internet to facilitate central upload. In these 
circumstances, the files will be protected by encryption. The UCSF site file servers are 
only accessible by network support specialists working in secure locations. The on-site 
file server will be electronically accessible only to study investigators through user 
password protection. Access to study data is protected and participant to the same 
security protections as other confidential health system data. Computer passwords are 
changed on a regular basis. Individual identifiers such as names and medical record 
numbers will be removed from study data files in the data processing steps and will not 
be accessible to collaborators accessing the database for further study as described in 
this study application.
The participating collaborators will maintain a data link from the study data but not to the 
personal identifiers (to permit reanalysis of the data files). In addition, all investigators and 
support staff involved with collection or entry of clinical data are HIPAA certified and  
have completed and are current with regard to IRB training. Investigators and project staff 
will sign confidentiality pledges annually HIPAA training annually. Datasets shared with 
external collaborators will be stripped of any identifying information according to HIPAA 
policy.
15 STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed. The SAP will contain any 
modifications to the analysis plan described below.
15.1 Data Sets Analyzed
Data sets from all participants enrolled in the study will be analyzed.
The primary efficacy endpoint will be assessed by medical history and physical exam, in 
addition to radiographic imaging performed at each study visit.
The secondary efficacy endpoints will be assessed by 24-hour urine collections (Litholink, 
Chicago, IL), and the analysis of the metallomic and metabolomics profiles of urine and 
stone samples that are collected.
15.2 Analysis of Primary Endpoint
The primary efficacy endpoint will be assessed in two ways over the course of the 3-year 
treatment period: 1) symptomatic stone recurrences, defined as renal colic, stone passage, 
or surgical removal of a stone; and 2) silent stone recurrences classified as stone growth or 
new stones, diagnosed on the basis of renal ultrasound, plain KUB x-ray, or if clinically 
indicated, CT scan. The analysis will be performed on the intention-to-treat principle in the 
treatment and placebo groups.

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15.3 Sample Size and Randomization
The target enrollment for this study is 50 participants, based on a conservative approach to 
determine the sample size needed to evaluate the effect of ALA supplementation. Two 
recent studies evaluating the medical management of cystinuric individuals have reported 
that among individuals who are compliant in taking medications, the average number of 
stone events per person is approximately 1 per year (Reference #'s 5, 9). The current study 
design will be powered at 90% to detect a clinically meaningful reduction of stone events at 
50% (0.5 stone events per year) with two-tailed alpha = 0.05. Based on a two-sided t- test, 
the following scenarios were considered for the standard deviation (SD) for the sample   
and sample size (n): SD 0.5, n=11; SD 0.75, n=24; SD 1, n=42. To account for a         
small dropout rate over the study duration, the enrollment of 50 participants was proposed. 
At UCSF, clinical volume approximates 60 nephrolithiasis patients per week, including 
those with cystinuria. At a recent cystinuria outreach event led by Drs. Stoller and Chi at 
UCSF    (http://stollerlab.ucsf.edu/?q=news/june-18-2015-cystine-patient-symposium),   over 
50 individuals with cystinuria attended among over 100 participants overall. We anticipate 
that 6-8 months will be required to accrue these participants.
Participants will be computer sequence-randomized to receive either ALA or placebo.
16 DATA COLLECTION, RETENTION AND MONITORING
16.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each participant treated 
with the study drug.
Entry will be performed electronically by the study coordinator directly into UCSF 
REDCap, a HIPAA-compliant data management system incorporated into the UCSF 
electronic medical record system, or uploaded in an automated fashion from our electronic 
medical record into REDCap. Participants will not be identified by name in the study 
database or on any study documents to be collected by the Sponsor (or designee), but will 
be identified by a participant number.
If a correction is required for any data entry, the time and date stamps track the person 
entering or updating data and creates an electronic audit trail.
The Investigator is responsible for all information collected on participants enrolled in this 
study. All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator. A copy of the CRF will remain at the 
Investigator’s site at the completion of the study.
16.2 Data Management Procedures
The data will be entered into a REDCap database. All procedures for the handling and 
analysis of data will be conducted using good computing practices meeting FDA 
guidelines for the handling and analysis of data for clinical trials.

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16.3 Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. 
Queries are entered, tracked, and resolved through the REDCap system directly. The study 
database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented.
16.4 Archival of Data
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.
All electronic files containing personal identifiers will be stored only on the UCSF site file 
servers located behind a firewall. Information transferred to the server for backup  
purposes will be done via secure ftp. Files may be transferred to other computers 
temporarily via the Internet to facilitate central upload. In these circumstances, the files 
will be protected by encryption. The UCSF site file servers are only accessible by network 
support specialists in locked rooms. The on-site file server will be electronically accessible 
only to study investigators through user password protection. No non-electronic files   
(such as paper surveys, consent forms, pathology data, etc.) will be kept for this study. 
Databases are backed up by the database administrator in conjunction with any         
updates or changes to the database.
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures.
16.5 Availability and Retention of Investigational Records
The Investigator must make study data accessible to the authorized representatives of the 
Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon 
request. A file for each participant must be maintained that includes the signed Informed 
Consent, HIPAA Authorization and Assent Form and copies of all source documentation 
related to that participant. The Investigator must ensure the reliability and availability of 
source documents from which the information on the CRF was derived.
All study documents (participant files, signed informed consent forms, copies of CRFs, 
Study File Notebook, etc.) must be kept secured for a period of two years following 
marketing of the investigational product or for two years after centers have been notified 
that the IND has been discontinued. There may be other circumstances for which the 
Sponsor is required to maintain study records and, therefore, the Sponsor should be 
contacted prior to removing study records for any reason.
16.6 Monitoring
Monitoring will be conducted by the Sponsor according to the U.S. CFR Title 21 Parts 50, 
56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the Investigator / 
Sponsor (or designee), will allow appropriate regulatory authorities to conduct on-site 
monitoring and/or auditing of all appropriate study documentation.

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16.7 Participant Confidentiality
Clinical data for these participants will be collected in our REDCap database, which is a 
secure, online HIPAA-compliant research data collection portal.
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number only. All study records will be kept in a 
locked file cabinet and code sheets linking a participant’s name to a participant 
identification number will be stored separately in another locked file cabinet. Clinical 
information will not be released without written permission of the participant, except as 
necessary for monitoring by the FDA. The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC).
17.1 Protocol Amendments
Any amendment to the protocol will be written by the Sponsor/Investigator. Protocol 
amendments cannot be implemented without prior written IRB/IEC approval except as 
necessary to eliminate immediate safety hazards to participants. A protocol amendment 
intended to eliminate an apparent immediate hazard to participants may be implemented 
immediately, provided the IRBs are notified within five working days.
17.2 Institutional Review Boards and Independent Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC prior to 
study initiation. Serious adverse experiences regardless of causality will be reported to the 
IRB/IEC in accordance with the standard operating procedures and policies of the 
IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the 
study. The Investigator will obtain assurance of IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
participant recruitment, payment or compensation procedures, or other pertinent 
information) will be submitted to the IRB/IEC. The IRB/IECs written unconditional 
approval of the study protocol and the informed consent form will be in the possession of 
the Investigator before the study is initiated. The IRB/IECs unconditional approval 
statement will be transmitted by the Investigator to the FDA prior to the shipment of study 
supplies to the site. This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the participants or when the change(s) involves only logistical or administrative aspects of 
the study. Such modifications will be submitted to the IRB/IEC and written verification 
that the modification was submitted and subsequently approved should be obtained.

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The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the participants of the conduct of the 
study; an annual update and/or request for re-approval; and when the study has been 
completed.
17.3 Informed Consent Form
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations.
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC. The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC. The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file.
A properly executed, written, informed consent will be obtained from each participant prior 
to entering the participant into the trial. Information should be given in both oral and 
written form and s participants (or their legal representatives) must be given ample 
opportunity to inquire about details of the study. If appropriate and required by the local 
IRB/IEC, assent from the participant will also be obtained. If a participant is unable to sign 
the informed consent form (ICF) and the HIPAA authorization, a legal representative    
may sign for the participant. A copy of the signed consent form (and assent) will be given 
to the participant or legal representative of the participant and the original will be 
maintained with the participant’s records.
17.4 Publications
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor/Investigator. The publication or presentation of any study results shall 
comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996.
17.5 Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of participants.
2.
Personally conduct or supervise the study (or investigation).

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3.
Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64.
5.
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.
6.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee).
7.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.
8.
Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to participants or others (to 
include amendments and IND safety reports).
9.
Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the participants.
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.

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APPENDIX 1. SCHEDULE OF STUDY VISITS
VISIT 1
(Initial Visit)
VISITS 2-9
(Month 4-32)
VISIT 10
(Month 36)
VISITS 11-16
(Month 40-56)
Informed Consent
X
Medical History
X
X
X
X
Complete Physical Exam
X
Abbreviated Physical Exam
X
X
X
Vital Signs
X
X
X
X
Wisconsin Stone-QoL survey
X
X
X
X
Record any Adverse Experiences
X
X
X
Concomitant medications review
X
X
X
X
Pill Count
X
X
X
Collect routine blood for clinical laboratory tests 
(CBCs, chemistries, BUN, creatinine).
If medically 
indicated
If medically 
indicated
If medically 
indicated
If medically 
indicated
Perform routine 24hr urine testing
X
X
X
X
Perform routine plain KUB x-ray and renal ultrasound
If medically 
indicated
If medically 
indicated
If medically 
indicated
If medically 
indicated
Perform low-dose CT abdomen
If medically 
indicated
If medically 
indicated
X
If medically 
indicated
Collect discarded blood and urine for research 
purposes, if presented
X
X
X
X
Collect passed stone specimens, if presented
X
X
X
X

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APPENDIX 2. PACKAGE INSERT OF ALPHA LIPOIC ACID
Please see the attached document.

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Protocol Template © CFFT TDN  Effective: 12 SEP 2007
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