Conditions: Suicidal Ideation
Keywords: Suicidal Ideation Veteran Uridine Neuroimaging
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for suicidal ideation in veterans.

The investigators hypothesize that the administration of a naturally occurring dietary supplement, uridine, will rapidly reduce suicidal ideation in veterans. The purpose of this study is to determine whether 4 weeks of uridine supplementation is an effective treatment for suicidal ideation in veterans, when compared to a group taking a placebo.

Detailed description:
Veteran suicides, attempts and suicidal ideation (SI) remain an urgent concern for the Veterans Health Administration (VHA). Research indicates that approximately half of veteran suicides take place within 1 month of the decedent's final VHA encounter, with one quarter occurring within 1 week. This provides a temporal window of opportunity to intervene, and necessitates development of a rapid-acting treatment for veterans with SI. Uridine shares similar brain mechanisms and neural effects with ketamine and lithium, treatments commonly used to reduce suicidal ideation. This study will test the novel intervention uridine as a rapid-acting oral treatment for veterans with suicidal ideation. The purpose of this study is to investigate whether uridine can decrease suicidal ideation in veterans when taken daily for 4 weeks.

In addition to treatment with the investigational drug versus placebo, the study includes a translational neuroimaging component: magnetic resonance spectroscopy (1H-MRS) brain scans are performed at baseline, and then repeated following 1 week of treatment with uridine or placebo. The scans do not use radiation, and are performed on a 3 Tesla MRI system that is approved for clinical use. The scans allow researchers to measure the concentrations of several chemicals in the brain that are may be involved in suicidal ideation.

Arms:
arm 1: Subjects randomized to this study arm will receive uridine 2000 mg daily by mouth for 4 weeks arm 2: Subjects randomized to this arm of the study will receive placebo 2000 mg daily by mouth for 4 weeks.

Interventions: intervention 1: Uridine intervention 2: Placebo
Intervention descriptions: intervention 1: Uridine is the active treatment in this clinical trial. intervention 2: Pill placebo is the inactive treatment comparator in this clinical trial.

Protocol document:
Prot_SAP_000.pdf: 
 
Clinical and Imaging Biomarker Trial of Uridine  
for Veterans With Suicidal Ideation:  
Protocol and Statistical Analysis Plan 
 
12 October 2022 
 
 
NCT: 03265964 
 
 


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Uridine for Veterans with Suicidal Ideation: 
a Magnetic Resonance Spectroscopy Study 
12 October 2022 
Version 1.60 
 
Principal Investigator 
 
Douglas Kondo, MD 
VISN 19 Rocky Mountain MIRECC 
VA Salt Lake City Healthcare System 
383 Colorow Drive, Salt Lake City, UT 84108 
801-587-1549 
doug.kondo@hsc.utah.edu 
 
Co-Investigators 
 
Perry Renshaw, MD, PhD, MBA 
VISN 19 Rocky Mountain MIRECC 
VA Salt Lake City Healthcare System 
383 Colorow Drive, Salt Lake City, UT 84108 
801-587-1216 
perry.renshaw@hsc.utah.edu 
 
Deborah Yurgelun-Todd, PhD 
VISN 19 Rocky Mountain MIRECC 
VA Salt Lake City Healthcare System 
383 Colorow Drive, Salt Lake City, UT 84108 
801-587-1202 
deborah.yurgelun-todd@hsc.utah.edu 
 
Young-Hoon Sung, MD 
University of Utah Department of Psychiatry 
383 Colorow Drive, Salt Lake City, UT 84108 
801-587-1555 
yh.sung@utah.edu 
 
Xianfeng Shi, PhD 
University of Utah Department of Psychiatry 
383 Colorow Drive, Salt Lake City, UT 84108 
801-587-0345 
xianfeng.shi@hsc.utah.edu 
 
Study Coordinators 
 
Danielle Boxer, MS; Colleen Fitzgerald, BS 
University of Utah Department of Psychiatry 
383 Colorow Drive, Salt Lake City, UT 84108 
801-587-1549 
danielle.boxer@utah.edu 


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TABLE OF CONTENTS 
 
A 
INTRODUCTION .................................................................................................................................. 4 
A1 
STUDY ABSTRACT .............................................................................................................................. 4 
A2 
PRIMARY HYPOTHESES AND SPECIFIC AIMS....................................................................................... 5 
A3 
PURPOSE OF THE STUDY PROTOCOL ................................................................................................... 5 
B 
BACKGROUND ..................................................................................................................................... 5 
B1 
PRIOR LITERATURE AND STUDIES ....................................................................................................... 5 
B2 
RATIONALE FOR THE STUDY ............................................................................................................. 11 
C 
STUDY OBJECTIVES ........................................................................................................................ 19 
C1 
PRIMARY AIM 1 ................................................................................................................................ 19 
C2 
SECONDARY AIMS 2 AND 3 ............................................................................................................... 19 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ............................................................. 20 
D 
INVESTIGATIONAL AGENT URIDINE ........................................................................................ 20 
D1 
URIDINE: AN ENDOGENOUS HUMAN PYRIMIDINE NUCLEOSIDE ...................................................... 20 
D2 
URIDINE: PRECLINICAL DATA .......................................................................................................... 21 
D3 
URIDINE: CLINICAL DATA ................................................................................................................ 21 
D4 
URIDINE: DOSING RATIONALE AND RISK/BENEFIT .......................................................................... 21 
E 
STUDY DESIGN .................................................................................................................................. 21 
E1 
OVERVIEW / DESIGN SUMMARY........................................................................................................ 21 
E2 
SUBJECT SELECTION AND WITHDRAWAL .......................................................................................... 21 
2.a 
Inclusion and Exclusion Criteria ................................................................................................ 21 
Inclusion Criteria .................................................................................................................................. 22 
Exclusion Criteria ................................................................................................................................. 22 
2.b 
Ethical Considerations ................................................................................................................ 22 
2.c 
Subject Recruitment Plans and Consent Process ........................................................................ 23 
2.d 
Randomization Method and Blinding .......................................................................................... 23 
2.e 
Risks, Benefits and Alternatives .................................................................................................. 23 
2.f 
Early Withdrawal of Study Participants ...................................................................................... 25 
2.g 
When and How to Withdraw Participants ................................................................................... 25 
2.h 
Data Collection and Follow-up for Withdrawn Participants ..................................................... 25 
E3 
STUDY DRUG .................................................................................................................................... 26 
3.a 
Description .................................................................................................................................. 26 
3.b 
Treatment Regimens .................................................................................................................... 26 
3.c 
Method for Assigning Participants to Treatment Groups ........................................................... 26 
3.d 
Preparation and Administration of Study Drug .......................................................................... 26 
3.e 
Treatment Adherence Monitoring ............................................................................................... 26 
3.f 
Concomitant Treatments .............................................................................................................. 27 
3.g 
Packaging of Study Drug ............................................................................................................ 27 
3.h 
Blinding of Study Drug ................................................................................................................ 27 
3.i 
Receiving, Storage, Dispensing and Return of Study Drug ......................................................... 27 
F 
STUDY PROCEDURES ...................................................................................................................... 27 
F1 
SCREENING FOR ELIGIBILITY............................................................................................................. 27 


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F2 
STUDY PROTOCOL SCHEDULE OF VISITS ........................................................................................... 27 
F3 
BASELINE SCREENING VISIT ............................................................................................................. 28 
F4 
WEEK 0 AND WEEK 1:  NEUROIMAGING VISITS. ............................................................................... 28 
F5 
WEEKS 1, 2, 3 AND 4:  RANDOMIZED TREATMENT VISITS. ................................................................ 29 
F6 
WEEK 5:  POST-TREATMENT FOLLOW-UP SAFETY VISIT. ................................................................. 29 
F7 
NEUROIMAGING VISITS (WEEK 0 AND WEEK 1):  PROTON-1 MAGNETIC RESONANCE SPECTROSCOPY 
(1H-MRS) SCANS. ...................................................................................................................................... 29 
F8 
SAFETY AND ADVERSE EVENTS ........................................................................................................ 31 
8.a 
Safety Monitoring ........................................................................................................................ 31 
8.b 
Medical and Safety Monitoring ................................................................................................... 31 
8.c 
Definitions of Adverse Events ...................................................................................................... 32 
8.d 
Classification of Adverse Events ................................................................................................. 32 
i 
Relationship to Study Participation ............................................................................................ 32 
ii 
Severity of Adverse Events ......................................................................................................... 33 
iii Expected and Unexpected Adverse Events ................................................................................ 33 
8.e 
Data Collection Procedures for Adverse Events ......................................................................... 33 
8.f 
Reporting Procedures .................................................................................................................. 33 
8.g 
Mandatory Safety Reporting Periods .......................................................................................... 33 
F9 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT .............................................................. 34 
G 
STATISTICAL PLAN ......................................................................................................................... 36 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................................... 36 
G2 
INTERIM MONITORING AND EARLY STOPPING ................................................................................. 36 
G3 
ANALYSIS PLAN AND STATISTICAL METHODS ................................................................................. 36 
G4 
MISSING OUTCOME DATA ................................................................................................................ 38 
H 
DATA HANDLING AND RECORD KEEPING .............................................................................. 40 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................................... 40 
H2 
TRAINING ......................................................................................................................................... 40 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS ............................................................................ 40 
H4 
RECORDS RETENTION ....................................................................................................................... 40 
I 
STUDY MONITORING, AUDITING, AND INSPECTING ............................................................ 40 
I1 
STUDY MONITORING PLAN ................................................................................................................ 40 
I2 
AUDITING AND INSPECTIONS.............................................................................................................. 45 
J 
STUDY ADMINISTRATION .............................................................................................................. 46 
J1 
ORGANIZATION AND PARTICIPATING CENTERS ................................................................................. 46 
J2 
FUNDING SOURCE AND CONFLICTS OF INTEREST .............................................................................. 46 
J3 
COMMITTEES ..................................................................................................................................... 46 
J4 
PARTICIPANT STIPENDS OR PAYMENTS.............................................................................................. 46 
J5 
STUDY TIMETABLE ............................................................................................................................ 46 
K 
ATTACHMENTS ................................................................................................................................ 47 
K1 
TARGETED/PLANNED ENROLLMENT TABLE ..................................................................................... 47 
K2 
QUESTIONNAIRES, SURVEYS AND RATING SCALES .......................................................................... 47 
K3 
URIDINE INVESTIGATOR’S BROCHURE AND BIBLIOGRAPHY ............................................................ 49 
L 
PROTOCOL BIBLIOGRAPHY AND REFERENCES CITED ..................................................... 83 
 


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A Introduction 
A1 Study Abstract 
Veteran suicides, attempts and suicidal ideation (SI) remain an urgent concern for the 
Veterans Health Administration (VHA).  Research indicates that approximately half of 
veteran suicides take place within 1 month of the decedent’s final VHA encounter, with 
one quarter occurring within 1 week.  This provides a temporal window of opportunity to 
intervene, and necessitates development of a rapid-acting treatment for veterans with SI. 
 
Intravenous ketamine has become the prototypical anti-suicidal drug, having been 
shown to rapidly reduce SI in some patients.  However there are significant concerns 
regarding ketamine in both veterans, and military personnel.  These include ketamine’s 
potential for toxicity and misuse, and the brief duration of its anti-suicidal effect. 
 
The ideal anti-suicidal treatment for use within the VHA system: 
 
1) Would be administered orally, rather than requiring intravenous infusion; 
2) Would achieve “target engagement” with the same neural substrates that 
ketamine does; 
3) Would have lower risk of medical and psychiatric adverse events, particularly 
among veterans and active duty military personnel; and 
4) Would have a more durable and lasting anti-suicidal effect, as the reduction in SI 
following ketamine administration lasts an average of 3 days, according to a 
recent systematic review of the ketamine literature.1 
 
Therefore this study will test the novel intervention uridine as a rapid-acting oral 
treatment for veterans with SI.  As described below, uridine’s potential to fulfill this role 
lies in the broad overlap in the brain mechanisms and neural effects shared by uridine, 
ketamine and the anti-suicidal drug lithium.  The reason for this surprising commonality 
may lie in the fact that ketamine’s mechanism-of-action dependent on activation of de 
novo pyrimidine biosynthesis – and the fact that uridine is the endogenous, circulating 
pyrimidine in man. 
 
To initiate testing of uridine for veterans with SI, we will conduct a four-week, double-
blind, placebo-controlled clinical trial of uridine 2000 mg daily for veterans with SI.  To 
make the study more informative, translational neuroimaging has been integrated into 
the protocol, in an attempt to identify some of the brain chemistry biomarkers of SI. 


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A2 Primary Hypotheses and Specific Aims 
Specific Aim 1: To Demonstrate that Uridine Decreases Suicidal Ideation in 
Veterans:  We hypothesize that 4 weeks of uridine 2000 mg daily will decrease the 
probability and severity of suicidal ideation, compared with placebo. 
 
Specific Aim 2. To Measure Rapid Changes in Brain GABA, in Uridine-Treated 
Veterans with Suicidal Ideation:  The hypothesis is that brain GABA levels, measured 
with magnetic resonance spectroscopy, will show a greater increase after 1 week, in 
uridine-treated vs. placebo-treated veterans with suicidal ideation. 
 
Specific Aim 3. To Examine the Durability of Uridine Treatment Response, in 
Veterans with Suicidal Ideation:  The hypothesis is that treatment responders will 
demonstrate a durable clinical response over 4 weeks,** in addition to acceptable 
patient compliance, satisfaction and engagement. 
 
** A systematic literature review of ketamine as a treatment for suicidal ideation 
was recently published.1 Rather than including only data from randomized, 
placebo-controlled trials, the authors included non-controlled data, open-label 
data, and case reports. The authors reported the reduction in suicidal ideation 
associated with ketamine treatment lasts an “average of 3 days” (see Reinstatler 
and Youssef, page 38).1 Thus Specific Aim 3 covers a period of time (i.e. 28 
days) that is roughly 10 times the mean duration-of-action of ketamine.1 
A3 
Purpose of the Study Protocol 
The purpose of the study protocol is to describe the study’s scientific rationale, and the 
procedures for acquisition and analyses of human subjects data. 
B Background 
B1 Prior Literature and Studies 
Background and Prior Literature 
Embedded in the VISN 19 Rocky Mountain Mental Illness Research, Education and 
Clinical Center (MIRECC) with its mission to reduce veteran suicide, this application 
pairs the investigational drug uridine with translational brain imaging, to address a critical 
unmet need: the lack of a rapid-acting treatment for veterans with suicidal ideation (SI). 
Suicidal behavior remains a concern for the Veterans Administration (VA), yet there is no 
proven treatment and few VA studies of SI have been conducted. Thus by testing a 
novel and hypothesis-based intervention, while concurrently pursuing ‘biomarkers’ of SI 
to inform future research, this proposal addresses 2 of 3 “issues for Congress” identified 
in the 2016 Congressional Research Office report [R42340] on suicide prevention in 
VA2: “building the evidence base,” and “increasing access to evidence-based mental 
healthcare.”2 
Recent VA suicide research points to a window of opportunity for intervention. First was 
the report that 23% of veteran suicides occur within just 7 days of the decedent’s final 


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VA visit, while over half (51%) occur within 30 days.3 This was followed by the finding 
that the two key ‘warning signs’ which increase the risk of suicide death within 7 days of 
the final visit are psychosis, and documented SI (Odds Ratio 3.46).4 A rapid-acting, well-
tolerated and easily-administered SI treatment would thus provide a powerful, impactful 
tool for VA prescribers. 
Intravenous (I.V.) ketamine has become the prototypical antisuicidal drug, with a rapid 
albeit temporary effect lasting 10 days or less.5 However ketamine is a phencyclidine 
derivative, which gives it dissociative and psychotomimetic properties, significant abuse 
liability,6 and ketamine is associated with permanent gastrointestinal and genitourinary 
damage. More concerning, in the setting of acute SI in VHA patients, are ketamine-
associated mania, tolerance and addiction, and even dysphoria with new-onset SI7 – all 
in psychiatric patients who received ketamine. In addition, a survey of military anesthesia 
clinicians found concerns regarding frank delirium, when ketamine is administered to 
combat veterans, or soldiers with any of the following: anxiety, traumatic brain injury 
(TBI), or posttraumatic stress disorder (PTSD).8 For use within VA, then, an alternative 
to ketamine – which ideally does not require an I.V. infusion every 10 days – is required. 
The serendipitous observation of ketamine’s rapid anti-suicidal effect provides an 
opportunity to investigate the neural substrates of SI. In this regard, neuroimaging can 
provide important insights. In line with this, the 2010 NIMH Advisory Council’s report, 
From Discovery to Cure, emphasized that treatment development should be guided by 
emerging scientific understanding of psychiatric disorders. Further, the Research 
Domain Criteria (RDoC) initiative advocates the study of specific symptoms, such as SI. 
Converging lines of evidence implicate disruptions in amino acid neurotransmission in 
the pathogenesis of suicidal behavior, including in veterans. Investigation is focused on 
alterations to gamma-Aminobutyric acid (GABA) and glutamine (Gln). To measure these 
in vivo, proton-1 magnetic resonance spectroscopy (1H-MRS) brain imaging is the sole 
current methodology. Importantly for this proposal, studies have used 1H-MRS to show 
that levels of GABA9 and Gln10 are increased in response to ketamine administration. 
Meanwhile Preliminary Data from our 1H-MRS studies of uridine (detailed below), 
suggest uridine may also be capable of engaging these two neurochemical targets. 
Uridine, the subject of this proposal, is a pyrimidine required for normal brain function.11 
Notably, ketamine’s rapid antidepressant effect depends on activation of the mechanistic 
target of rapamycin (mTOR) pathway,12 and two publications in Science report that the 
function of mTOR is to activate de novo pyrimidine synthesis.13, 14 Because uridine is the 
circulating human pyrimidine, this means that ketamine is an obligate up-regulator of 
uridine. In addition as shown in Table 1, the literature reflects a remarkably diverse 
overlap in the neural effects and brain mechanisms shared by uridine, ketamine and 
lithium, another drug believed to possess anti-suicidal properties. mTOR acts to 
phosphorylate CAD, the multifunction enzyme complex that catalyzes the first three 
steps of pyrimidine synthesis, the final product of which is uridine triphosphate (UTP).15 
Three other facts support uridine’s rationale as a treatment for SI: first, the discovery of 
pyrimidine neurotransmission;16 second, the fact that the CAD gene is down-regulated in 
the brains of suicide victims;17 and third, ketamine18 and the uridine prodrug PN40119 
both increase the concentration of brain-derived neurotrophic factor (BDNF).


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Preliminary Studies at the University of Utah 
 
Preliminary Study #1:  Open-Label Uridine Increases Serum Levels of Uridine, and 
Rapidly Decreases Suicidal Ideation in Bipolar Depression. 
Methods: Twenty-four adolescents with bipolar depression were enrolled for a 6-week 
open-label study of uridine 1000 mg daily. Pre- and post-treatment serum uridine 
levels were measured. Suicidality was measured with Item #13 of the Children’s 
Depression Rating Scale-Revised (CDRS-R).20  
Serum Uridine Results: The normal range for serum uridine is 1.9-8.4 nmol/ml.21 The 
mean baseline uridine was 5.4 nmol/ml; at week 6 the mean was 8.8 nmol/ml 
(Cohen’s d=1.86; Effect Size=0.68). 
Suicidal Ideation Results: As shown in Figure 1, suicidal ideation decreased over 6 
weeks, with the majority of change occurring during the first week of treatment (mean 
week 1 score=1.37; mean week 6 score=1.33). 
 
 
 
 
Conclusions: These data demonstrate that oral uridine is absorbed systemically, and 
increases serum uridine values. Furthermore, 97.6% of the decrease in SI was observed 
at the end of week 1.


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Preliminary Study #2:  In a Placebo-Controlled Trial, Uridine Reduced Suicidal 
Ideation, and Neuroimaging Suggests ‘Target Engagement’ with Anterior 
Cingulate GABA and Glutamine. 
Methods: N=34 adolescents with bipolar depression were enrolled in a follow-up study 
to our open-label protocol. This was a randomized, double-blind, placebo-controlled 
study of uridine 1000 mg daily. 1H-MRS scans were performed at baseline, and 
repeated following 6 weeks of randomized treatment. 
 
 
 
Suicidal Ideation Results: The presence of suicidal behavior, defined as either an 
attempt, plan, or SI, was determined with the Columbia-Suicide Severity Rating Scale 
(C-SSRS). As shown in Figure 3, at baseline 9 of 10 subjects in the placebo group 
endorsed suicidal behavior, compared to 9 of 11 in the uridine group (Chi 
Square=0.292; p=0.59). Below right, after 6 weeks we found a trend favoring uridine: 4 
of 10 placebo-treated patients endorsed suicidal behavior on the day of their 2nd brain 
scan, versus 1 of 11 in the uridine group (Chi Square 2.89; p=0.08). Another way to 
compare treatments is by calculating relative risk (RR) of suicidal behavior. The RR of 
suicidal behavior in placebo vs. uridine was 2.27 (95% confidence interval, 1.04–4.96; 
p=0.04). In addition, the number needed to treat (NNT) was 1.96 (95% confidence 
interval, 1.18–5.91). 
 
We next analyzed the probability that subjects endorsed SI after just 1 week of uridine 
or placebo treatment. As shown in Figure 4, the between-group difference was non-
significant (p=0.2). However, inspection of the slope of the treatment group data 
suggests our results were limited by the sample size. 


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1H-MRS Imaging Results:  Subjects were scanned before and after 6 weeks of 
randomized treatment. The analyses focused on amino acid neurotransmitters 
including GABA.  Direct measurement of GABA poses technical challenges, due to 
other 1H-MRS metabolites that overlap the GABA peak and are present at higher 
concentrations.  To overcome this, and to reduce confounding due to the inter-
individual differences in human brain chemistry, within-subject metabolite ratios are 
often employed for analysis. 
 
One such ratio is GABA/Glx, which is referred to as the inhibition/excitation ratio.  The 
entity Glx (glutamate + glutamine) is a peak in 1H-MRS spectra that contains 
overlapping contributions from Glu and Gln. 
 
As shown in Figure 5, we found that GABA/Glx was significantly increased in the 
uridine group, compared with placebo (p=0.01). 
 
 
 


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Figure 6 displays the change in another ratio of 1H-MRS metabolites, the 
Glutamine/Glutamate Ratio (Gln/Glu).  Recalling that ketamine increases Gln,10 as 
well as a ‘proxy’ measure of Gln,22 our results are consistent with uridine having a 
similar effect, albeit reduced Glu could also account for the increase in the Gln/Glu 
ratio that we observed. 
 
 
 
 
 
To eliminate the inherent ambiguity of expressing 1H-MRS results as the ratio between 
two metabolites, we have developed and validated novel methods (described below) 
that allow individual measures of GABA, Gln and Glu despite their overlapping 
resonances.  The proposed study thus has the potential to provide new information 
regarding the in vivo differences in neurochemistry between suicidal and non-suicidal 
veterans. 


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Preliminary Study #3:  New Imaging Methods Applied to a 3-Tesla High-Field MRI 
Scanner Enable Valid and Reliable Individual Measures of GABA, Glutamine and 
Glutamate. 
Rationale: Low spectral resolution and severe metabolite peak overlap are associated 
with1H-MRS data acquired from human brain using clinical MR systems. The objective 
of this study was to interrogate the magnitude and variability of the between-
metabolite correlation coefficients as calculated in human brain using 2-dimensional J-
resolved 1H-MRS and “ProFit” analysis. 
Methods: Spectra were acquired from the anterior cingulate cortex (ACC) and parietal-
occipital cortex (POC) of n=10 healthy adult volunteers at a magnetic field strength of 
3 Tesla. 
Results: Favorable between-metabolite correlation coefficients (<20%) were observed 
for a range of 1H-MRS metabolites (Table 2). Most ACC and POC metabolites showed 
acceptable intra- and inter-subject CV values of <15% and <20%, respectively. The 
group mean correlation coefficient existing between ACC GABA and Gln was 
calculated as 1.45% + 1.0%; between ACC Gln and Glu it was -18% + 4.1%. 
 
 
 
Conclusions: The observed signal discrimination makes these techniques suitable for 
investigating ACC GABA, Gln and Glu in a variety of brain-based disorders. 
B2 Rationale for the Study 
Suicidal Behavior is an Urgent Concern for the Veterans Administration. 
The high risk of suicide in veterans who receive care in the Veterans Health 
Administration (VHA) has persisted, despite efforts to improve mental health services 
and programs aimed at suicide prevention. Suicide is more common among VHA 
patients than in the general population. For example suicide is the ninth leading cause of 
death in the U.S. population, but ranks first and second, respectively, among female and 
male veterans. In fact compared to non-veterans, the number of veteran suicides is 
approximately 60% higher than expected (Standardized Mortality Ratio (SMR) = 1.63).23 
This burden falls disproportionately on female veterans, whose rate of suicide is nearly 
600% higher than expected (SMR = 5.89).23 Despite this, in a systematic review of n=91 


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suicide prevention publications, none were focused on veteran populations. In part 
because of this, veteran-specific reviews have concluded there is a gap in randomized 
controlled trials of suicide-related interventions.24 To bring needed innovation to 
treatment development for veterans, recommendations include using suicide-related 
outcomes, examining rarely-studied treatments and testing interventions that can be 
delivered ‘upstream’ of an actual suicide attempt or death. Taken together, the rate of 
suicide among veterans and the lack of evidence-based treatments for suicidal patients 
in VHA point to a critical unmet need for veteran-focused clinical research in this area. In 
addition to controlled trials of efficacy and effectiveness, attention is now focused on the 
discovery objectively-measureable ‘biomarkers’ of suicide.25 Therefore we propose a 4-
week, double-blind, placebo-controlled clinical trial of uridine that features translational 
brain imaging at baseline, and following treatment with either uridine or placebo. 
 
There is a Critical Unmet Need for Rapid-Acting Treatments for Veterans with 
Suicidal Ideation. 
At this time, only clozapine is approved the U.S. Food and Drug Administration (FDA) to 
reduce suicidal behavior. This indication is for patients with schizophrenia; however 94% 
of attempted or completed suicides reported by VHA Suicide Prevention Coordinators 
(SPCs) occur in veterans with a primary or secondary diagnosis of depression or bipolar 
disorder. Clearly, research in non-schizophrenic veterans with SI is needed. 
 
A series of recent studies have investigated the timing and content of the final VHA 
appointment attended by veterans who died by suicide. Among the key findings was 
among veterans with a depression diagnosis, 23% of suicide completers saw a VHA 
provider within 7 days of their suicide, and 51% had been seen within 30 days.3 Another 
important result was that roughly half of final VHA contacts took place in primary care, as 
opposed to the mental health service.3 In the primary care setting, 18-48% of veteran 
suicide decedents were assessed for suicidal thoughts,26 a minority of which (38%) had 
endorsed SI when asked. The investigators concluded that areas for improvement 
include the management of SI in primary care, increased referrals to mental health, and 
attention to mental health issues, in other VHA settings.3 Thus a rapid-acting treatment 
for SI that could be delivered in the primary care setting, could constitute an  important 
opportunity for suicide reduction in VHA. Even with a goal as important as suicide 
reduction, it may not be possible to offer manualized psychotherapy and/or I.V. ketamine 
infusions, in every primary care clinic in VHA. However just as oral medication for type II 
diabetes is available in 100% of those clinics, so too could a proven treatment for SI. 
 
We believe that an orally-administered, rapid-acting treatment for SI would help to 
address several of the issues identified by this research. Within the 7- and 30-day 
windows identified by Smith et al.,3 lies the opportunity to intervene in veterans with SI. 
Whereas other promising somatic SI treatments, such as lithium or repetitive transcranial 
stimulation (rTMS), would be administered by the mental health service, a safe and 
effective rapid-acting SI treatment could be started by any VHA prescriber, including 
emergency department physicians--perhaps serving as a ‘bridge’ to a referral to mental 
health. Given that easy access to care is a protective factor against suicide, an 
intervention available VHA system-wide could have a significant impact. 
 
The absence of FDA-approved medications for SI is a recognized public health issue. 
The problem is exacerbated by the fact that patients with SI or prior suicide attempts are 
often excluded from FDA registration trials, on scientific and ethical grounds. At the 


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same time, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) has designated “suicidal behavior disorder” as a condition for further study (p. 
801), and the National Institute of Mental Health (NIMH) has adopted experimental 
medicine studies of “target engagement” as a model for clinical trials. The proposed pilot 
study will evaluate uridine’s effect on SI at the critical 7-day and 30-day intervals 
identified through outcomes research, and serve as a companion to the Better 
Resiliency Among Veterans and Non-Veterans With Omega-3's (BRAVO) study, which 
employs imaging but focuses on chronic, as opposed to rapid-onset, treatment effects.27 
 
Neuroimaging of the Anterior Cingulate Cortex (ACC) is a Powerful Tool for use in 
the Development of Novel Mental Health Treatments. 
In psychotropic drug development, neuroimaging has progressed to the point where it is 
used in a variety of ways: to validate biomarkers of disease and treatment response, to 
define a dose-response relationship, or to demonstrate “target engagement” with a 
clinically-relevant brain mechanism. The concept of “target engagement” refers to 
expanding the focus of clinical research from simple tests of efficacy, e.g. scores on the 
Hamilton Rating Scale for Depression, to include objective measures of disease 
mechanism, or the mechanism-of-action of the intervention. Recognizing the inherent 
complexity of psychiatric disorders, the NIMH has expanded the definition of “target 
engagement” to include a treatment’s hypothesized mechanism-of-action and its ability 
to modify a disease, behavior or functional outcome. One way to conceptualize this is 
that interventions are used as probes of disease mechanisms, as well as tests of 
efficacy. This allows negative clinical trial results to be informative: if “target 
engagement” is not associated with clinical improvement, the target is abandoned, and 
resources can be devoted to the discovery of new treatment targets. 
 
Recent discoveries at the intersection of mood disorders and SI highlight the importance 
of the glutamatergic system in suicide. The system includes the amino acid 
neurotransmitters glutamate (Glu), glutamine (Gln) and gamma-Aminobutyric acid 
(GABA). As the only method for measuring these neurochemicals in vivo, proton-1 
magnetic resonance spectroscopy (1H-MRS) is uniquely suited for studying SI. In a 
recent review of the role of GABA and Gln in the mechanism-of-action of ketamine, 
Lener et al. noted that innovation in MRS imaging techniques that improves our ability to 
individually measure cerebral GABA, Glu and Gln are needed to advance the field, 
through the use of biomarkers to create biologically homogenous subgroups, in order to 
deploy targeted interventions.28 It is therefore notable that at our site, 1H-MRS methods 
have been recently developed allow us to individually quantitate Glu, Gln and GABA,29 
which is unreliable without specialized methods. 1H-MRS has been used to study the 
effects of lithium and ketamine,9 two drugs believed to have anti-suicidal properties.


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Glutamatergic neurons account for >80% of synapses in the cerebral cortex. Synaptic 
Glu is taken up by astrocytes and converted to Gln, and studies combining spectroscopy 
with positron emission tomography (PET) have shown that this “Glutamate-Glutamine 
Cycle” (Figure 7) is the major metabolic pathway in the central nervous system (CNS), 
consuming ~85% of glucose delivered to brain.30 After neuronal release into the synaptic 
cleft, Glu is taken up by astrocytes, where it is converted to Gln by glutamine synthetase. 
Gln is then shuttled into neurons, where it is converted back to Glu by glutaminase. 1H-
MRS Glu and Gln are believed to represent glutamatergic function because: 1) Glu does 
not cross blood-brain barrier, and must be synthesized in CNS; 2) The Glu and Gln 
content of macromolecules including proteins does not contribute to 1H-MRS signals; 
and 3) The Glu -> Gln flux is directly coupled to neuronal activity, and displays a 1:1 
stoichiometry with glucose oxidation. Rapid conversion of Glu to Gln is a neuroprotective 
measure, intended to prevent hyperactivation of Glu receptors, glutamate-mediated 
excitotoxicity, and cell death via apoptosis. Gln from astrocytes is the precursor for 
GABA synthesis in neurons, and GABA->Gln flux comprises 23% of total (Glu plus 
GABA) neurotransmitter cycling and 18% of total neuronal tricarboxylic acid cycle flux.31 
Thus the contribution of GABAergic neurons and inhibition to cortical energy metabolism 
has broad implications, and dysfunction of the amino acid neurotransmitter cycling has 
predictable effects on GABA concentrations. 
 
Since the seminal work of Drevets et al. published in Nature,32 the anterior cingulate 
cortex (ACC) has often been the focus of neuroimaging studies of mood-related 
symptoms. Because of its role in processing both emotion and cognition, we have 
selected the ACC as the region-of-interest for the imaging in this proposal. In addition, 


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PubMed lists n=74 publications for the search parameters “suicide or suicidal AND 
anterior cingulate.” Finally, in addition to two systematic reviews implicating the ACC in 
suicidal behavior,33, 34 there is one study of veterans with, and without, a history of SI, 
that found significant differences in the ACC.35 
 
Ketamine is the Prototypical Rapid-Acting Anti-Suicidal Drug.  However, Ketamine 
May Be Unsafe for Veterans. 
Beginning with the original report of the drug’s rapid-acting antidepressant activity, 
enthusiasm for ketamine built to the point that NIMH Director Dr. Thomas Insel wrote of 
ketamine, “The doom and gloom surrounding medication development, at least for 
depression, seems to be rapidly resolving.”36  In 2010 came the first report of ketamine 
as a rapid-acting treatment for suicidal thoughts,1 and there are now several reports 
highlighting ketamine’s effect on SI, with a rapid onset ranging from 40 minutes to 10 
days.1 Although experts have pointed to the need for more research prior to ketamine 
use in clinical settings, the drug is being sold online and by compounding pharmacies, 
and for-profit ketamine clinics have opened around the United States. 
 
There are a number of drawbacks associated with using ketamine to treat SI in 
depression. First is the evidence for ketamine’s short duration-of-action, with SI returning 
in as soon as 1-2 days.37 Next, ketamine is a derivative of phencyclidine, which gives it 
dissociative and psychotomimetic properties. Ketamine has also been shown to have 
both mu opioid,38 and stimulant-like effects39 -- and it is not in dispute that ketamine is a 
drug of abuse.6 A striking similarity between the biological and clinical properties of 
ketamine and alcohol has also been noted. In terms of feasibility within VHA as a 
treatment for acute SI, potential problems include reports of ketamine-associated 
mania,40 tolerance and addiction,41 and dysphoria,7 all in mental health patients receiving 
treatment (as opposed to ketamine abusers). Most alarming are the reports of new-onset 
SI in response to ketamine,7 and completed suicide while under the influence of 
ketamine.42 Furthermore, a survey of military anesthesia clinicians found significant 
concerns regarding delirium, when ketamine is administered to the following patient 
groups: combat veterans, soldiers with traumatic brain injury (TBI), or patients with 
posttraumatic stress disorder (PTSD).8 For use within VHA, then, alternatives to 
ketamine may be required. And finally, all research involving veterans must be ethical. In 
addition to the many unanswered scientific questions regarding ketamine, concerns 
have been raised regarding the potential for breaches of moral, ethical and medico-legal 
principles, when ketamine is administered off-label in psychiatry.43 
 
The Brain Imaging Technique Magnetic Resonance Spectroscopy (MRS) Can be 
Utilized to Reveal the In Vivo Effects of Ketamine on Human Brain Chemistry. 
1H-MRS has been used to investigate ketamine’s effects on brain chemistry, in humans 
and animal models. For example, ketamine reduces depression-like behavior and 
increases ACC GABA in chronically-stressed rats.44 Ketamine also increases Gln, in rat 
ACC and prefontal cortex.45 Another study combined 1H-MRS with carbon-13 MRS, and 
found that sub-anesthetic ketamine significantly increased prefrontal GABA and Gln.46 
 
Human 1H-MRS studies have reported similar findings. Rowland et al. studied healthy 
volunteers, and found that ketamine significantly increases ACC Gln.10 A study of 
depressed patients reported that ketamine significantly increased prefrontal GABA 
above baseline values.9 And finally, Salvadore and colleagues reported that lower 
prefrontal Glx/Glu, a proxy measure for Gln, predicts a greater response to ketamine.22 


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Taken together, animal and human studies suggest that ketamine enhances GABA and 
Gln in brain. 
 
Converging Scientific Evidence Implicates the Neurotransmitters GABA and 
Glutamine in Suicidal Behavior. 
The neurobiology of suicidal behavior has not been fully elucidated, but evidence is 
accumulating for several brain systems. These include the glutamatergic system, which 
includes the neurotransmitters Glu, Gln and GABA. The imaging in this proposal focuses 
on GABA and Gln, because they can be measured using 1H-MRS. Other likely 
contributors include: cortisol,47 the glucocorticoid stress response and hypothalamic-
pituitary-adrenal (HPA) axis; interleukin 6 (IL-6)47 and the immune system inflammatory 
response; and brain-derived neurotrophic factor (BDNF),47 a neurotrophic growth factor. 
Although these cannot be measured in vivo, evidence will be presented below, that 
uridine and its nucleotides alter cortisol, IL-6 and BDNF -- in the opposite direction of 
their pro-suicide associations -- thus providing further support for uridine. 
 
GABA: The Glutamate-Glutamine Cycle described above is a major regulator of 
GABA metabolism, and modulates GABA neurotransmission by regulating GABAA 
subunit composition. The literature supports GABA-related alterations in suicide at the 
neurochemical, genetic, cellular, localization and functional levels.48 For instance in 
suicide decedent brains, GABA receptor subunit genes are “globally altered.” Recently it 
was reported that low GABAA expression levels are associated with suicide. There is 
also evidence for epigenetic hypermethylation of the GABAA promoter region, 
suggesting a potential mechanism for this. 
 
Interestingly biomarkers of SI in the peripheral circulation have also been studied, 
among male veterans of Operation Enduring Freedom and Iraqi Freedom (OEF/OIF). 
The investigators were unable to measure GABA or Gln, but did find elevations of spinal 
cord and retina transmitter glycine, in the serum of veterans with SI.49  
 
Importantly for this proposal, uridine is a known modulator of GABA receptors, and when 
administered to mice, uridine increases GABA concentrations by 96% after 80 minutes.50 
This caused the investigators to speculate that in addition in increasing GABA, uridine 
may impact the dopaminergic system possibly via agonistic effects at GABAA 
receptors.50 Thus uridine may have a ‘dual’ mechanism underlying its GABAergic 
effects: 1) Increasing the neurotransmitter level; and 2) Biological activity at the GABAA 
receptor. This would explain why uridine is believed to be involved in sleep, and has 
shown promise as an antiepileptic. 
 
Glutamine (Gln): The literature on Gln in suicide is small but intriguing. For example 
Gln levels are low in suicide victim brains.51 Post-mortem work also provides what may 
be a crucial insight: glutamine synthetase, the enzyme that catalyzes Gln synthesis, is 
differentially expressed in suicide decedents with vs. without depression.52 Suicide 
research has a built-in confound, because ~90% of suicide victims have a mental illness. 
The recent findings related to Gln and suicide may help investigators begin to parse the 
differences between the risk for mood and other psychiatric disorders, and the risk for 
suicide itself. 
 
Uridine is a Safe, Hypothesis-Driven Strategy for Engaging Suicide-Related Neural 


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Targets in the Brain – Without the Toxicity and Risks Associated with Ketamine 
and Lithium. 
The purinergic system appeared early in evolution, using adenosine triphosphate (ATP) 
and uridine triphosphate and diphosphate (UTP; UDP) as transmitters.53 The system is 
involved in modulating behavioral motivation and reward, as well as neuro-regeneration. 
Uridine receptors are expressed on all primary CNS cell types including neurons, 
astrocytes, microglia and endothelium. In mammalian brain, uridine nucleotides serve as 
native agonists at four specific receptors: P2Y2, P2Y4, P2Y6 and P2Y14.11 
 
Uridine Pharmacokinetics:  Uridine is orally bioavailable, is actively transported 
across the blood-brain barrier (BBB), and taken up by neurons and astrocytes via 
proteins of the SLC29 family. The salvage pathway then converts uridine sequentially to 
UMP, UDP and UTP. Human trials have shown that oral administration of uridine or a 
precursor increases plasma uridine concentration: this is critical, because mammalian 
brain has limited capacity to synthesize uridine, and thus depends on uptake from the 
circulation.54 Brain uptake of circulating uridine was first demonstrated in the 1970s. This 
was followed by evidence that uridine transport across the BBB begins within 15 
seconds of administration. Tritiated uridine was then used to trace uridine’s path from 
blood to cerebrospinal fluid (CSF), then to the extracellular space in brain, followed by 
entry into cells, and ultimately phosphorylation. It was next demonstrated that 
administration of a uridine source by gavage increases brain concentrations of both 
uridine and UTP, within 30 minutes. In the experiment utilizing the closest relative to 
man, uptake of tritiated uridine into monkey choroid plexus, and then to multiple brain 
regions, was confirmed following intravenous injection.55 
 
Uridine Metabolism Pathways:  P2Y4 and N-methyl-D-aspartate receptor (NMDA) 
receptors co-localize precisely in fluorescence studies, and immunoprecipitation shows 
that P2Y4 is present within NMDA receptor immune complexes. Approximately half of 
ACC neurons express P2Y4, with 100% co-expressing the NMDA receptor. P2Y4 
receptors are also present on astrocytes, though there are no extant expression studies 
of the ACC. With regard to functional data, similar to the NMDA receptor antagonist 
ketamine, in rat cortex uridine decreases NMDA-induced 45Ca2+ uptake into 
synaptosomes, in a concentration-dependent manner.56 Using recombinant NMDA 
receptors, it was further demonstrated that UTP reduces Glu-evoked electrical current, 
suggesting a model of competitive antagonism at the Glu binding site of the NMDA 
receptor. In addition to NMDA receptor blockade, sub-anesthetic doses of ketamine 
paradoxically increase Glu release and glutamatergic transmission. Likewise, UTP 
activation of P2Y4 receptors stimulates Glu release from astrocytes.57 Direct astrocyte-
to-neuron signaling (“gliotransmission”) was reported in Nature and Science in 1994.58, 59 
Thus astrocytes can modulate synaptic transmission by releasing Glu via exocytosis. 
This pathway is regulated by UTP’s activation of P2Y receptors. Notably, it is thought 
that increased glutamate activation of AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole 
propionic acid) receptors, in combination with decreased NMDA activity -- i.e. the 
NMDA/AMPA balance -- is the key to ketamine’s rapid effect on mood and suicidality. In 
light of this, it is noteworthy that uridine acts at NMDA receptors, decreasing the calcium 
flux of NMDA activation and increasing the current produced by AMPA stimulation.56 
 
Uridine Mechanisms-of-Action that are Relevant to Suicidal Behavior: This 
proposal focuses on GABA, because in addition to being strongly implicated in suicide,48 
GABA is measurable in vivo using 1H-MRS. However there are a multitude of other, 


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interrelated brain mechanisms associated with suicidality that uridine has also been 
shown to impact. A significant amount of evidence has accumulated for the stress HPA 
axis, and cortisol activity (corticosterone in rodents). There is replicated evidence that 
baseline cortisol levels are low in suicide attempters, and that HPA axis activity is 
blunted in suicide attempters, when compared to patients with similar clinical 
characteristics who have never attempted suicide.60 Meanwhile, adrenocortical cells 
increase both production,61 and secretion,62 of cortisol in response to UTP. The 
mechanism for this is a non-activating K+ current (Iac), that sets the resting membrane 
potential. ATP stimulates cortisol secretion, by inhibiting the Iac; UTP and UDP also 
inhibit Iac, by up to 81.4%, thereby mediating cortisol secretion.61 Two other drugs with 
anti-suicidal effects -- ketamine and lithium -- also increase cortisol levels. 
 
Table 1 Brain Mechanisms Common to Uridine*, Ketamine and Lithium 
DISEASE 
EFFECT 
URIDINE * 
KETAMINE 
LITHIUM 
Suicide 
Engages Glutamatergic Neurotransmitter System 
Preliminary Data 
10, 63 
64, 65 
Suicide 
Increased GABAA Receptor Activity 
50 
66 
67 
Suicide 
Increased Cortisol or Corticosterone 
68 
69 
70 
Suicide 
Increased Brain-Derived Neurotropic Factor 
19 
18 
71 
Suicide 
Decreased Interleukin 6 
72 
73 
74 
Suicide 
Decreased GSK3 Function 
75 
76 
77 
Suicide 
Increased Synapse Formation 
78 
12 
79 
Suicide 
Increased Long-Term Potentiation 
80 
81 
82 
 * Includes Uridine Precursors, and Uridine Nucleotides such as Uridine Triphosphate (UTP) 
    Ketamine’s rapid antidepressant effect is dependent on mTOR activation.12   mTOR activation leads to de 
novo pyrimidine synthesis,13, 14 and the endogenous, circulating human pyrimidine = uridine.83 
 
Abbreviations:  GABA, gamma-aminobutyric acid; GSK3, glycogen synthase kinase 3 beta 
 
BDNF has also been strongly associated with suicide. As published in Nature and 
elsewhere, response to the prototypical rapid anti-suicidal drug ketamine is dependent 
on BDNF synthesis and release.84 Here again, uridine has activity: the orally-
administered uridine prodrug PN401 increases cortical BDNF by 11%.19 
 
Recent work has focused on the immune system and inflammation in suicide. 
Specifically, serum and CSF measures of IL-6 are higher in suicide attempters vs. non-
attempters.85 Uridine, in the form of UTP and UDP, inhibits IL-6 release.72 Similarly 
ketamine and lithium, have both been shown to decrease IL-6. 
 
Finally, along with the HPA axis, perhaps the most evidence has accumulated for 
abnormalities of the serotonergic system in suicide. Inflammation may lead to serotonin 
deficiency via consumption of tryptophan, the serotonin precursor. Consistent with this, 


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selective serotonin reuptake inhibitor (SSRI) drugs are associated with a decreased risk 
of suicide. It is well-established that the onset of clinical benefit from an SSRI occurs 2-3 
weeks after drug initiation, at the earliest. It is of specific relevance for this proposal, 
then, that chronic administration of the SSRI paroxetine for 24 days induces “profound” 
alterations in pyrimidine metabolism, with increased ratios in the high-to-low energy 
uridine nucleotides, i.e. UTP/UDP/UMP,86 which the investigators stated suggests their 
involvement in the “delayed therapeutic treatment effect” of SSRIs.86 
 
Summary of the Scientific Rationale for this Study. 
Novel, rapid-acting treatments for veterans with SI are urgently needed. A promising 
lead in this arena is presented by uridine. As shown in Table 1 above, the literature 
reflects a startlingly diverse overlap in effects relevant to SI shared by ketamine, lithium 
and uridine. What accounts for the commonality in effects and directionality shared by 
uridine, ketamine and lithium? The answer may lie in the mechanistic target of 
rapamycin (mTOR) pathway, on which the behavioral effects of ketamine are 
dependent.12 Two Science articles reported that mTOR activates de novo pyrimidine 
synthesis.13, 14 This is relevant to our proposal, as uridine is central to de novo 
biosynthesis. In fact, the authors of one paper found that rapamycin disrupted their 
experiment, but that it was rescued by application of uridine, in order to bypass 
pyrimidine biosynthesis.14, 87 The fact that mTOR stimulates pyrimidine synthesis implies 
that ketamine up-regulates uridine as a downstream effect. This hypothesis was 
confirmed by Weckmann et al., who showed that pyrimidine metabolism is enriched and 
uridine concentration increases, 2 hours after ketamine injection.88 
 
Experts recommend that with respect to the neurobiology of suicide, studies that acquire 
neuroimaging before and after interventions are instrumental for understanding the 
mechanisms, and treatment response, in suicidality. Furthermore, the imaging method 
for this proposal, 1H-MRS, has been called “a pathway to diagnosis, novel therapeutics, 
and personalized medicine.”89 Ketamine’s anti-suicidal effect appears to be independent 
of its antidepressant activity,90 which offers the prospect that the proposed study will 
enable us to gather data regarding uridine’s effect on SI, and simultaneously investigate 
ACC GABA as a biomarker of SI. 
C Study Objectives 
C1 Primary Aim 1 
Aim 1. To Demonstrate that Uridine Decreases Suicidal Ideation in Veterans.  We 
hypothesize that 4 weeks of uridine 2000 mg daily will decrease the probability and 
severity of suicidal ideation, compared with placebo. 
C2 Secondary Aims 2 and 3 
Aim 2. To Measure Rapid Changes in Brain GABA, in Uridine-Treated Veterans 
with Suicidal Ideation.  The hypothesis is that GABA levels, measured with magnetic 
resonance spectroscopy, will show a greater increase after 1 week in uridine-treated vs. 
placebo-treated veterans with suicidal ideation. 
 
Aim 3. To Examine the Duration/Durability of Uridine Treatment Response, in 
Veterans with Suicidal Ideation.  The hypothesis is that veterans with suicidal ideation 
randomized to uridine will demonstrate a durable clinical response over 4 weeks, in 
addition to acceptable patient compliance, satisfaction and engagement. 


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C3 Rationale for the Selection of Outcome Measures 
The clinical outcome measures for this study were selected following a review of the 
suicidal ideation clinical trials literature.  For example, the Columbia-Suicide Severity 
Rating Scale (C-SSRS) and Beck Scale for Suicide Ideation (SSI) were both 
administered, in nearly every study of suicidal ideation that has resulted in a peer-
reviewed publication to date.  Therefore, selection of the C-SSRS means that this 
study’s results will be interpretable in the context of the extant literature.  In addition, the 
C-SSRS has been widely adopted for use by both the VA mental health service, and by 
the active duty Armed Forces.  Furthermore it is well-known that the U.S. Food and Drug 
Administration (FDA) recommends that the C-SSRS be administered in clinical trials of 
psychiatric drugs, antiepileptic drugs, and drugs with central nervous system activity 
[http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm225130.pdf]. 
All the clinical rating scales utilized in this study are standardized and validated, and 
their psychometric properties have been tested and published. 
 
The magnetic resonance spectroscopy imaging, i.e. “translational neuroimaging,” brain 
chemistry outcome measures of “target engagement,” were selected based the 
Preliminary Studies conducted in our lab, and the converging scientific evidence that the 
amino acid neurotransmitters GABA, Glutamate and Glutamine may together play a role 
in suicidal behavior.  Under the National Institute of Mental Health (NIMH) Strategic Plan 
[https://www.nimh.nih.gov/about/strategic-planning-reports/highlights/highlight-what-is-a-target.shtml], 
clinical trials must now utilize the “experimental medicine” format, in which the treatment 
intervention’s “target” is specified; the term “target” refers to the hypothesized 
mechanism-of-action and it’s ability to modify disease, behavior or functional outcomes.   
 
In the case of this study, we hypothesize that Uridine will rapidly reduce suicidal ideation 
in veterans, and that this clinical effect will correlate with a concomitant increase, i.e. 
“target engagement” with, concentrations of GABA in the anterior cingulate cortex. 
D Investigational Agent Uridine 
D1 Uridine: An Endogenous Human Pyrimidine Nucleoside 
Uridine is the circulating pyrimidine in human beings, and is required for normal brain 
function.11  The purinergic system appeared early in evolution, and uses adenosine 
triphosphate (ATP) and uridine triphosphate and diphosphate (UTP; UDP) as 
transmitters.53  The system is involved in modulating behavioral motivation and reward, 
as well as neuroregeneration.  Uridine receptors are expressed on all primary cell types 
within the central nervous system; this includes neurons, astrocytes, microglia and 
endothelium.  In mammalian brain, uridine nucleotides are the native agonist at four 
specific purinergic receptors:  P2Y2, P2Y4, P2Y6 and P2Y14.11 
 
In terms of safety versus potential toxicity, it is well-established that uridine is a key 
constituent in human mother’s breast milk.91-94  Furthermore, uridine is compounded as 
an ingredient into commercial infant formula products.95 
 
Previously published studies of uridine, and uridine precursor drugs, have not provided 
evidence of any medically-significant morbidity or mortality, associated with uridine 
administration.  In fact two uridine precursor drugs have recently been approved for sale 


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by prescription in the U.S.96, 97  Other uridine precursors are available as dietary 
supplements, and are sold “over-the-counter” (OTC) in the U.S., i.e. without a 
prescription,98, 99 as is uridine itself (https://binscience.com/brain-health-cognitive-support/choline-
supreme; https://www.absorbyourhealth.com/product/uridine/). 
D2 Uridine: Preclinical Data 
Preclinical data is outlined in the Uridine Investigator’s Brochure, which is included below 
in Section K3. 
D3 Uridine: Clinical Data 
Clinical data is presented above in Section B.  Additional clinical data are presented in 
the Uridine Investigator’s Brochure, which is included below in Section K3. 
D4 Uridine: Dosing Rationale and Risk/Benefit 
The proposed study is a single-center study, targeting a volunteer sample of veterans 
aged 18-65 with SI, to contrast the degree of change in C-SSRS and ACC GABA 
obtained between 2 treatment strategies: uridine 2000 mg daily or matching placebo. 
The dose in our previous adolescent uridine studies was 1000 mg daily; this was well-
tolerated and no significant toxicity was observed in laboratory blood and urine studies, 
12-lead electrocardiograms, or magnetic resonance imaging of the brain. In addition, 
there were no unresolved treatment-emergent adverse events reported by participants. 
In addition, the Uridine Investigator’s Brochure reports that in human studies, doses up 
to 4000 mg – i.e. twice the dose administered in this study – have not been associated 
with dose-limiting adverse events or medical harm. 
E Study Design  
E1 Overview / Design Summary 
This protocol is 4-week, randomized, double-blind, placebo-controlled clinical trial of 
uridine 2000 mg daily for Veterans with suicidal ideation. 
Translational neuroimaging has been integrated into the study design.  Magnetic 
resonance spectroscopy brain scans will be performed at baseline (“pre-treatment”), and 
then repeated after 7 days of treatment with uridine or placebo (“post-treatment”). The 
imaging will measure whether change in suicidal thoughts is associated with “target 
engagement,” i.e. altered brain chemistry metabolites, including GABA. 
 
As noted above, a systematic review found the reduction in suicidal thoughts in 
ketamine treatment responders lasts an average of ~3 days.1 Thus the study is of more 
than adequate length (4 weeks), for comparison with ketamine’s duration-of-action. 
E2 Subject Selection and Withdrawal 
2.a 
Inclusion and Exclusion Criteria 
 
 
 


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Inclusion Criteria 
Inclusion Criterion 
Rationale 
Must be able to Provide Informed Consent 
Good Clinical Practice 
Must be a Veteran of the U.S. Armed Forces 
Population of Interest 
Columbia-Suicide Severity Rating Scale 
Indicates Current Suicidal Ideation 
Disorder of Interest 
Beck Scale for Suicide Ideation Score > 4 
Indicator of Significant Suicidal Ideation 
History of > 1 Suicide Attempt or Hospitalization 
to Prevent Suicide in Past 12 Months or 
Functionally Impairing Suicidal Ideation Not Due 
to a DSM Axis II Diagnosis, in Past 12 Months 
Minimizes Placebo Response; Justifies 
Treatment 
Females and Males Ages 18-65 Inclusive 
Matches Neuroimaging Outcome Domains 
Willing and Able to Identify an Alternative 
Contact, e.g. Family Member or Friend 
Safeguard of Participant Safety 
 
Exclusion Criteria 
Exclusion Criterion 
Rationale 
Schizophrenia or Other Psychotic Disorder 
Requires Different Treatment 
Active Substance Use Disorder Requiring 
Stabilization (N.B. Does Not Include Nicotine). 
Requires Different Treatment 
Unstable Medical Condition(s) 
Requires Medical Treatment Before Valid 
Psychiatric Assessment Can Be Performed 
Pregnancy or Breastfeeding 
Avoid Risk to the Unborn/Breastfed Child 
Contraindication to MRI, e.g. Metallic Implant or 
Claustrophobic Anxiety 
Standard Procedure for Imaging Research 
Concurrent Enrollment in Another Clinical Trial 
Standard Procedure for Clinical Research 
Significant Risk of Protocol Non-Adherence 
(e.g. lives >50 miles from the hospital, and has 
no automobile or alternate transportation). 
Unethical to Impose Research Burden on 
Participants Likely to Drop Out or Be 
Withdrawn 
 
2.b 
Ethical Considerations  
Participants will be withdrawn by the principal investigator, at any point in time when it is 
deemed no longer in the participant’s best interests to continue in the study.  This 
includes protocol non-adherence, as it is not possible to ascertain participant safety if the 
participant does not present for their scheduled study appointments, and does not 
respond to phone calls and emails from research personnel. 
 
The patient population the study targets for enrollment, i.e. veterans with suicidal 
ideation, is a high-risk group. Thus it is anticipated that serious adverse events (SAEs) 
may occur during the course of the study. These will be handled according the policies 


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and regulations of the U.S. Veterans Health Administration, the U.S. Food and Drug 
Administration, and University of Utah Institutional Review Board. 
2.c 
Subject Recruitment Plans and Consent Process 
Participants will be recruited through clinician referrals, and IRB-approved advertising.  
The Salt Lake City VA Medical Center has a suicide prevention office, an inpatient 
psychiatry unit and a large network of multifaceted mental health outpatient programs.  
Recruitment efforts will target each of these resources, on an ongoing basis. 
 
Veterans will provide both verbal and written informed consent, prior to the 
performance of any study-related procedures.  They will also be told that informed 
consent is an ongoing ‘process’, as opposed to a one-time ‘event’ – and that they are 
welcome to revisit any aspect of it at any time.  They will also be informed that research 
participation is 100% voluntary, which means that they are free to withdraw consent for 
further study participation at any time, for any reason – and in addition they are not 
required to offer a reason, should they choose to withdraw consent. 
 
The Salt Lake City VISN 19 Rocky Mountain MIRECC has been serving as site for the 
VA Cooperative Studies Program Study 590 (CSP #590; Lithium for the Prevention of 
Recurrent Suicide Attempts; PI Dr. Ira Katz). As a result of this experience, the MIRECC 
has developed a system of identifying and screening veterans at the Salt Lake City 
station who have a significant history of suicidal behavior. Many potential CSP #590 
participants refuse that study when approached – due to a prior history of receiving 
Lithium treatment, or because of recommendations from peers to avoid Lithium. We 
anticipate that veterans with suicidal ideation who refuse CSP #590 may be willing to 
consider enrolling in the uridine study as an alternative. 
2.d 
Randomization Method and Blinding 
A randomized, double-blind, placebo-controlled format will be used.  The VA Salt Lake 
City Research Pharmacy will receive and package the active uridine capsules and 
matching placebo capsules. No study personnel who have participant contact will 
participate in this.  The study drug will be stored in, and dispensed by, the VA Salt Lake 
City Research Pharmacy. 
 
Block randomization will be performed in Stata (StataCorp LLC, College Station, 
Texas), by research personnel who have no contact with participants, and no contact 
with the VA Salt Lake City pharmacy.  Based on the Stata output, a randomization log 
will be created which will be used to assign consecutively-enrolled participants to one of 
two treatment arms (e.g. ‘A’ or ‘B’) representing uridine or placebo, for the clinical trial. 
2.e 
Risks, Benefits and Alternatives 
Benefits:  This is an IND study, so there are no guaranteed benefits to participants in 
this study. 
 
Alternatives:  At present the only medication with FDA approval for suicide prevention is 
clozapine, for patients with schizophrenia.  However, veterans with schizophrenia are 
not eligible to enroll in this study; therefore, there are currently no FDA-approved 
alternative treatments available to the potential participants for this study. 
 


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The Potential Risks of Participation Include: 
▪ 
During the intake and assessment interview, participants may become 
emotionally upset when asked about their psychiatric history including suicide 
attempts, or past experience of physical and/or sexual abuse, or traumatic 
experiences during military service and/or civilian life. 
 
▪ 
Participants may experience discomfort or swelling when blood is drawn for 
laboratory testing.  Rarely, mild infection can result from these blood draws. 
 
▪ 
It is possible that a participant’s illness could worsen during the study.  This could 
be unrelated, or related, to the study.  Veterans with suicidal ideation are at-risk 
for depressive symptoms, self-injurious behaviors, substance use disorders, 
worsening suicidal ideation, suicide attempts and psychiatric hospitalization as 
part of their condition.  Study psychiatrists are available 24 hours per day, 365 
days per year, including weekends and holidays. If a participant’s illness worsens 
to the point that he or she presents an imminent suicidal or homicidal danger to 
themselves or to others, they will be hospitalized. Participants who are 
hospitalized will be withdrawn from the study. 
 
▪ 
It is possible that treatment with uridine will not be effective for veterans with 
suicidal ideation, and that study participation will therefore delay the start of an 
effective treatment.  If there were an FDA-approved drug to treat suicidal ideation 
other than Clozapine for persons with schizophrenia, study personnel would 
inform veterans of that fact during this study’s informed consent process.  
However, veterans with schizophrenia are not eligible to enroll in the study 
because the presence of a psychotic disorder is one of the Exclusion Criteria. 
 
▪ 
The researchers will take precautions to safeguard participant confidentiality, but 
it is possible that a breach of confidentiality could occur. 
 
▪ 
Participants may experience gastrointestinal discomfort as a result of taking 
study medication.  Therefore, we recommend taking the study medication with 
food to reduce possible stomach discomfort. 
 
▪ 
In a research study of advanced cancer patients,100 continuous intravenous (IV) 
infusions of uridine were administered at doses of 1.0 and 2.5 g/m2/hour (or 1809 
mg/hour and 4524 mg/hour, for a reference person 170 cm tall and weighing 70 
kg, i.e. 5 feet 8 inches and 155 pounds). In the same study, intermittent uridine IV 
infusions were given to advanced cancer patients, at doses of 1.0-3.0 g/m2/hour 
(1809 mg to 5429 mg/hour), for 72 hours.100  In the intermittent group IV uridine 
for 3 hours alternated with 3-hour infusion-free periods. The total uridine in the 
intermittent treatment patients was between 21708 mg and 65148 mg, over a 72-
hour period. The advanced cancer patients’ blood levels of uracil were markedly 
elevated during the uridine infusions, and remained elevated during the 3-hour 
infusion-free periods. This cancer researchers concluded that this indicated, “a 
rapid and saturated catabolism of uridine to uracil.”100 
 
In humans, ribonucleic acid (RNA) is a molecule that participates in the coding, 
regulation and expression of genes. RNA is made up of four nucleotide bases, 
including adenine, cytosine, guanine and uracil. In animal research, rats fed a 


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diet of 3% uracil for 15 weeks developed bladder stones.101 The bladder stones 
were made of uracil, which does not dissolve well in water or urine. When the 
uracil 3% diet was stopped after 15 weeks, the researchers found the uracil 
stones gradually dissolve and disappear.101 However the uracil 3% was 
continued for a total of 30 weeks in 5 rats. In these animals, transitional cell 
cancer of the bladder was found in 1 of the 5 rats.101 The bladder tissue of rats is 
sensitive to mechanical irritation, and foreign bodies are known to cause tumors 
in rodents; this lead the researchers to comment that the hyperplasias (including 
1 bladder cancer) and papillomas observed in the rats “were probably not due to 
a carcinogenic effect of uracil itself.”101 However, uracil could not be ruled out as 
the direct cause of the cancer found in 1 out of the 5 rats that were fed uracil 3% 
for 30 weeks. Therefore, the scientists’ final conclusion about their research was:  
“It is unknown whether this (cancerous) transformation was due simply to the 
mechanical stimuli of the uracil stones or to some other unknown factors.”101 
2.f 
Early Withdrawal of Study Participants 
Participants will be withdrawn automatically, if they experience a serious adverse event 
and are hospitalized.  In addition, the principal investigator retains the right to withdraw 
participants from the study, if in the PI’s judgment it is no longer in the participant’s best 
interests to continue, e.g. if additional treatment(s) that are outside of the study protocol 
are clinically indicated, and it is unethical to withhold such treatment(s). 
 
Because this protocol is not approved for “Research With Prisoners,” if a participant is  
incarcerated during the study, they will be withdrawn. 
 
The principal investigator may also withdraw participants, if they are unable or 
unwilling to be adherent to the protocol. This is because protocol non-adherence renders 
a participant’s research data invalid and unusable. When this occurs, and therefore 
nothing of scientific value can be gained from an individual’s further participation, it is 
unethical to impose further research burden(s) on the participant. In cases where the 
principal investigator arrives at this conclusion vis-à-vis non-adherence and continued 
participation, it is their ethical responsibility to withdraw the participant. 
2.g 
When and How to Withdraw Participants 
Participants will be informed they are being withdrawn from the study during a face-to-
face meeting with the principal investigator. Clinical assessments will be collected that 
mirror the rating scales administered at the Week 4 visit. In addition, safety labs will be 
performed to document any treatment-emergent laboratory abnormalities. 
 
Participants in clinical trials are sometimes “Lost To Follow-Up,” meaning they stop 
coming to their appointments and no longer return phone calls and emails from the study 
staff. Sometimes this occurs because the participant has physically relocated, or the 
subject simply decides to no longer interact with the research team. If this occurs, staff 
will send a letter to the participant’s last known mailing address via U.S. Mail, requesting 
that the participant return for a final visit, for clinical and laboratory testing. 
2.h 
Data Collection and Follow-up for Withdrawn Participants 
The principal investigator may withdraw participants for reasons including adverse 
effects, safety concerns or protocol violations. In addition, participants may elect to 


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discontinue study participation at any time. The research team will ask the participant to 
return the unused portion of the study medication, and the facility’s treating mental 
health providers will assume responsibility for further patient care. 
 
Participants who prematurely discontinue treatment due to an adverse effect or other 
event will be asked to participate in a clinical assessment approximately 4 weeks after 
the date of their last dose of study drug, to complete safety assessments. In addition, if 
indicated the principal investigator will repeat laboratory testing at this visit, to identify 
any treatment-emergent abnormalities. 
 
E3 Study Drug 
3.a 
Description  
Uridine is a naturally-occurring pyrimidine nucleoside, that is essential for the synthesis 
of RNA and biomembranes. It is also a critical element in the regulation of cellular 
energetics and post-translational modifications; and in the synthesis of membrane ion 
channels, receptors, intracellular glycoproteins and glycolipids, excretion of drugs, 
steroids and bilirubin. Uridine is present in human breast milk,91 and is compounded into 
commercial infant formulas.102 
3.b 
Treatment Regimens  
Uridine and matching pill placebo will be administered for 4 weeks at a fixed dose of 
1000 mg twice daily by mouth, i.e. a total daily dose of 2000mg/24 hours. 
3.c 
Method for Assigning Participants to Treatment Groups  
As described above, a randomization log will be generated using the statistical software 
Stata (Release 15; StataCorp, College Station, TX).  The VA Salt Lake City Research 
Pharmacy will utilize this log to assign consecutively enrolled participants to one of the 
two treatment arms (i.e. uridine or placebo). 
3.d 
Preparation and Administration of Study Drug  
The oral uridine study drug, and matching pill placebo, will be prepared for the study by 
Natural Pharmacia International, Inc. (NPI; Burlington, MA). 
 
Dr. Perry Renshaw is Medical Director of the VISN 19 Rocky Mountain MIRECC, and 
one of the investigators on this study’s research team.  Dr. Renshaw is also the holder 
and sponsor of Investigational New Drug Application (IND) #74,122 for human studies of 
uridine; the IND was issued to Dr. Renshaw by the U.S. Food and Drug Administration.  
Dr. Renshaw has conducted several previous clinical trials of uridine, and for each of 
these studies the U.S. Food and Drug Administration granted its approval for NPI to 
serve as the manufacturer and provider of the investigational drug uridine. 
3.e 
Treatment Adherence Monitoring  
Adherence to treatment will be monitored.  Participants will be asked to bring their study 
drug bottle with them to appointments, and pill counts will be monitored with the 
percentage of pills taken as-directed to be estimated. In addition to this, verbal inquiry 
and discussion of adherence will occur at study visits. 


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In addition, during the time between the ‘pre-treatment’ and ‘post-treatment’ brain scans, 
i.e. during the first 7 days of randomized, placebo-controlled treatment, participants will 
receive daily reminders to take their study drug from research staff. These will occur via 
the participant’s preference of a combination of confidential methods, such as the 
following:  email messages that do not contain Protected Health Information (PHI); 
and/or cellular phone text messaging. Email reminders can be automated using the 
RedCap software application package. Based upon individual preference, standard 
telephone calls will also be available, as a reminder method to support adherence with 
investigational drug. 
3.f 
Concomitant Treatments 
Concomitant medications, psychotherapy participation and adjunctive psychosocial 
interventions will be recorded at baseline, and any changes to the participant’s mental 
health treatment plan will be recorded during the study. 
3.g 
Packaging of Study Drug 
Uridine and matching pill placebo will be manufactured by Natural Pharmacia 
International, Inc. (Burlington, MA) and shipped to the VA Salt Lake City Research 
Pharmacy. There, investigational study drug will be packed in bottles containing a 
uridine or matching pill placebo, with all bottles labeled:  “Uridine/Placebo.” 
3.h 
Blinding of Study Drug 
The study has a double-blind design:  the participants and all research staff who have 
contact with participants, will be blind to treatment assignment (uridine vs. placebo). The 
capsules of uridine and placebo will be identical in appearance and weight. The blind will 
be maintained at the VA Salt Lake City Research Pharmacy 
3.i 
Receiving, Storage, Dispensing and Return of Study Drug 
At VA Salt Lake City and the University of Utah, investigational new drug (IND) studies 
are conducted in accordance with the principles of Good Clinical Practice, and in 
compliance with the U.S. Food and Drug Administration’s published guidance 
documents for investigational drug studies. 
F Study Procedures  
F1 Screening for Eligibility 
Potential participants will undergo a telephone screening, which establishes basic 
eligibility, i.e. “Are you enrolled as a patient in the VA health care system?” or “Are you 
currently enrolled in another clinical trial or research study?” Potential participants who 
pass the telephone screen will be invited for a baseline / screening visit, at which 
Informed Consent and a structured diagnostic interview are conducted. 
F2 Study Protocol Schedule of Visits 
The protocol is a 4-week randomized placebo-controlled trial, followed by a final safety 
visit that takes place 1 week after participants have discontinued study drug. 
 


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Uridine Randomized Controlled Trial: Schedule of Procedures 
WEEK # - 1 
0 
1 
2 
3 
4 
5 
Informed Consent 
 
 
 
 
 
 
 
SCID-5-RV Diagnostic Interview 
 
 
 
 
 
 
 
PhenX Demographic Common Data Elements 
 
 
 
 
 
 
 
Medical History; Physical Examination 
 
 
 
 
 
 
 
Serum Laboratory Tests; Urinalysis; Urine Drug Screen 
 
 
 
 
 
 
 
Pregnancy Test (females) 
 
 
 
 
 
 
 
Magnetic Resonance Spectroscopy Brain Scan 
 
 
 
 
 
 
 
Adverse Events; Concomitant Medications 
 
 
 
 
 
 
 
** C-SSRS, SSI, SBQ-R, INQ, ACSS, FNRS, BPAQ, RFLI, MADRS, HAM-A, BIS-II 
 
 
 
 
 
 
 
Patient Satisfaction; Patient Engagement 
 
 
 
 
 
 
 
Safety Planning Intervention 
 
 
 
 
 
 
 
 
** Note: The assessment measures that are included in the study protocol, and will be 
administered to participants, are described in detail in Section F9 below, entitled “Study 
Outcome Measurements and Ascertainment.” 
F3 Baseline Screening Visit 
Baseline-Screening Visit: Written and verbal consent are obtained prior to any study 
procedures.  The following assessments are administered:  Structured Clinical Interview 
for DSM-5, Research Version (SCID-V-RV); Beck Scale for Suicide Ideation (SSI); 
Columbia-Suicide Severity Rating Scale (C-SSRS); Suicidal Behaviors Questionnaire-
Revised (SBQ-R); Interpersonal Needs Questionnaire (INQ); Acquired Capability for 
Suicide Scale (ACSS); Frustrative Nonreward Responsiveness Subscale (FNRS); Buss-
Perry Aggression Questionnaire (BPAQ); Reasons for Living Inventory (RFLI); 
Montgomery-Asberg Depression Rating Scale (MADRS); Hamilton Rating Scale for 
Anxiety (HAM-A); Barratt Impulsiveness Scale, Revised Form (BIS-II).  A medical history 
and physical exam are performed.  Laboratory tests include a complete blood count, 
comprehensive metabolic panel, urinalysis and urine drug screen. 
F4 Week 0 and Week 1:  Neuroimaging Visits. 
Week 0 and Week 1 - MRS Brain Scanning Visits: The format is the same for the Week 
0 (pre-treatment) and Week 1 (post-treatment) scan visits. Neuroimaging with Magnetic 
Resonance Spectroscopy is performed, to measure any ‘rapid’ alterations in brain 
chemistry associated with 1 week of treatment with uridine vs. placebo. Clinical 
assessments are also collected. 


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F5 Weeks 1, 2, 3 and 4:  Randomized Treatment Visits. 
Week 1, 2, 3, 4 – Treatment Visits:  At these visits participants’ clinical status is 
assessed with the aforementioned rating scales, adverse events and concomitant 
medications are recorded, and the 24-hour safety plan is reviewed. 
F6 Week 5:  Post-Treatment Follow-Up Safety Visit. 
Investigational drug treatment with uridine or placebo will be discontinued at the Week 4 
visit, in compliance with the directions of the FDA. The protocol’s final visit will occur at 
Week 5, when participants have been off study drug for one week.  Clinical and safety 
assessments will be performed, participants will be thanked for their participation, and 
plans will be coordinated for participants to follow-up with their mental health treatment 
team. As a safety measure, study psychiatrists will remain available to study participants 
on a 24/7/365 basis until the participant has an appointment with a member of their VA 
mental health treatment team. Participants who are not enrolled with the VA Mental 
Health Service will be referred for an intake appointment. 
F7 Neuroimaging Visits (Week 0 and Week 1):  Proton-1 
Magnetic Resonance Spectroscopy (1H-MRS) Scans. 
Proton-1 Magnetic Resonance Spectroscopy (1H-MRS) Brain Scans:  Scans will be 
acquired on a Siemens 3-Tesla whole-body MRI system (Siemens AG, Erlangen, 
Germany). Participants may discontinue scanning at any time if they experience 
discomfort, e.g. claustrophobic anxiety.  
 
Anatomic MRI:  Imaging to rule out structural abnormalities is obtained at the baseline 
scan, and board-certified Radiologists review all study scans. Scanning is performed at 
the University of Utah Neuropsychiatric Institute. The MR anatomic session allows 
localization of the Region of Interest (ROI) grid.  
 
Two-Dimensional (2D) J-Resolved Proton MR Spectroscopy and Prior Knowledge 
Fitting (ProFit) Data Acquisition:  A circularly polarized body coil and a manufacturer-
supplied 12-channel phased-array head coil are used for radiofrequency (RF) 
transmission and signal reception, respectively. Participants are positioned supine with 
foam pads used to fixate the head within the coil housing. Three orthogonal low-
resolution proton-weighted gradient echo (repetition time/echo time [TR/TE] = 20/5 ms; 
field-of-view (FOV) = 280 x 280 mm; matrix size = 192 x 144; 8 mm slice thickness) 
localizer images are obtained to confirm optimal head positioning. 
 
Subsequently, static magnetic field (B0) shimming is performed over the whole head 
FOV using a standard phase map method. Three-dimensional (3D) high-contrast and 
high-resolution T1-weighted, magnetization-prepared, rapid gradient echo (MP-RAGE; 
TR/TE/TI = 2000/3.53/1100 ms; FOV = 256 x 256 x 224 mm; isotropic 1 mm in-plane 
resolution) MR images are then acquired and used to facilitate accurate MRS voxel 
positioning and for post-hoc within-MRS voxel tissue-type segmentation. The MRS 
anterior cingulate voxel measures 25 x 25 x 30 mm3 for and is obliqued along the sagittal 
plane and positioned to cover predominantly gray matter. Within-voxel B0 shimming is 
achieved using a manufacturer-supplied automated phase map procedure in 
combination with interactive manual shimming, until a full-width at half-maximum 


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(FWHM) of < 11 Hz is observed for the real component of the ACC unsuppressed water 
signal.  
 
A standard PRESS sequence was modified to enable 2D J-resolved 1H-MRS 
measurements, where the first PRESS TE period (TE1) is fixed at 12 ms and the second 
TE period (TE2) is progressively incremented to sample the second (J) dimension. 
Spatial localization is achieved using a Hanning-filtered RF pulse of 2.6 ms duration 
(bandwidth (BW) = 5 kHz) followed by two identical optimized RF pulses of 7.0 ms 
duration (BW = 1 kHz) for slice-selective refocusing. The 2D J-resolved 1H-MRS 
parameters are as follows: TR/TE = 2400/31-229 ms; TE = 2 ms; 4 signal averages per 
TE step with online averaging; 2D spectral width = 2000 x 500 Hz; 2D matrix size = 2048 
x 100).  
 
The spectral data are obtained using a maximum-echo sampling scheme whereby the 
analogue-to-digital converter (ADC) on-time was fixed for all 100 TE steps. Outer-
volume suppression (OVS) is achieved using six saturation bands positioned at least 
1.5-cm away from the MRS voxel faces; band saturation is achieved using hyperbolic 
secant adiabatic full passage RF pulses. A three-pulse water elimination through T1-
effects (WET) scheme is interleaved with the OVS module for global water suppression. 
In addition, water unsuppressed 2D 1H-MRS data are acquired from the voxel with 2 
signal averages recorded for each TE step. The RF transmitter carrier frequency is set to 
3.0 and 4.7 ppm for water suppressed and unsuppressed data, respectively. 
 
Tissue Segmentation: Skull stripping and whole brain tissue-type segmentation is 
performed on MP-RAGE images using the BET and FAST tools provided with the 
FMRIB software library. In-house MATLAB (version R2010b, The MathWorks, Natick, 
MA) functions are used to extract the 3D volume corresponding to the positioned MRS 
voxel to obtain the within-voxel gray matter (GM), white matter (WM) and cerebrospinal 
fluid (CSF) tissue content for each patient. The GM percentage is calculated as the ratio 
to total brain matter. 
 
Spectral Processing and Quantification: The 12-channel receive-only head coil is 
operated in the 4-cluster mode with each cluster comprised of 3 coil elements. Before 
channel recombination, eddy current distortions initially are accounted for using a 
previously reported time-domain method, where each TE step from a given 2D 1H-MRS 
dataset is corrected using the corresponding cluster-specific water unsuppressed 
recorded at the same TE. Coil cluster-specific signal weighting coefficients are 
determined on an individual basis using the real component of the phased unsuppressed 
water signal data. A weighting coefficient for a given cluster is calculated as the 
maximum amplitude of the corresponding water spectrum, divided by the sum of the 
maximum amplitudes for all four-coil clusters. The weighting coefficients determined for 
each patient are applied to all water suppressed and unsuppressed FID data before 
signal recombination. The eddy current corrected and signal weighted time domain data 
from all four clusters are recombined on a TE-by-TE basis to afford a 2D matrix, 
characterized by 100 TE steps and 2048 complex points. The residual water signal is 
removed from each row of water suppressed 2D matrices using a Hankel singular value 
decomposition (HSVD) routine written in MATLAB. Finally, the 2D matrix is reformatted 
to produce the individual file types required for ProFit read-In. The ProFit algorithm is 
applied identically to all 1H-MRS data using the supplied 2D basis set generated without 
considering the effects of spatial localization. Before the 2D fast Fourier transformation 


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(FFT), the raw 2D matrix is zero-filled to 200 points along the indirectly detected (J)-
dimension.  
 
The basis set is comprised of nineteen 1H-MRS metabolites including Glutamate (Glu), 
Glutamine (Gln), GABA, Creatine (Cre), N-acetyl aspartate (NAA), and Lactate (Lac). 
The Cre methylene (CH2) and methyl (CH3) protons are fitted separately. For 
considering Cramer-Rao Lower Bound (CRLB) on the individual metabolite 
concentrations, the ProFit software first constructs the Fisher information matrix, and all 
metabolite CRLB values are calculated by the ProFit software with CRLB values <20% 
included in the data set. The software was further modified to calculate signal-to-noise 
(SNR) ratios based on the NAA CH3 resonance at 2.0 ppm. 2D spectral regions-of-
interest (ROI) are defined between 9.0 and 10.0 ppm and 1.75 and 2.25 ppm, which 
correspond to noise and NAA ROIs, respectively. All points along the J-dimension are 
used for reconstructing the 2D ROls. The SNR is defined as the maximum absolute peak 
height calculated for the NAA ROI divided by the standard deviation of the real part of 
the noise ROI. The estimated metabolite 2D peak areas are normalized to the short TE = 
31 ms unsuppressed water signal, which is calculated after fitting a Voigt lineshape to 
the real component of the phased frequency-domain unsuppressed water data. The 
nonlinear least-squares "lsqnonlin" function provided with the MATLAB Optimization 
Toolbox™ is used to fit the water data, with the initial estimate for signal amplitude being 
patient-specific, and based on the maximum peak amplitude. An initial estimate of 8 Hz 
is used for signal linewidth (LW) with the lower and upper bounds set to 1 and 20 Hz, 
respectively. The resulting metabolite/water ratios are corrected for within-voxel CSF-
fraction determined using the relevant segmented MRI data. 
F8 Safety and Adverse Events 
8.a 
Safety Monitoring 
Adverse events are recorded at baseline (i.e. prior to administration of investigational 
drug), and at every subsequent study visit. The National Institutes of Health Common 
Terminology Criteria for Adverse Events (CTCAE) will be used to classify events by 
organ system, with events further classified as either ‘Related’ or ‘Unrelated’ to study 
participation. 
8.b 
Medical and Safety Monitoring 
Investigators and the Research Team. The VISN 19 Rocky Mountain MIRECC 
Medical Director, Co-Director, principal investigator, co-investigators, and research 
coordinators will work as a team to monitor the study. The research team has worked 
closely together at the University of Utah since 2008, and has conducted clinical 
research with a variety of high-risk populations, including:  veterans with traumatic brain 
injury and/or posttraumatic stress disorder and/or suicidal ideation and/or substance use 
disorders; adults and adolescents with treatment-resistant depression; adults and 
adolescents with bipolar disorder; and major psychotic-spectrum disorders such as 
schizophrenia. In conducting research with these challenging and complex patient 
populations, we have built a reservoir of experience to draw upon, and we have never 
been investigated, or sanctioned for unsafe conduct of human subjects research by any 
regulatory body or agency with oversight of our human studies. 
 


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Independent Expert Monitoring. For reasons outlined in the paragraph above, there is 
no scientific rationale for independent medical experts to monitor this study. The 
research team has conducted two prior clinical trials of uridine at the University of Utah, 
and for neither study did the U.S. Food and Drug Administration and University of Utah 
Institutional Review Board recommend that an Independent Medical Expert be employed 
as a medical monitor. 
 
Independently-Chartered Data Monitoring Committee (DMC). An independent Data 
Monitoring Committee (DMC) will be chartered to monitor the study. The DMC consists 
of clinicians with experience treating patients with suicidal ideation, and scientists with 
experience in suicide research. The Committee will be vested with the authority to halt 
the study, if it concludes based on the yearly DMC Report that the study’s risks to 
participants have become unacceptable, and the PI cannot agree with the Committee on 
how to revise the study so it can proceed safely. 
8.c 
Definitions of Adverse Events 
An “adverse event” is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the occurrence is considered to be drug-related 
(21 CFR 312.32(a)). 
 
The National Institutes of Health Common Terminology Criteria for Adverse Events 
(CTCAE) will be utilized to classify adverse events by organ system, with events further 
classified as “Related” or “Unrelated” to study participation and/or underlying illness. 
8.d 
Classification of Adverse Events 
The investigators will follow and adhere to the U.S. Food and Drug Administration 
document, entitled:  “Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE Studies” (December 2012). 
i 
Relationship to Study Participation 
An adverse drug reaction will be classified as “related” to study participation, in the event 
a causal relationship with investigational drug is suspected or confirmed. 
 
The diagram below was published by the U.S. Food and Drug Administration, to depict 
the relationship between adverse events, suspected adverse drug reactions, and 
adverse reactions: 


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ii 
Severity of Adverse Events 
Adverse events will be classified as ‘Mild’, ‘Moderate’ or ‘Severe’. 
 
A separate category is reserved for occurrences classified as Serious Adverse Events 
(SAEs). An adverse event or suspected adverse drug reaction is considered “serious” if, 
in the view of the investigator or the sponsor, it results in any of the following outcomes:  
Death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect (21 CFR 
312.32(a)). 
iii 
Expected and Unexpected Adverse Events 
“Expected” adverse events are those listed in the drug’s Package Insert or the 
Investigator’s Brochure, as well as the adverse events that are known to be associated 
with other medications in the same class of drugs. 
 
An “Unexpected” adverse event is defined as an adverse event reported by a study 
participant, that is not listed in any of the above documentation. 
8.e 
Data Collection Procedures for Adverse Events 
At each participant contact, staff will inquire about adverse events and record them on 
the Case Report Form for entry into the study’s RedCap database. 
8.f 
Reporting Procedures 
Reportable adverse events will be documented for submission to FDA using Forms 
3500A and 1571. 
8.g 
Mandatory Safety Reporting Periods 
Initial Reporting: Unexpected serious suspected adverse reactions and observations 
from animal studies suggesting significant risk to human subjects will be reported to FDA 
no later than within 15 calendar days following receipt of the information. Unexpected 


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fatal or life-threatening suspected adverse reactions will reported no later than 7 
calendar days following initial receipt of the information. 
 
Follow-up Reporting: Information pertaining to a previously-submitted safety report will 
be submitted to FDA no later than 15 calendar days after the information is received. 
The type of report (initial or follow-up) will be indicated, and identified using the specific 
type of report: 
▪ 
“IND Safety Report” for 15-day reports; or 
▪ 
“7-day IND Safety Report” for unexpected fatal or life-threatening suspected 
adverse reaction reports; or 
▪ 
“Follow-up IND Safety Report” for follow-up information. 
F9 Study Outcome Measurements and Ascertainment 
The Structured Clinical Interview for DSM-5–Research Version (SCID-5-RV).103  
The Structured Clinical Interview for DSM-5 (SCID-5-RV) is a semi-structured interview 
guide for making DSM-5 diagnoses, in the context of a research study.  It is 
administered by a clinician or trained mental health professional who is familiar with the 
DSM-5 classification and diagnostic criteria for mental disorders. 
 
PhenX – Mental Health Research Core Measures.104  Investigators are encouraged 
to include the PhenX Core measures in VHA-funded mental health research.  The 
research team will therefore include “Tier 1” PhenX Core Mental Health Measures in the 
study protocol. 
 
The Beck Scale for Suicide Ideation (SSI).105  The SSI is a 19-item self-report 
instrument, with each item scored 0-2, for a maximum total score of 38.  A score of > 4 
has been reported to confer an increased risk of eventual death by suicide.106   Therefore 
as an indicator of clinically-significant suicidal ideation, this will serve as one of the 
study’s inclusion criteria. 
 
The Columbia-Suicide Severity Rating Scale (C-SSRS).107  The C-SSRS is a 
suicidal ideation rating scale created by researchers at Columbia University to evaluate 
suicidality in patients ages 12 years and up.  It rates an individual's degree of suicidal 
ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with 
specific plan and intent."  The scale identifies behaviors which may be indicative of an 
individual's intent to commit suicide.  An individual exhibiting even a single behavior 
identified by the C-SSRS is thought to be 8 to 10 times more likely to commit suicide. 
 
The Suicidal Behaviors Questionnaire-Revised (SBQ-R).108  The SBQ-R is a brief 
self-report measure of past suicidal behaviors.  The questionnaire assesses four 
domains: previous suicide attempts, frequency of suicidal ideation, previous suicidal 
communication, and subjective likelihood of future suicide attempt. 
 
The Interpersonal Needs Questionnaire (INQ).109  This measure was designed to 
measure participants’ current beliefs about the extent to which they feel connected to 
others (i.e., Belongingness), and the extent to which they feel like a burden on the 
people in their lives (i.e., Burdensomeness).  These, along with the Acquired Capacity 
for Suicide, are some of the key concepts of the Interpersonal Theory of Suicide,110, 111 


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which is a prevalent model of suicidal behavior in clinical psychology. 
 
The Acquired Capability for Suicide Scale (ACSS).112  The ACSS is a 5-item 
measure designed to assess one’s fearlessness about, and ability to enact, lethal self-
injury. These, along with Burdensomeness and Thwarted Belongingness, are some of 
the key concepts of the Interpersonal Theory of Suicide,110 which is a prominent model 
of suicidal risk and behavior in clinical psychology. 
 
The Buss-Perry Aggression Questionnaire (BPAQ).113 Within the National Institute 
of Mental Health’s (NIMH’s) Research Domain Criteria (RDoC) initiative, “Frustrative 
Nonreward” is designated as a “Negative Valence System,” that can be measured via 
self-report with the BPAQ.114  To make this study’s results interpretable in the context of 
RDoC, the BPAQ will therefore be administered. 
 
The Frustrative Nonreward Responsiveness Subscale (FNRS).115  The FNRS is a 
self-report subscale to be used with the BIS/BAS Scales, the well-established measure 
originally developed by Carver and White.116  The FNRS measures lowered approach 
motivation, following nonreward.  Within the NIMH RDoC framework, this “Frustrative 
Nonreward” is designated as a “Negative Valence System,” that can be measured using 
the FNRS.117  Inclusion of the FNRS will therefore support the relevance of the study’s 
findings, in the context of RDoC. 
 
The Reasons for Living Inventory (RFLI).118  The RFLI includes 48 self-report items 
that measure respondent attitudes about living versus attempting or committing suicide, 
and the reasons that underlie them.  The RFLI includes subscales for survival and 
coping beliefs, responsibility to family members, child-related concerns, fear of suicide, 
fear of social disapproval and moral objections.  Each item is rated on a Likert scale 
ranging from 1 (“not at all important”) to 6 (“extremely important”).  Ratings on the 
individual items are added together to give scores for the individual subscales, and to 
obtain an overall score for the entire inventory; higher scores reflect greater reasons for 
living.  The RFLI is a brief, low-burden, and widely-used questionnaire with good internal 
reliability, test-retest reliability and concurrent validity.  Importantly, the RFLI also 
captures changes in beliefs (e.g., reductions in suicidal behavior). 
 
The Montgomery-Asberg Depression Rating Scale (MADRS).120  The MADRS is a 
ten-item diagnostic questionnaire used to measure the severity of depressive episodes 
in patients with mood disorders.  It was designed to be sensitive to the changes brought 
on by antidepressant medication treatment.  The MADRS suicide item has been shown 
to have a correlation of r > .80 with the first five items of the Beck SSI.121   
 
The Hamilton Rating Scale for Anxiety (HAM-A).122  The HAM-A was one of the first 
rating scales developed to measure the severity of anxiety symptoms, and remains 
widely-used in both research and clinical settings. The scale consists of 14 items, each 
defined by a series of symptoms, and is designed to measure both psychic anxiety (i.e. 
mental agitation and psychological distress) and somatic anxiety (i.e. physical 
complaints and symptoms related to anxiety). The HAM-A is a frequent outcome 
measure in clinical trials of both medication and psychotherapy. 
 
The Barratt Impulsiveness Scale, Revised Form (BIS-II).123  The BIS-II is a 
questionnaire designed to assess the personality and behavioral construct of 


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impulsiveness.  It is the most widely-used measure of impulsive personality traits, and 
has helped to advance our understanding of the relationship between impulsivity other 
clinical phenomena, including suicidal behavior.  The BIS-II includes 30 items that are 
scored to yield six first-order factors (attention, motor, self-control, cognitive complexity, 
perseverance and cognitive instability impulsiveness), and three second-order factors 
(attentional, motor and non-planning impulsiveness). 
 
Safety Planning Intervention (SPI).124  The SPI has been identified as a best 
practice by the Suicide Prevention Resource Center/American Foundation for Suicide 
Prevention Best Practices Registry for Suicide Prevention (www.sprc.org), which can be 
administered as a stand-alone intervention. The SPI consists of a written, prioritized list 
of coping strategies and sources of support that patients can use to alleviate a suicidal 
crisis. The basic components of the SPI include (a) recognizing warning signs of an 
impending suicidal crisis; (b) employing internal coping strategies; (c) utilizing social 
contacts and social settings as a means of distraction from suicidal thoughts; (d) utilizing 
family members or friends to help resolve the crisis; (e) contacting mental health 
professionals or agencies; and (f) restricting access to lethal means. 
G Statistical Plan  
G1  Sample Size Determination and Power 
Sample Size Calculations. Each Approach section and Specific Aim maintains an 
adequate estimated required sample size. The minimum required sample size satisfying 
our study hypotheses is n=72 veterans with SI, or n=36 each in the uridine and placebo 
groups. We anticipate ~20% attrition due to dropouts and unusable scans due to motion 
artifact in the scanner. A total enrollment of n=90 supports our research goals. 
G2  Interim Monitoring and Early Stopping 
Interim data analyses will be performed by staff who have no contact with research 
participants, for inclusion in the annual DMC Report. Because a major portion of Year 1 
of the study will be devoted to administrative and research start-up tasks, we anticipate 
enrollment, and thus the total sample size, will be modest at the conclusion of Year 1.  
Therefore, interim analyses will be included in the annual DMC Report for Years 2, 3, 
and 4. The analysis will be performed using a modified Kaplan-Meier approach,125 with 
pre-specified Peto-Haybittle monitoring boundaries.126, 127  Use of statistically 
conservative Peto-Haybittle stopping rules (i.e. p<0.001) for an investigational drug’s 
benefit and futility, avoids prematurely terminating a clinical trial when there is insufficient 
scientific evidence to do so.128, 129 
 
The study’s independently-chartered DMC will use the interim analysis, together with the 
DMC Annual Report’s comprehensive summary of unanticipated, related and serious 
adverse events, in its determination of whether to halt the study on ethical and/or 
scientific grounds. 
G3  Analysis Plan and Statistical Methods 
 


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Specific Aim 1. To Demonstrate that Uridine Decreases Suicidal Ideation in 
Veterans:  We hypothesize that 4 weeks of uridine 2000 mg daily will decrease the 
probability and severity of suicidal ideation, compared with placebo. 
 
This hypothesis evaluates the efficacy of uridine in rapidly decreasing the probability of 
“wish to be dead” in veterans with SI. Based on our C-SSRS preliminary data (Figure 4), 
the change in binary probability is estimated to be 0.42 and 0.11 for uridine and placebo, 
respectively. The autocorrelation is assumed to be 0.65. Consequently, when 
longitudinal logistic regression analysis (Generalized Estimating Equation) is used for 
n=2 repeated measures of “Wish to be Dead,” the required sample size is calculated to 
be a total of n=72 (n=36 per treatment group), at an alpha level of 0.01 and 80+% power 
with an independent working correlation.130 
 
We will also score the C-SSRS quantitatively after the PhenX recommendations and the 
publication of Sahlem et al,131 with whom we have corresponded. Analyses of a 
continuous variable (C-SSRS scoring range 0-25) are likely to have superior power to 
analyses of dichotomous variable (e.g. presence vs. absence of SI). Thus, we believe 
our estimated sample size is ‘conservative’, and that power is more than adequate. 
 
Specific Aim 2. To Measure Rapid Changes in Brain GABA, in Uridine-Treated 
Veterans with Suicidal Ideation:  The hypothesis is that brain GABA levels, measured 
with magnetic resonance spectroscopy, will show a greater increase after 1 week, in 
uridine-treated vs. placebo-treated veterans with suicidal ideation. 
 
This hypothesis tests whether uridine will alter the inhibition/excitation ratio and increase 
GABA, the major inhibitory neurotransmitter in brain. The Preliminary Data from our 
uridine study of adolescent bipolar depression suggests that an increase in GABA/Glx is 
associated with uridine administration (Figure 5). The effect size for GABA/Glx was 
approximately 11% of the mean, with a standard deviation of 16%. Therefore, if we set 
the anticipated minimum detectable effect size (MDES)132 for the proposed study at 
11%, a total sample size of n=72 achieves 88% power to detect the change in GABA/Glx 
ratio associated with uridine treatment (two repeated measures, and a conservative 
intra-class correlation of ρ=0.65). 
 
Specific Aim 3. To Examine the Durability of Uridine Treatment Response, in 
Veterans with Suicidal Ideation:  The hypothesis is that veterans whose suicidal 
ideation responds to treatment with uridine will demonstrate a durable clinical response 
over 4 weeks, in addition to acceptable patient compliance, satisfaction and 
engagement. 
 
We believe it is worth noting our previous experience with conducting a 6-month uridine 
extension trial. In our placebo-controlled uridine trial of bipolar depression, a total of 
n=37 participants were randomized. Of those, n=28 completed 6 weeks of randomized 
treatment and 2 brain scans, and were subsequently offered the 6-month extension 
phase of the protocol. Of these n=18 (64.3%) completed all six months of open-label 
uridine. We are therefore optimistic that for veterans whose suicidal ideation responds to 
uridine, we may be able to demonstrate a more ‘durable’ anti-suicidal effect, than the 
average 3-day duration of reduced SI with ketamine infusions, that was reported by a 
systematic review of the peer-reviewed ketamine literature.1 


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Milestones and Indicators of Uridine Feasibility as a Rapid-Acting Treatment for 
Veterans with Suicidal Ideation in a 4-week Randomized Placebo-Controlled Trial:  
▪ Evaluate screening feasibility.  Indicator = Number screened per month. 
Goal = 2-3/month. 
▪ Evaluate recruitment feasibility.  Indicator = Number enrolled per month. 
Goal = 1-2/month. 
▪ Evaluate retention feasibility.  Indicator = Retention rate for each treatment group 
(uridine and placebo). 
▪ Evaluate randomization feasibility.  Indicator = Proportion eligible who enroll. 
Goal > 90%. 
▪ Evaluate assessment feasibility.  Indicator = Fealty to the PhenX Measures and C-
SSRS; duration of visit. 
▪ Evaluate treatment adherence.  Indicator = Adherence rates for each treatment group 
(uridine and placebo). 
▪ Evaluate implementation feasibility.  Indicator = Participant satisfaction. 
▪ Evaluate data collection, management and sharing feasibility.  Indicator = No missing 
data in key variables for analysis, except for missed study visits or failed brain scan 
attempts (e.g. due to claustrophobic anxiety, or subject movement in the scanner 
during the MRI).  No unauthorized release of Protected Health Information.  Data is 
securely archived and transferrable to digital media for data sharing. 
G4  Missing Outcome Data 
Missing data has become an important topic in contemporary clinical trials design and 
analysis. Publications on the prevention, and statistical management, of missing data 
have been published recently by the National Research Council,133 the New England 
Journal of Medicine,134 Biological Psychiatry,135 and the American Journal of 
Psychiatry.136 We have reviewed this and other literature on this subject, and will follow 
published expert recommendations. 
 
Missing data are defined as values that are not available, and that would be meaningful 
for analysis if they had been observed and recorded. The assumption that statistical 
methods can compensate for missing data is not always justified; therefore aspects of 
trial design, and conduct, that limit the likelihood of missing data are an important 
consideration in human subjects research. 
 
The missing data article in the New England Journal of Medicine (Table 1; page 1356)134 
lists eight key “ideas” for limiting missing data, in the design of a clinical trial. The 
protocol for this study adopts four of these eight recommendations: 
 
▪ 
Target a population that is not adequately served by current treatments and 
hence has an incentive to remain in the study. 
 
▪ 
Utilize add-on designs, in which a study treatment is added to an existing 
treatment, typically with a different mechanism-of-action known to be effective in 
previous studies.  (This study does not feature a medication “washout,” and 


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veterans will have uridine or placebo added to their existing medications.) 
 
▪ 
Shorten the follow-up period for the primary outcome.  (The primary 
neuroimaging endpoint is collected following 1 week of treatment, and the 
primary clinical endpoint data is collected after 4 weeks of treatment.) 
 
▪ 
Avoid outcome measures that are likely to lead to substantial missing data.  
(Almost every study conducted by our research team at the University of Utah 
has an imaging component. Our experience with magnetic resonance 
spectroscopy dates back 29 years, to in vivo measurement of lithium in human 
brain.137 The cumulative experience allows us to minimize the amount of missing 
data in our current research studies.) 
 
Four statistical methods for handling missing data, that are often utilized in published 
reports of longitudinal treatment trials, include the following: 
 
1) Complete-Case Analysis: analyzing only participants with no missing data; 
2) Single Imputation Methods: these include use of the last observation carried 
forward, or baseline observation carried forward, for analysis; 
3) Estimating-Equation Methods; and 
4) Methods Based on a specified Statistical Model. 
 
Complete-case analysis and single imputation methods were strongly discouraged by a 
panel of statistical experts convened by the National Research Council.133  By contrast, 
weighted estimating equations and multiple-imputation models offer an important 
advantage:  they are capable of incorporating auxiliary information about the missing 
data into the analysis, and also provide standard errors and p-values that take missing 
data uncertainty into account, including it the analyses.  For example, pattern mixture 
models can incorporate the pattern of missing data in the study’s dataset into the 
model.138  Another approach is shared parameter modeling, in which the assumptions 
with regard to missingness are incorporated into the model.139  To assess the robustness 
of the study’s statistical results, sensitivity analyses will be performed using a variety of 
assumptions; if the “treatment effect” associated with uridine is maintained for a range of 
clinically-plausible offset assumptions, then the reductions in suicidal ideation and/or the 
increases in brain GABA concentrations will be considered to be robust.  An issue we 
could encounter, is that the statistical methods for handling missing data can be reliant 
on relatively large sample sizes.140  If our dataset is not sufficiently large for reliable and 
valid utilization of the methods advocated by the National Research Council, we will 
explore other options and consult with other neuroimaging laboratories. 
 
The principal investigator and research coordinator will monitor the Case Report Forms 
(CRFs) for missing data. When missing data is noted, the CRF is flagged. The principal 
investigator and study coordinator will review forms with missing or ambiguous data on 
an ongoing basis. If possible, participants will be contacted in an attempt to collect the 
missing data. If the data cannot be captured, it will be coded in the study’s database as 
“missing.”  The quantity, and rate of missing data will be included in the annual report to 
the study’s Data Monitoring Committee. 


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H Data Handling and Record Keeping  
H1 Confidentiality and Security 
Only research staff will have access to participants’ Protected Health Information (PHI); 
this information will be stored in locked cabinets, and on password-protected computers 
inside locked offices.  The hard drives of all computers used for the study are encrypted 
by the University of Utah’s Information Technology department.  Data analyses will be 
performed in the aggregate, and no participant’s PHI will be featured in scientific 
presentations or publications. 
H2 Training  
All study personnel are required to complete research ethics training through the 
Collaborative Institutional Training Initiative [CITI; www.citiprogram.org]. 
H3 Case Report Forms and Source Documents 
The study’s Case Report Forms will contain participants’ initials, and a unique study 
identification number.  CRF binders are stored in locked cabinets, in locked offices, and 
on a floor that requires badge identification to access.  All documentation and reports 
transmitted as required, e.g. to the Institutional Review Board, U.S. Food and Drug 
Administration, or the centralized VA Data Monitoring Committee will be HIPAA 
compliant. 
H4 Records Retention 
In terms of “records retention,” the research team will comply with all aspects of the 
“Guidance on VA Research Records and the Impact of the Federal Records Act.” 
I Study Monitoring, Auditing, and Inspecting  
I1 
Study Monitoring Plan  
The principal investigator (PI) is responsible for monitoring the quality and completeness 
of study data. In addition, all VA merit review grant clinical trials are required to be 
monitored by the VA’s national, centralized Clinical Science Research & Development 
Data Monitoring Committee (DMC). In compliance with that VA requirement, this study 
will be monitored by the DMC. 
 
Purpose and Responsibilities of the National Veterans Administration 
Centralized Data Monitoring Committee (DMC). The DMC is primarily responsible for 
safeguarding the interests of study participants, assessing the safety and efficacy of trial 
interventions, and monitoring the progress of the study. The DMC will conduct reviews of 
this clinical trial, and monitor its recruitment. The DMC will serve as an independent 
advisory group to the Veteran Administration’s Director of Clinical Science Research & 
Development (CSR&D), and is required to provide recommendations about starting, 
continuing, and stopping the study. 
Approximately every 4 months, the DMC will receive data from the research team, and 
will evaluate the following: 


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• 
Review the study protocol, pertinent accessory documents, and plans for data 
and safety monitoring 
• 
Review methodology used to help maintain the confidentiality of the study data 
and the results of monitoring by reviewing procedures put in place by 
investigators to ensure the privacy of study participants  
• 
Monitor study design, procedures, and events to maximize study safety and 
minimize risks to study participants   
• 
Evaluate the progress of the study, including periodic assessments of data 
quality and timeliness, participant recruitment and retention, participant risk 
versus benefit, performance of the study site(s), and other factors that may affect 
study outcome 
• 
Consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the study  
• 
Review serious adverse event (SAE) documentation and safety reports and 
make recommendations regarding protection of the safety of the study 
participants 
• 
Report to the  Director, CSR&D, and the Principal Investigator (PI) on issues 
concerning study safety progress 
• 
Evaluate and report to the Director, CSR&D, and the study PI on any perceived 
problems with study conduct, enrollment, sample size, and/or data collection 
• 
Provide to the Director, CSR&D, and the PI a recommendation regarding 
continuation conditionally or unconditionally, probation, termination or other 
modifications of the study based on the cumulative experience including the 
observed benefit or adverse effects of the treatment under study; as well as data 
observations that indicate the likelihood of definitively addressing the goals of the 
study. 
The VA DMC is responsible for identifying mechanisms for the completion of various 
tasks that will impact the safety and efficacy of study procedures and overall conduct of 
the study. 
 
The study team will furnish the VA Centralized DMC Office with the following reports, at 
a minimum of 30 days, before each meeting or conference call in order to allow the DMC 
members adequate time to review and prepare for the meeting at hand. Meeting 
materials will include the following research reports and data: 
• 
Adverse Events (AE) Data 
• 
Serious Adverse Events (SAE) Data 
• 
Unexpected Problems (UP) Data 
• 
Graphed Enrollment Data (Actual versus Projected) 
• 
Recruitment and Retention Data 
• 
Statistical Analysis of Study Progression. 


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The DMC will review the above information at DMC meetings depending on the type of 
review being conducted to ensure proper conduct of the study. The DMC may also apply 
other metrics in making its assessments such as targeted enrollment versus actual 
enrollment. 
 
Proper records will be collected at each DMC meeting to ensure that there is a physical 
record of any and all decisions and recommendations. The required documentation for 
DMC meetings for the study includes the following:  
• 
Identification of DMC members available for the meeting 
• 
Identification of DMC administrative personnel available for the meeting 
• 
Identification of excused members 
• 
Notification of changes in membership and next scheduled DMC meeting 
• 
Review of study data 
• 
Review of study summary report 
• 
Committee recommendations and approvals. 
The VA CSR&D Program Staff will be responsible for the preparation of committee 
minutes that address the above. Minutes must then be reviewed for accuracy in 
collaboration with the VA DMC Administrator and VA DMC Manager and then endorsed 
by the DMC Chairperson before being submitted to Director of CSR&D for the VA, for 
final approval. Meeting minutes, endorsed by the DMC’s Chairperson, must be 
submitted to the Director, CSR&D within a timely manner, typically 10 working days 
following a convened DMC meeting.  
 
The Director, CSR&D, will review the meeting minutes, request additional information 
and then endorse the minutes. A copy of these minutes, reflecting the committee’s 
review, and the Director, CSR&D’s, requests or recommendations, is then sent to the PI 
and the PI’s VA facility Associate Chief of Staff for Research (ACOS/R). 
 
Once DMC minutes have been endorsed by the Director, CSR&D, they are considered 
final and archived with other VA DMC documentation. Investigators receive copies of 
signed and approved minutes from the DMC for open sessions only while the study is 
active. 
 
The finalized DMC meeting minutes from the national centralized VA DMC, will be 
submitted to the University of Utah Institutional Review Board annually.  
 
Tracking and Monitoring of Data as Required by the University of Utah 
Institutional Review Board.  The following is a summary of the data that will be 
collected and reported to the Institutional Review Board (IRB), when the study’s IRB 
application undergoes its annual review. 
I. Proposed amendments to the study protocol, and the IRB’s decision to approve 
or not to approve them. 
 


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II. An accounting of the total number, and the rate, of Adverse Events reported to 
the research team by study participants, presented by treatment condition 
(Investigational Drug vs. Healthy Control) and by event category: 
a. Serious Adverse Events and their outcomes 
b. Unanticipated Adverse Events 
c. Adverse Events related to the research 
d. Adverse Events unrelated to the research 
 
III. A description of Unanticipated Problems that have occurred, and their outcomes: 
a. Unexpected, research-related adverse events 
b. Breaches of participant confidentiality or privacy that involved real or 
potential risks, such as unauthorized use or disclosure of participants’ 
protected health information (PHI) 
c. New information about the effect on health or safety, or any life-
threatening problem or death caused by, or associated with, the study 
investigational drug 
d. New information indicating a change to the risks or benefits of the 
research that may be different than initially presented to the IRB 
e. Publication(s) showing that the risks or potential benefits of the research 
may be different than initially presented to the IRB 
f. 
A change in FDA labeling, or withdrawal from the market of the 
investigational drug (uridine) used in the research protocol 
g. Incarceration of a participant, because the study is not permitted to enroll 
prisoners 
h. Complaints from participants or others involved in the research that 
indicate unexpected risks to participants, and their outcomes  
 
IV. A list of any warning or determination letters regarding the investigational drug 
(uridine) issued by a funding agency or regulatory body, including the Office of 
Human Research Protections (OHRP), the Department of Health and Human 
Services (DHHS), or the Food and Drug Administration (FDA):  
a. Warning Letters 
b. Notice of Initiation of Disqualification Proceedings and Opportunity to 
Explain Letter (NIDPOE) 
c. Notice of Opportunity for Hearing (NOOH) 
d. Notice of Disqualification 
e. Consent Agreements 
f. 
Clinical Hold Letters  
V. A list of Protocol Deviations that occurred, and their outcomes: 


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a. Deviations that were intended to eliminate an apparent or immediate 
hazard to a research participant 
b. Deviations that caused harm to participants or others, or placed them at 
increased risk of harm – including physical, psychological, economic, or 
social harm 
c. Episodes of Serious Noncompliance, meaning an act or omission to act 
that resulted in increased physical, psychological, safety, or privacy risk 
that compromised the rights and welfare of participants 
d. Episodes of Continued Noncompliance, meaning a pattern of repeated 
actions or omissions to act suggesting the future likelihood of 
reoccurrence, and that indicated a deficiency in the ability or willingness 
of the research team to comply with the Code of Federal Regulations 
(CFR) or the policy, requirements, and determinations of the IRB 
governing human participant research at the University of Utah 
 
VI. A list of Breaches of Privacy that occurred, their outcomes, and 
recommendations for added protections to reduce the likelihood of reoccurrence 
 
VII. A list of Breaches of Confidentiality that occurred, their outcomes, and 
recommendations for added protections to reduce the likelihood of reoccurrence 
 
VIII. An assessment of the study’s Data Quality and Integrity: 
a. An evaluation of participant Recruitment and Retention, including the 
reasons given for early withdrawal in participants who did not complete 
the protocol 
b. An evaluation of participants’ adherence to the study protocol: 
i. Adherence to the study medication regimen 
ii. Missed clinic visits 
iii. Completion rate of procedures, such as MRI scans and laboratory 
studies 
iv. Recommendations to increase protocol adherence, if applicable 
c. An evaluation of the completeness and quality of the key data elements 
needed to characterize the participants and their primary and secondary 
outcome measures 
d. An evaluation of the research team’s efforts at data capture and 
management, including the quantity of Missing Data and 
recommendations to reduce the rate of Missing Data, if applicable 
e. An evaluation of data entry and accuracy, and recommendations for 
improvement, if applicable 
 
The integrity of the study’s data will be protected and monitored through: a) training for 
research team members; b) research staff meetings; c) regular review of case report 
forms (i.e. paper data), and regular review of electronic data (i.e. RedCap database). 


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Adverse Events Monitoring. At each research visit, the investigator will record 
information regarding any adverse events that have occurred by specifically questioning 
and, when appropriate, by examination. All adverse events occurring during the study 
period will be documented. The investigator will follow the clinical course of each 
adverse event until resolution, stabilization, or until it has been determined that the 
research procedures or interventions were not the cause of the adverse event. Serious 
adverse events that are ongoing at the end of the study period will be followed to 
determine a final outcome. The PI will determine whether an unexpected adverse event 
is related or unrelated to the investigational drug, or to a research study procedure. An 
adverse event is “related to the research” if in the opinion of the PI, it was more likely 
than not related to the investigational agent or intervention. If unanticipated problems 
(UPs) or unanticipated adverse events (UAEs) occur, they will be promptly reported to 
the FDA in accordance with published guidelines. 
 
Tracking of Participants and Data. Using a password-protected computer with 
access limited to study personnel, the research team will use an encrypted computers to 
record the research data in RedCap. Participant screening, eligibility status, and consent 
for participation status will be recorded in the Participant Screening Database. 
 
As participants enroll in the study, a record in the Participant Tracking Database will be 
created with entries for each visit containing each piece of data captured. The date of 
the visit will be entered into the database.  Missed visits will be recorded, along with the 
reason. Within each visit, a variable will be coded for each data point expected for that 
evaluation, containing either the data a code for “missing data.”  If a participant 
withdraws from the study prior to completing the protocol, the date and reason for early 
termination will be recorded in the Participant Tracking Database. The study’s 
recruitment, retention, protocol adherence, and protocol completion data will be 
monitored on an ongoing basis, and the research team will identify and address problem 
areas that arise. 
 
Data Confidentiality and Security. Study CRFs will be designed to contain 
participants’ initials and a unique study identification number. All documentation and 
reports transmitted to the IRB, FDA, and VA DMC will be HIPAA compliant. Only the 
study staff will have access to participants’ Protected Health Information (PHI), and this 
information will be stored in locked cabinets in a locked office, and on encrypted, 
password-protected computers inside locked offices. The hard drives of all desktop, 
laptop and notebook computers used for the study are encrypted by the University of 
Utah’s and/or Salt Lake City VA Medical Center’s Information Technology departments. 
Data analyses will be performed in the aggregate, and no participant’s PHI will be 
featured in scientific presentations or publications. 
I2 
Auditing and Inspections 
The study will undergo an Investigational New Drug (IND) pre-review at the University of 
Utah. Once the study begins, the research team will comply with all inspection and 
auditing requests and directives from the U.S. Department of Veterans Affairs, the U.S. 
Food and Drug Administration and the University of Utah Institutional Review Board. 


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J Study Administration 
J1 Organization and Participating Centers 
In one sense, this clinical trial is considered a multi-site study, because the study’s 
research data will be collected at two sites:  1) the Salt Lake City VA Medical Center; 
and 2) the University of Utah School of Medicine, where the research-dedicated MRI 
scanner is located. However, the Salt Lake City VA and University of Utah are affiliated 
with one another, and the investigators for this study are appointed to the medical staff 
of both institutions. 
J2 Funding Source and Conflicts of Interest 
The funding source is a Merit Review grant (1-I01-CX001611) from the Veterans Health 
Administration.  Conflicts of interest at the University of Utah are identified and managed 
through the Conflicts of Interest Office, in the Office of the Vice-President for Research. 
J3 Committees 
This study is a single-site, small-scale, translational neuroimaging trial.  It is not 
anticipated that there will be a need for standing committees. 
 
J4 Participant Stipends or Payments 
Participant Compensation for Time and Travel. Veteran participants will be offered   
compensation for time and travel for their initial informed consent, evaluation and 
screening visit. The compensation is $100 for each of two brain MRI imaging visits 
(Week 0 and Week 1), $25 for the randomized treatment non-MRI study visits (Weeks 2, 
3 and 4).  The compensation is $75 for the final Week 5 visit, which includes clinical 
assessments and safety laboratory testing including blood and urine sample collection. 
 
If you are traveling more than 50 miles round trip per study visit, you will be given an 
additional $20 for each completed research visit. Therefore, your total compensation for 
the study will be $590.  
 
 
J5 Study Timetable 
 
 


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K  Attachments  
K1 Targeted/Planned Enrollment Table  
After accounting attrition and subject movement artifact in the MRI scanner that renders 
data unusable, we plan to enroll a sample of n=90 veterans, in order to collect a complete 
clinical and imaging datasets for n=72 participants, all at the Salt Lake City Veterans 
Affairs Medical Center.  Participants will be adults of both genders, and of any race and 
ethnicity.  Because of the potential for brain chemistry to change with advancing age, we 
plan to enroll participants between the age of 18 and 65 years. To our knowledge, there 
are no known race or ethnic differences in clinical response, or adverse events, 
associated with uridine. Therefore, the proposed study is designed to include all eligible 
minority participants, who are estimated to comprise 10% of the total sample. The 
Targeted/Planned Enrollment Table below is based upon demographics for Utah taken 
from the 2010 United States Census, which showed that the Salt Lake City metropolitan 
area has a population that is greater than 80% white.  African-American, Asian and Native 
American persons combined to make up 5.8% of the local population.  Similarly in 2013, it 
was estimated that approximately 10% of veterans in the VA Salt Lake City catchment 
area were female. 
 
 
 
K2 Questionnaires, Surveys and Rating Scales 
Inclusion of copies of the clinical assessment measures and questionnaires that will be 
administered to veteran participants in this protocol (e.g. SCID-5-RV, C-SSRS, SSI, 
SBQ-R, INQ, ACSS, FNRS, BPAQ, MADRS, PhenX) would increase the length of this 
protocol by >200 pages. 
 
Therefore, copies of all the instruments are readily available from the research team, but 
have not been compiled within this document.  However, they are described above in 
Section F9, which includes references for each instrument or questionnaire. 
 
 
 


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K3 Uridine Investigator’s Brochure and Bibliography 
Uridine (RG2417) 
 
INVESTIGATOR’S BROCHURE 
 
 
Edition No: 7 
Release Date: May 20, 2009 
Replaces Previous Edition:  6 (February 27, 2008) 
 
This Investigator’s Brochure is provided to you as a principal investigator, potential investigator, 
or consultant for review by you, your staff, and Institutional Review Board/Ethics Committee. 
The information contained in this document is privileged and confidential, and except to the 
extent necessary to obtain informed consent, must not be disclosed unless such disclosure is 
required by federal or state law or regulations. Persons to whom the information is disclosed in 
confidence must be informed that the information is confidential and must not be disclosed by 
them. 
 
TABLE OF CONTENTS 
 
ACRONYMS AND ABBREVIATIONS 
i 
1 
INTRODUCTION 
1 
1.1 
BACKGROUND 
1 
1.2 
CLINICAL USES OF URIDINE AND URIDINE PRODRUGS 2 
1.2.1 
Oral Uridine 
4 
1.2.2 
IV Uridine 
5 
1.2.3 
Uridine Prodrugs 
5 
1.3 
BIPOLAR DISORDER 6 
1.3.1 
Uridine Treatment in Bipolar Depression 
7 
1.4 
RG2417 (URIDINE) 
8 
1.4.1 
Non-clinical studies 
8 
1.4.2 
Clinical studies 8 
2 
PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES 10 
2.1 
ACTIVE CONSTITUENT OF THE RG2417 FORMULATION 10 
2.2 
PHARMACEUTICAL PROPERTIES 10 
2.3 
MANUFACTURING 10 
2.4 
PHYSICAL PROPERTIES 
10 
2.4.1 
Specifications for RG2417 Tablets 
11 
2.4.2 
Specifications for Placebo Tablets. 
11 
2.5 
FORMULATION 
11 
2.5.1 
RG2417 Formulation 
11 
2.5.2 
Placebo Formulation 
12 
2.6 
STORAGE AND HANDLING 12 
2.7 
INTENDED ROUTE OF ADMINISTRATION 12 
3 
NON-CLINICAL STUDIES 
13 


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3.1 
PHARMACOLOGY 
13 
3.1.1 
Testing for Anticonvulsant and Neuroprotective Activity of Uridine 
14 
3.1.2 
Activity of Uridine in Forced Swim Test in Rodents 
15 
3.2 
SAFETY PHARMACOLOGY 16 
3.2.1 
Neurobehavioral evaluation of TAU in male rats 16 
3.2.2 
Evaluation of repeat oral dosing of TAU on cardiovascular function 
17 
3.3 
TOXICOLOGY 
17 
3.3.1 
Single Dose Toxicology Study in Rats (HLS RSZ-002) 18 
3.3.2 
7-Day Repeat Dose Study of TAU in Rats (HLS RSZ-004) 
19 
3.3.3 
28-Day Repeat Dose Toxicity Study of TAU in Rats (HLS RSZ-005) 
19 
3.3.4 
13 Week Oral Toxicity Study in Rats Dosed with TAU with a 4-Week Recovery 
Period (HLS 08-2056) 20 
3.3.5 
28 Day Repeated Dose Toxicity of TAU in Beagle Dogs (HLS 02-3010) 20 
3.3.6 
13 Week Oral Toxicity Study in Dogs Dosed with TAU with a 4-Week Recovery 
Period (HLS 08-3323) 21 
3.3.7 
Bacterial Mutagenicity Assay 
22 
3.3.8 
In vitro Mouse Lymphoma Assay 
23 
3.4 
PHARMACOKINETICS AND TOXICOKINETICS IN ANIMALS 
23 
3.4.1 
Absorption and elimination of uridine in rats after 1 or 28 days of dosing with 
TAU (HLS RSZ-005) 24 
3.4.2 
Absorption and elimination of uridine in dogs after 1 or 28 days of dosing with 
TAU (HLS 02-3010) 
25 
4 
EFFECTS IN HUMANS 
26 
4.1 
PREVIOUS HUMAN EXPERIENCE WITH RG2417 
26 
4.1.1 
RG2417-02: Healthy Volunteers. 
26 
4.1.2 
RG2417-01: Bipolar I Depression 
29 
4.1.3 
RG2417-03: Bipolar I Depression 
33 
4.2 
ANTICIPATED BENEFITS AND RISKS 
34 
4.3 
MARKETING EXPERIENCE 34 
5 
SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR 
35 
5.1 
INVESTIGATIONAL PRODUCT 
35 
5.2 
DRUG SAFETY 
35 
5.3 
ADVERSE REACTIONS 
35 
5.4 
METHOD OF ADMINISTRATION 
36 
5.5 
CONTRAINDICATIONS 
36 
5.6 
SPECIAL WARNING AND SPECIAL PRECAUTIONS FOR USE 
36 
5.7 
INTERACTIONS WITH OTHER MEDICATIONS AND OTHER FORMS OF 
INTERACTION 
36 
5.8 
UNDESIRABLE EFFECTS 
36 
5.9 
OVERDOSE 
36 
5.10 
SHELF LIFE 
36 
5.11 
SPECIAL PRECAUTIONS FOR STORAGE 
36 
5.12 
NATURE AND CONTENTS OF CONTAINER 36 
6 
REFERENCES 37


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ACRONYMS AND ABBREVIATIONS 
AUC 0-∝ 
bid 
Area under the curve To be taken twice a day 
 
CGI-S Clinical Global Impressions Scale, Severity Scale 
 
cGMP Current Good Manufacturing Practices  
CHO 
Chinese hamster ovary  
Cmax ClT CNS Maximum concentration Clearance 
Central Nervous System 
CO2 CSF 
Carbon Dioxide Cerebrospinal Fluid 
 
DNA 
Deoxyribonucleic acid  
ECG 
Electrocardiogram 
 
FOB 
Functional observation battery  
g 
Gram  
g/d 
Grams/day 
 
GABA Gamma aminobutyric acid 
 
GAF 
Global assessment of functioning 
 
GI 
Gastrointestinal  
H2O HAM-A Water 
Hamilton Anxiety Scale  
HPLC High performance liquid chromatography 
 
hr 
Hour 
 
IND 
Investigational New Drug 
 
IP 
Intraperitoneal  
IV 
Intravenous 
 
kg 
Kilogram 
 
L 
Liter 
 
μg 
Microgram 
 
µM 
Micromolar 
 
µmol 
Micromole 
 
MADRS 
Montgomery and Asberg Depression Rating Scale 
 
MCC Microcrystalline Cellulose 
 
mg 
Milligram 
 
mL 
Milliliter 
 
mm 
Millimeter 
 
m2 
Square meter 
MRS 
Magnetic Resonance Spectroscopy 
Na+ 
Sodium 
ND 
Not determined 
NMT Not more than 
NLT 
Not less than 
NOAEL 
 
No observed adverse effect level PK 
Pharmacokinetics 
PO 
Per oral 
PRPP Phosphoribosyl pyrophosphate 
Q-LES-Q 
Quality of Life Enjoyment & Satisfaction Questionnaire RNA 
Ribonucleic 
acid 
RSD 
Relative standard deviation 
RT 
Retention Time 
T1/2 
Half-life 
TAU 
Triacetyluridine 
Tmax Time at maximum concentration 
UMP 
Uridine monophosphate 
UMPS uridine monophosphate synthetase USP United State Pharmacopoeia 
Vd 
Apparent volume of distribution 
YMRS Young Mania Rating Scale 
5-FU 
Fluorouracil 
ω3FA Omega-3 fatty acid


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1 
INTRODUCTION 
 
RG2417 is a solid oral formulation of uridine, a naturally occurring pyrimidine nucleoside. 
Uridine is essential for the synthesis of RNA and biomembranes. It is also a critical element in the 
regulation of cellular energetics and post-translational modifications; synthesis of membrane ion 
channels, receptors, intracellular glycoproteins and glycolipids, excretion of drugs, steroids and 
bilirubin. RG2417 is being developed as a treatment for suicidal ideation, bipolar disorder, 
anxiety, epilepsy and attention-deficit hyperactivity disorder. 
 
1.1 
Background 
 
Uridine is a naturally occurring pyrimidine nucleoside with numerous physiological, metabolic 
and structural functions. It plays a role in such diverse pathways as synthesis of biomolecules, 
regulation of cellar energetics and excretion of drugs (Figure 1). 
 
 
 
Uridine is synthesized from aspartate through a multistep pathway involving the dehydrogenation 
of dihydroorotate to orotic acid. The de novo synthetic pathway described in Figure 2 occurs 
primarily in the liver. However, uridine can also be obtained from endogenous salvage pathways 
following degradation of RNA, DNA or nucleotides and from dietary intake. Uridine is taken up 
from the gut or from circulation via facilitated diffusion or specific uridine transporters. After 
absorption from the gut, uridine is converted to UMP and enters cellular metabolism. Uridine 
concentrations in plasma, bone marrow and CSF are tightly regulated and range from 2 to 8 µM, 
depending on species [1, 2]. Over 90% of endogenous circulating uridine is cleared in a single 
pass through the liver by the metabolic activity of uridine phosphorylase and is replaced in a 
highly regulated manner by “new uridine” formed from de novo synthesis [1]. Because  of the 
presence of active transporters in a variety of tissues, concentrations within cells are much higher 
than plasma levels. Uridine synthesis is coupled to oxidative phosphorylation in the mitochondria 
via dihydroorotatedehydrogenase. It is hypothesized that disorders that disrupt mitochondrial 
function, such as oxidative stress, lead to a decrease in cellular pyrimidine synthesis. 
Supplementation in these disorders is likely to benefit pyrimidine homeostasis and oxidative 
phosphorylation, and the many downstream pathways dependent on these functions. 
 


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1.2 
Clinical Uses of Uridine and Uridine Prodrugs 
 
The pharmacology of uridine has been extensively studied and a number of uridine formulations 
and prodrugs have been used in a wide variety of clinical indications including uridine deficient 
states, autism, diabetic neuropathy, rescue regimens for cancer chemotherapy and antiretroviral 
therapy, mitochondrial disease, HIV-associated lipoatrophy and bipolar depression (Table 1). 
 
 
 


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Uridine is well tolerated by humans. The maximum tolerated dose was 10 to 12 g/m2 (~ 250 
mg/kg) for a single oral dose of uridine in solution and 5 g/m2/dose for a multiple- dose regimen. 
Since uridine is relatively poorly bioavailable a number of “prodrugs” have also been studied. 
These range from classical prodrugs such as acetylated uridine to molecules such as cytidine 
which is metabolized to uridine in vivo. 
 
1.2.1 
Oral Uridine 
 
Oral uridine has been used in numerous indications for durations of over 20 years. The most 
common side effects seen are diarrhea and nausea. 
 
Toxicity and pharmacokinetics of oral uridine in solution were studied in single-dose 
administrations escalating from 0.3 to 12 g/m2 and as multiple-dose administrations every six 
hours for three days at doses of 5 and 10 g/m2 in six healthy volunteer/subjects and in nine 
patients with metastatic colorectal cancer [3]. The maximum tolerated dose was 10 to 12 g/m2 
(~250 mg/kg) for a single dose of uridine and 5 g/m2/dose for the multiple- dose regimen. 
Diarrhea was the dose-limiting toxic effect. For single-dose oral uridine in solution given at 8 -12 
g/m2, peak plasma concentrations were 60 to 80 µM or 10-20    fold higher than basal levels [3]. 
Absorption from the gastrointestinal tract was saturated at dose levels of 8 g/m2, since higher 
doses did not result in increased peak levels. The mean residence time was approximately four 
hours and the apparent volume of distribution was 11.5 L/kg. Plasma uridine clearance had a 
mean value of 41 mL/kg/min and appeared to be independent of the dose of uridine. The 
bioavailability was low, ranging from 5.8% to 20% depending on dose [3]. 
 
Long-term exposure of 20 years or more in patients with hereditary orotic aciduria, an inborn 
error of metabolism that produces a primary deficiency in uridine biosynthesis, has shown uridine 
to be well tolerated at doses of up to 300 mg/kg/day. Several of these patients received uridine 
during their reproductive years and had normal progeny [4]. The report included two women who 
between them had six pregnancies, and one man who fathered a single child. Six of the seven 
infants were normal. The seventh was born with several congenital anomalies ultimately shown to 
be due to aneuploidy due to a familial balanced chromosomal translocation found in the mother 
and several other family members. 
 
Uridine exhibited mild-to moderate side-effects of diarrhea and nausea when used in the above 
mentioned indications of colorectal cancer [3] and hereditary orotic aciduria [4], as well as in the 
six healthy volunteer/subjects. These gastrointestinal side effects may have been due, in part, to 
local irritation as very large doses of formulations with poor bioavailability (<10%) were used. 
 
In a clinical form of Autism Spectrum Disorder (ASD), patients were found to excrete uric acid at 
a level that was greater than two standard deviations above the normal mean, with de novo purine 
synthesis elevated approximately four-fold over normal control subjects [5, 6]. Page et al. [7] 
report that one of these hyperuricosuric autistic patients showed dramatic improvement with oral 
dosing of uridine increased from 50 to 500 mg/kg/day. Side effects included intermittent diarrhea 
and poor weight gain in one subject. 
 
In a case report studying adenyl succinate lyase deficiency [8] uridine was administered orally at 
50 mg/kg/day over two months to a single patient. The patient reportedly tolerated the dosing 
without complaints, and the investigator reported an increase in intracellular 
phosphoribosylpyrophosphate (PRPP). Gallai et al. [9] treated patients with diabetic peripheral 
neuropathy with oral uridine in a double-blind, placebo-controlled study. Forty patients received 


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900 mg/day for over six months. Subjects reported no side effects and investigators observed an 
increase in lipid metabolism and an improvement   on electromyography (EMG). 
 
Uridine is also used as supplemental therapy in patients with uridine monophosphate synthetase 
(UMPS) deficiency. This disorder results in a deficiency of endogenous uridine and is 
characterized by symptoms such as failure to thrive, megaloblastic anemia, language and motor 
delays and immune deficiency. Following administration of uridine, most abnormalities were 
reversed. In these cases, patients were administered up to 
300 mg/kg/day divided into 3-5 doses. The requirement for supplemental uridine however, is life-
long [4]. 
 
Uridine supplementation using natural dietary extract has been used in the treatment of 
mitochondrial toxicity associated with nucleoside analogue reverse transcriptase inhibitors 
(NRTIs) [10]. The activity of uridine to counteract HIV associated lipoatrophy was demonstrated 
in 20 patients on stable antiretroviral therapy. Treatment over a 3 month period was associated 
with a significant change in body morphometry without elevating cholesterol, decreasing lean 
body mass or fasting insulin levels [11]. 
 
1.2.2 
Intravenous Uridine 
 
IV uridine has been used to “rescue” normal cells in cancer patients undergoing certain types of 
chemotherapy at doses that have resulted in sustained elevations in plasma uridine, sometimes 
exceeding 2,000 µM [12, 13]. The main side effects seen with IV uridine are phlebitis at the site 
of the infusion and transient shivering and fever. The absence of gastrointestinal side effects at 
these doses suggests that the diarrhea noted with high doses of oral uridine may be due to local 
irritation by the oral formulation used in those studies and reflect the formulation’s reduced 
bioavailability. 
 
1.2.3 
Uridine Prodrugs 
 
Due to the low bioavailability of uridine in solution, other “prodrugs” of uridine have been 
investigated including triacetyl uridine (2’, 3’, 5’-tri-O-acetyluridine; TAU) and cytidine. TAU is 
rapidly converted to uridine before entry into the bloodstream by the action of blood and tissue 
esterase activity. Pharmacokinetic studies of TAU in rats and dogs demonstrated that its 
bioavailability was increased 6-7 fold compared to free uridine at the same dosage. The 
bioavailability of uridine in man is higher than in animals. 
 
TAU has been used in open label studies of children with neurological or renal manifestations of 
mitochondrial dysfunction [14-16]. Doses of 2 g/m2 were administered to the children three times 
daily for up to 2 years. Significant symptomatic improvement was noted in the accompanying 
renal tubular acidosis [14-16]. In children with a pre- existing seizure disorder, there was a brief 
increase in seizure frequency followed by a decline to below baseline levels [17]. No other 
adverse events were reported. The theoretical argument for treating with exogenous uridine is to 
compensate for uridine synthesis through elevation of cellular uridine levels. In vitro, cells 
impaired by mitochondrial depletion, using ethidium bromide, regain proliferative capacity when 
supplemented with uridine and pyruvate. Additionally, fibroblasts derived from patients with 
mitochondrial disease are dependent on uridine supplementation for survival [18]. 
 
TAU has also been used to “rescue” normal cells during certain types of cancer chemotherapy 
[13, 19]. The uridine competes with anti-cancer uridine analogs, such as 5-FU, thus partially 


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sparing non-cancerous tissues [13, 19]. In the chemotherapy studies, patient received 6 g of TAU 
four times a day with no adverse effects [19, 20]. Kelsen et al. [19] sought to determine the 
appropriate dose of TAU to use as rescue therapy. They investigated doses of 3.3 g, 6.6 g, and 9.9 
g, given as a liquid suspension, every six hours for ten doses after a bolus infusion of 5-FU. The 
5-FU and subsequent TAU was dosed weekly for six weeks followed by a two-week rest period. 
Uridine bioavailability was about 7%, the elimination half-life was 2-4 hours, and the volume of 
distribution was 0.634 L/kg. In the setting of 5-FU toxicity, therapeutic blood levels of uridine 
were 50- 250 µM. Peak levels were obtained 2-3 hours after an oral dose. 
 
1.3 
Bipolar disorder 
 
Bipolar disorder is a chronic illness associated with substantial morbidity and mortality, ranking 
worldwide behind only unipolar depression and alcohol abuse among psychiatric illnesses for 
related disabilities [21, 22]. The lifetime financial burden of bipolar disorder in the United States 
is about $625,000 per patient, depending on treatment refractoriness and chronicity of symptoms 
[23]. Although lithium and anticonvulsants such as valproic acid have substantially improved the 
prognosis of bipolar disorder, many individuals are unable to tolerate treatment-related side-
effects. Incomplete clinical response, relapse and recurrence remain common clinical problems 
[24-27]. The depressive phase of bipolar disorder is particularly challenging to treat and is 
understudied in comparison to bipolar mania [28]. One of the most vexing challenges in the 
treatment of bipolar depression has been the induction of mania in patients receiving treatment for 
depression with standard antidepressants [29]. 
 
Although the exact mechanism of action of uridine in the treatment of bipolar depression is not 
known, several lines of evidence suggest a possible role. 
 
First, bipolar disorder appears to be characterized by the decreased expression of genes coding for 
mitochondrial proteins responsible for oxidative phosphorylation [30]. Studies of brain high-
energy phosphate metabolism with magnetic resonance spectroscopy (MRS) and genetic studies 
have demonstrated mitochondrial dysfunction in subjects with unipolar and bipolar disorders [31-
33]. Because of this dysfunction, mitochondrial oxidative phosphorylation is compromised in 
favor of glycolysis. Uridine may alleviate mitochondrial dysfunction by increasing the synthesis 
of uridine high- energy phosphates. 
 
Second, bipolar disorder is related to concomitant increases in CNS lactate and glutamate [34], 
and provision of exogenous uridine has been shown to decrease lactate production during periods 
of cerebral ischemia [35]. Bipolar patients not taking medications have approximately 20% 
higher levels of brain lactate on proton MRS compared to healthy volunteers, and brain lactate 
levels correlate with the severity of depression [34]. Hence, exogenous uridine is hypothesized to 
impact the pathophysiology of bipolar disorder by decreasing brain lactate levels. 
 
Third, gamma aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the 
mammalian brain, and impairment of its function is thought to play an important role in mood 
disorders [24-26]. Clinical trials have determined that certain GABA-mimetics have 
antidepressant properties [29, 30, 33]. Uridine inhibits in vitro GABA binding in  the frontal 
cortex, hippocampus and thalamus, thus inhibiting its reuptake. Taken together with the 
observation that 14 day pyrimidine administration increases  GABAergic activity, it is 
hypothesized that oral uridine will increase GABAergic activity [32, 36, 37]. 
 


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Fourth, uridine works synergistically with omega-3 fatty acid (ω3FA) in rat models of depression 
[38]. It is hypothesized that uridine increases membrane synthesis, thus facilitating the 
incorporation of ω3FAs into neuronal membranes and increasing phospholipid membrane fluidity 
[39, 40]. 
 
Finally, uridine and uridine prodrugs have had antidepressant effects on rats and in humans. 
Uridine exhibited antidepressant-like effects in the rat forced swim test [38], and TAU and 
cytidine showed modest effects in patients with bipolar depression without inducing mania [41]. 
There are also preliminary clinical reports that uridine has anxiolytic and antidepressant effects 
[42]. 
 
1.3.1 
Uridine Treatment in Bipolar Depression 
 
Researchers have directly examined the effects of TAU on bipolar depression. TAU was well-
tolerated and patients showed modest improvements in mood without the induction of mania 
(Stoll, personal communication) [41]. 
 
Nineteen patients were studied in a 6-week, dose-escalation study with TAU. Patients started at 6 
g/day and, depending on response and tolerability, the dose was increased by an additional 6 
g/day every two weeks to a maximum of 18 g/day. This TAU dosing corresponds to 4 g/day to 12 
g/day of uridine. Montgomery-Asberg Depression Rating Scale (MADRS) scores decreased 
modestly for both unipolar and bipolar subjects over the course of the 6-week study, suggesting a 
decrease in depression. Depressive symptoms for the bipolar subjects were the lowest at week 3 
of the study, whereas depressive symptoms for the unipolar depressed subjects were lowest at the 
end of the study. Mania symptoms improved for bipolar subjects as indicated by a decrease in 
Young Mania Rating Scale (YMRS) scores. Modest improvement in the Clinical Global 
Impression of Severity (CGI-S) in the bipolar patients was seen during the first 4 weeks of 
treatment with TAU. Both bipolar and depressed subjects also showed modest improvements in 
the Global Assessment of Functioning (GAF) and the Hamilton Anxiety Scale (HAM-A) when 
comparing baseline to week six. Side effects included mild self- limited hypomania, dizziness, 
stomach cramps, nausea, decreased appetite, increase in constipation, diarrhea, muscle cramps, 
headaches, fatigue, sleep problems, increased flatulence, decreased libido, and visual disturbance 
(including some loss of depth perception) and eye pain. Neither of the latter two events was 
related to study drug, according to an examining ophthalmologist. One patient did leave the study 
because of a mild worsening of hypomania that was present at baseline (Stoll, personal 
communication). 
 
A study in bipolar I disorder with RG2417 has also been completed and details of this study are in 
Section 4.1.2. 
 
1.4 
Uridine (a.k.a. RG2417) 
 
1.4.1 
Non-clinical studies 
 
The toxicology of elevated blood and tissue levels of uridine can be difficult to assess in animals 
without an efficient means of oral drug delivery due to species-specific, high levels of uridine 
phosphorylase in the gut (the main catabolic enzyme of uridine). The prodrug triacetyl uridine 
(TAU) provides a means of assessing the potential toxic consequence of elevated uridine on 
physiology since it is readily absorbed by passive diffusion and converted to uridine before 
circulation in the blood. Studies in rats and  dogs have been performed to investigate the toxicity 


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of uridine through dosing with TAU. The NOAEL in rats dosed twice daily with TAU for 13 
weeks was 990 mg/kg/day uridine (equivalent to TAU at 1500 mg/kg/day). The NOAEL in dogs 
dosed twice daily with TAU for 13 weeks was also 990 mg/kg/day uridine (equivalent to TAU at 
1500. mg/kg/day). 
 
1.4.2 
Clinical studies 
 
Previously, uridine/RG2417 was studied in two Repligen sponsored clinical trials (Table 2). The 
studies included a Phase I healthy volunteer study to compare the safety and pharmacokinetics of 
RG2417 administered at 1, 2 or 4 g as tablets or as an oral solution. The other study was a Phase 
II study to assess the safety and tolerability of RG2417 administered at 2 or 4 g/day for six weeks 
in the treatment of bipolar I disorder. 
 
 
 
The most common adverse events reported in these studies were headache, fatigue and 
gastrointestinal events such as dry mouth, nausea, abdominal pain and dyspepsia. There was only 
one serious adverse event report that was possibly related to uridine/RG2417. This subject, with a 
co-morbid hypertension experienced a worsening of this pre-existing condition and required in-
patient monitoring. There were no other ischemic or cardiopulmonary sequelae of this event. 
 
In general, uridine/RG2417 is safe and well tolerated when dosed at up to 4 g/day for 6 weeks. 
 
Currently, a Phase IIb clinical trial to further assess the safety and efficacy of uridine/RG2417 in 
eight weeks of oral dosing in bipolar I depression is being conducted under protocol RG2417-03, 
entitled, “A Phase II Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Study to 


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Assess the Safety, Tolerability and Efficacy of RG2417 (Uridine) in the Treatment of Bipolar I 
Depression.” 
 
This study is a randomized, eight-week, double blind, placebo-controlled, Phase II study to assess 
the safety and efficacy of uridine/RG2417 in bipolar I depression. One hundred and fifty (150) 
subjects of both sexes will be enrolled at up to thirty (30) sites and will be randomized on a 1:1 
basis to receive either placebo or uridine/RG2417. 
 
2 
PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES 
 
2.1 
Active Constituent of the Uridine/RG2417 Formulation 
 
The active constituent of RG2417 is uridine (Uracil-1-β-D-Ribofuranoside), which has the 
formula C9H12N2O6 and a molecular weight of 244 g/mole. The structure of RG2417 is shown 
in Figure 3. 
 
 
 
2.2 
Pharmaceutical Properties 
 
Uridine is a naturally occurring pyrimidine nucleoside with numerous physiological and 
metabolic functions. The biological pathways uridine participates in range from cell membrane 
synthesis to excretion of compounds to cellar energetics (see Figure 1). In addition, uridine 
synthesis is coupled to oxidative phosphorylation in mitochondria via dihydroorotate 
dehydrogenase. 
 
2.3 
Manufacturing 
 
Uridine study drug and matching pill placebo are manufactured by Natural Pharmacia 
International, Inc. (NPI; Burlington, MA), which is a Good Manufacturing Practice facility. 
 
2.4 
Physical Properties 
 


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Uridine/RG2417 tablets are uncoated, oval, and white to off-white in color, with dimensions of 
0.64 x 0.23 inches. They have an average weight of 750 mg. When used, matching placebo is 
visually identical to RG2417 tablets. The specifications for uridine/RG2417 and placebo tablets 
are shown in Table 3 and Table 4, respectively. 
 
2.4.1 
Specifications for Uridine/RG2417 Tablets: Table 3 Uridine Specifications 
 
 
 
2.4.2 
Specifications for Placebo Tablets Table 4: Placebo Specifications 
 
 
 
2.5 
Formulation 
 
2.5.1 
Uridine/RG2417 Formulation 
 
Uridine/RG2417 tablets weigh 750 mg and contain 500 mg of RG2417. Tablets have the 
composition listed in Table 5. Tablets are designed for immediate release of RG2417. 
 
Table 5: Formulation of 500 mg RG2417 Tablets 


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2.5.2 
Placebo Formulation 
 
Placebo tablets weigh 750 mg and have the composition listed in Table 6. 
 
 
 
2.6 
Storage and Handling 
 
Uridine/RG2417 and placebo tablets should be stored at room temperature, between 20°C and 
30°C. 
 
2.7 
Intended Route of Administration: 
 
Uridine/RG2417 is intended for daily oral dosing. 
 
3 
NON-CLINICAL STUDIES 
 
Uridine is found in circulation in humans at approximately 2-5 µM. Uridine-containing 
metabolites are formed from either exogenous or endogenous sources of uridine. The absorption 
and metabolism of exogenous uridine are influenced by the location and level of the enzyme 
uridine phosphorylase. Many animals, including rodents, contain high levels of this enzyme 
compared to man, especially in the gut. This makes pharmacology and toxicology assessments 
relevant to man more difficult. To circumvent this problem, prodrugs of uridine, such as 
triacetyluridine (TAU), that are converted to uridine prior to entering the circulation can be used 
and provide a means of obtaining high blood and tissue levels of uridine in rats and dogs. 
 
3.1 
Pharmacology 
 
Two factors that affect the bioavailability of oral doses of uridine are the mechanism of drug 
absorption from the gut and the process of drug catabolism. Uridine uptake is mediated by 
equilibrative and concentrative nucleoside transporters. The metabolism of uridine is controlled 


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by uridine phosphorylase. The extent to which these systems are constant across species will 
determine if animal pharmacology is predictive of drug exposure in humans. 
 
The most relevant nucleoside transporter for uridine uptake is the CNT1 receptor which functions 
in a Na+ dependent manner [43, 44]. The receptor distribution is highest in stomach and 
duodenum, decreasing through the jejunum and ileum [45]. The relative receptor density across 
different species is not well defined. An active transport system that is regionally restricted to the 
upper gastrointestinal tract would suggest that uridine uptake might be saturable and limited to 
early times after ingestion. Pilot studies in pigs showed decreased absorption efficiency with 
enteric-coated solid dose forms of uridine (data on file). 
 
While the brain takes up uridine and converts the nucleoside to phosphorylated forms [46], the 
homeostasis of circulating uridine appears to take place principally in the liver. Catabolism of 
uridine in the liver is controlled by uridine phosphorylase, the enzyme that converts uridine to 
uracil [2]. Catabolism proceeds through dihydrouracil dehydrogenase, dihydropyrimidinase, and 
ureidopropionase ending at ß-alanine [47].  Uridine phosphorylase is present in liver non-
parenchymal cells while the running enzymes are present in hepatocytes. 
 
Uridine phosphorylase is present in rodents at high levels in the GI tract as well as the liver. Non-
rodent animals have lower GI levels but have relatively abundant enzyme in liver non-
parenchymal cells. Humans appear to possess relatively low levels of uridine phosphorylase in 
the GI tract, which is the postulated mechanism of higher bioavailability. Conversely, dosing of 
uridine in rodents, dogs or minipigs leads to high levels of uracil because passage through the GI 
epithelium and liver in these animals converts uridine to the base and results in poor and variable 
availability of the nucleoside. 
 
3.1.1 
Testing for Anticonvulsant and Neuroprotective Activity of Uridine 
 
Anticonvulsants have been used to treat aspects of bipolar I disorder (valproate, carbamazepine, 
lamotrigine). Since such an activity may be relevant for use in bipolar depression, RG2417 was 
screened in one electrical and two chemical induced seizure models. Uridine/RG2417 was dosed 
at 30-300 mg/kg IP 1-4 hours before seizure induction. Studies were conducted using both rats 
and mice (4/group). RG2417 did not alter seizure severity in any of the three models. 
 
Uridine/RG2417 was also tested in two models of epileptogenesis, recovery from status 
epilepticus and hippocampal kindling [48]. In the recovery model, status epilepticus was induced 
with lithium-pilocarpine. After termination of seizures, rats were dosed with uridine/RG2417 four 
times per day at 150 mg/kg IV for 14 days (6/group). At that time, animals were tested in the 
Morris water maze, then sacrificed and selected hippocampal histopathology sections scored for 
neuronal cell loss. Uridine/RG2417-treated animals were significantly improved in finding the 
water maze platform. There was no statistically significant improvement in histology scores. 
 
Uridine/RG2417 was also tested in a rapid kindling model. Rats were kindled via repeated 
hippocampal stimulation (8/group, 12 stimulations/day over 4 days). The number of stimulations 
required to achieve seizures of defined severity with or without treatment indicates effectiveness 
in reducing the rate of kindling. RG2417 treatment resulted in an increase in the number of 
stimulations to reach the more severe stage 4 and 5 seizures (p< 0.05, t test). These results are 
interpreted as demonstrating a modest neuroprotective effect [48]. 
 


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To further study the possible antiepileptogenic properties of uridine, we compared the rate of 
kindling with uridine or levetiracetam when kindling stimulation was done just once per day. We 
administered uridine either once or three times daily (12/group, 200 mg/kg per dose), and used 
normal saline (NS) and levetiracetam (LEV) as negative and positive controls [49]. 
 
There were significant differences between the saline group and the rats given U3 (F(1)  = 4.617, 
p = 0.043) and LEV (F(1)  = 15.22, p <0.001). There was also no difference in the LEV and U3 
groups (F(1) = 3.515, p = 0.063) [49]. Figure 4 shows that both levetiracetam and uridine (given 
three times daily) slow the kindling rate and that levetiracetam and thrice daily uridine injections 
are equivalent in slowing the kindling rate. 
 
Figure 4: Effect of RG2417 in a Daily Kindling Model 
 
 
3.1.2 
Activity of Uridine in the Rodent Forced Swim Test 
 
An animal model of antidepressant effects of drugs often used when studying depression in man 
is the rodent forced swim test [50]. The procedure measures the behavior of immobility in an 
inescapable cylinder of water. Compounds with antidepressant activity in man reduce the 
immobility time in this model. This model has been used to show that treatment with cytidine, a 
pyrimidine rapidly converted to uridine in blood, has an antidepressant effect in rats [38]. The 
positive effect of uridine is potentiated in rats by combined treatment with omega 3 fatty acids 
[51]. 
 
This result has been reproduced in mice as well. Animals were injected with uridine IP three 
times over a 24 hour period prior to testing in the cylinder of water. Figure 5 shows the 
antidepressant effect of uridine dosing in BALB/c mice as reflected by a decrease in total 
immobility time. 


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Figure 5: Effect of RG2417 in the Forced Swim Model Performed in BALB/c Mice 
 
3.2 
Safety Pharmacology 
 
3.2.1 
Neurobehavioral evaluation of TAU in male rats 
 
The purpose of this study was to assess the potential acute neurotoxicity of uridine in adult male 
rats after oral dosing with TAU. This study consisted of four groups of animals each containing 
eight adult male rats. Animals were dosed once by oral gavage at either 0 mg/kg (placebo), 300 
mg/kg, 1000 mg/kg or 2000 mg/kg of TAU. Functional observational battery tests were 
performed pre-dose and at 1 and 24 hours post-dose. Categories evaluated were activity/arousal, 
neuromuscular, sensorimotor, autonomic and physiological. Each animal was scored on a 
standard 12-point Functional Observation Battery (FOB). 
 
No neurobehavioral changes were observed in any rats administered TAU at doses up to 2000 
mg/kg. The NOAEL for this study was 1320 mg/kg uridine (equivalent to 2000 mg/kg TAU). 
 
3.2.2 
Evaluation of repeat oral dosing of TAU on cardiovascular function 
 
An evaluation of cardiac function in beagle dogs was done in conjunction with a twenty eight-day 
repeat dose toxicology study (HLS 02-3010). 
 
Electrocardiographic data were collected pre-dosing, on day twenty-eight and at the end of the 
recovery period. Data was analyzed for anomalies in ECG, including measures of QT interval. No 
anomalies were identified in the ECG-derived measures of cardiac performance. This study 
concludes that the no observed effect level for formulated TAU on cardiac function is 1320 
mg/kg/day uridine (equivalent to 2000 mg/kg TAU). 
 
3.3 
Toxicology 
 
The toxicology of elevated blood and tissue levels of uridine can be difficult to assess in rats and 
dogs without an efficient means of oral drug delivery due to species-specific, high levels of 


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uridine phosphorylase (EC 2.4.2.3) in the gut. The prodrug triacetyl uridine (TAU) provides a 
means of assessing the potential toxic consequence of elevated uridine on animal physiology 
since it is readily absorbed by passive diffusion and converted to uridine before circulation in 
blood. Even at high oral doses of TAU and after repeated dosing for 28 days it is not possible to 
detect TAU in the bloodstream  while uridine levels are elevated more than 1000-fold. The 
bioavailability (efficiency of absorption) of uridine after uridine dosing in rats and dogs is 7-16% 
but with TAU is 40- 70%. Thus TAU provides a means of achieving higher blood levels of 
uridine in rats and dogs for toxicology assessments. 
 
A number of studies have been performed to investigate the toxicity of uridine through prodrug 
dosing (TAU) in animals. The TAU used for these studies was ≥99.0% triacetyluridine. These 
studies are summarized in Table 7. 
 
  Table 7: In Vivo Triacetyl-Uridine Toxicology Study Summary 
 
 
3.3.1 
Single Dose Toxicology Study in Rats (HLS RSZ-002) 
 
The purpose of this study was to assess the acute oral toxicity of uridine (dosed as TAU) to the 
rat. Ten rats (five male and five female) received a single oral gavage dose of TAU formulated in 
0.75% hydroxy propyl methycellulose at a dose level of 2000 mg/kg bodyweight (1320 mg/kg 
uridine equivalents). Animals were observed for clinical response to treatment and body weight 
over fourteen days after which they were euthanized and subjected to a macroscopic examination. 
 
Clinical signs of reaction to treatment were confined to increased salivation in two females. There 
were no abnormalities seen during the macroscopic examination. 
 
The results of this study indicate the no observed adverse effect level (NOAEL) oral dose to rats 
is considered to be greater than 1,320 mg/kg uridine (equivalent to > 2000 mg/kg TAU). 
 
3.3.2 
7-Day Repeat Dose Study of TAU in Rats (HLS RSZ-004) 


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The purpose of this study was to assess the toxicity of uridine when administered twice daily by 
oral gavage as TAU to CD rats for a period of seven consecutive days. The study consisted of one 
control and three treated groups. Each study group, consisting of four male and four female rats, 
was administered TAU by oral gavage at 0 mg/kg/day (placebo control), 300 mg/kg/day (low 
dose), 1000 mg/kg/day (mid dose) or 2000 mg/kg/day (high dose), equivalent to 200, 660, or 
1320 mg/kg/day as uridine, respectively, for seven consecutive days. Animals were observed and 
monitored daily during the seven-day treatment period including food and water consumption, 
body weight, and observation after each dose. Upon termination, all rats were subjected to a 
macroscopic examination and organ weights were recorded. 
 
There were no treatment related changes in body weights, food consumption or organ weights at 
any dose level. Two of the eight animals receiving 2000 mg/kg/day TAU showed pelvic dilation 
of the kidney. Salivation was seen after dosing in animals dosed at 2000 mg/kg/day and for one 
male and one female at 1000 mg/kg/day. In conclusion, oral administrations up to 1,320 
mg/kg/day uridine (equivalent to 2000 mg/kg/day TAU) produced no significant toxic response 
and the NOAEL was 660 mg/kg/day. 
 
3.3.3 
28-Day Repeat Dose Toxicity Study of TAU in Rats (HLS RSZ-005) 
 
The purpose of this study was to assess the toxicity of uridine when administered twice daily by 
oral gavage as TAU to CD rats for twenty-eight consecutive days and to assess the reversibility of 
any adverse effects of treatment following a four-week recovery period. The study consisted of 
one control and three treated groups. Each study group, consisting of ten male and ten female rats 
and designated as the Main Phase animals, was administered TAU by oral gavage at 0 mg/kg/day 
(placebo control), 300 mg/kg/day (low dose), 1000 mg/kg/day (mid dose) or 2000 mg/kg/day 
(high dose) equivalent to 200, 660, or 1320 mg/kg/day as uridine, respectively for twenty-eight 
consecutive days. An additional five male and five female rats designated as Recovery Phase 
animals received TAU either at 0 mg/kg/day (placebo control) or 2000 mg/kg/day for twenty-
eight consecutive days. Upon completion of treatment, all Main Phase animals were euthanized 
while the Recovery Phase animals remained on the study for an additional four weeks (not dosed) 
after which they were euthanized. 
 
There were no drug related body weight or food consumption changes noted. Elevations in serum 
lactate observed in control animals were decreased in the mid and high dose groups. As observed 
in the seven-day repeat dose study a high incidence of salivation associated with dosing was 
apparent in animals receiving 2000 mg/kg/day of TAU and a low incidence in animals receiving 
1000 mg/kg/day. Examination of all urine samples indicated the presence of crystals at 2000 
mg/kg/day TAU. The NOAEL was 660 mg/kg/day uridine (equivalent to 1000 mg/kg/day TAU). 
The NOAEL is based on microscopic findings in kidney and thyroid tissue. 
 
3.3.4 
13 Week Oral Toxicity Study in Rats Dosed with TAU with a 4-Week Recovery Period 
(HLS 08-2056) 
 
The purpose of this study was to assess the toxicity of uridine when administered twice daily as 
TAU by oral gavage at dose levels 300, 750, or 1500 mg/kg/day to Sprague- Dawley CD rats for 
13 weeks and to assess the reversibility of any adverse effects following a 4-week post-dose 
recovery period. 
 


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The study consisted of one control group (fifteen males and fifteen females 0 mg/kg/dose) and 
three treatment groups (ten males and ten females 300 mg/kg/day; ten males and ten females 750 
mg/kg/day; and fifteen males and fifteen females 1500 mg/kg/day). TAU was administered by 
oral gavage twice daily for thirteen consecutive weeks. The four study groups were 0 mg/kg/day 
(placebo control), 300 mg/kg/day (Low Dose), 750 mg/kg/day (Mid Dose), or 1500 mg/kg/day 
(High Dose) equivalent to 0, 198, 495, or 990 mg/kg/day as uridine, respectively. At the end of 
the treatment period, up to ten animals/sex/group were euthanized and necropsied. At the end of a 
four week recovery period, five animals/sex in the 0 mg/kg/day and 1500    mg/kg/day groups 
were euthanized and necropsied. Satellite animals (nine/sex/group) were dosed twice daily, 
approximately eight hours apart with vehicle, 300, 750 or 1500 mg/kg/day TAU and blood was 
collected on Days 45 and 90 for toxicokinetic analysis. 
 
Parameters evaluated during the study were: viability, clinical observations, ophthalmology, body 
weights, food consumption, clinical pathology (termination of dosing and end of recovery), organ 
weights, macroscopic observations and microscopic pathology. 
 
There was a slight decrease in food consumption in males at 1500 mg/kg/day and increases in 
neutrophils at 750 and 1500 mg/kg/day and monocytes and eosinophils at 1500 mg/kg/day. In 
females, serum phosphorus was increased at 1500 mg/kg/day. These changes were minimal and 
not considered adverse effects. With the exception of phosphorus levels in females at 1500 
mg/kg/day, these effects were no longer evident at the end of the recovery period. In conclusion, 
the NOAEL was 990 mg/kg/day uridine (equivalent to 1500 mg/kg/day TAU). 
 
3.3.5 
28 Day Repeated Dose Toxicity of TAU in Beagle Dogs (HLS 02-3010) 
 
The purpose of this study was to assess the toxicity of uridine when administered twice daily as 
TAU by oral gavage to dogs at dose levels of 300, 1000 and 2000 mg/kg/day. 
 
TAU for twenty-eight days and to assess the reversibility of any adverse effects following a 
twenty-eight-day recovery period. 
 
The study consisted of one control (three male and three female) and three treated groups (five 
male and five female per group). TAU was administered by oral gavage twice daily for a period 
of four weeks. The four study groups consisted of 0 mg/kg/day (placebo control), 300 mg/kg/day 
(Low Dose), 1000 mg/kg/day (Mid Dose) or 2000 mg/kg/day (High Dose) equivalent to 200, 660, 
or 1320 mg/kg/dose as uridine, respectively. After treatment, terminal necropsy was performed 
on three animals/sex/group and after a 28- day recovery period the remaining two 
animal/sex/group were euthanized. 
 
Parameters monitored during this study included clinical signs and measurements of body weight, 
food consumption and ECG. Complete clinical pathology was performed once prior to 
commencement of treatment, at the end of treatment and at the end of the recovery period. 
Microscopic analysis of control and high dose group animals was completed at the end of 
treatment and after a thirty-day recovery period. At termination, all dogs were subjected to a 
macroscopic examination and the weights of specific organs were recorded. 
 
The administration of 2000 mg/kg/day of TAU was associated with a 40-50% decrease in mean 
platelet count after twenty-eight days. This finding was not evident following a twenty-eight-day 
recovery period and was not associated with any changes in prothrombin time and activated 
partial thromboplastin time. Also, at 2000 mg/kg/day of TAU, two out of six animals showed 


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minimal abnormal histopathology in mesenteric lymph nodes and thyroid tissue. There was no 
macroscopic or microscopic findings related to test article administration in animals examined 
after a thirty-day recovery period. 
 
In conclusion, changes observed in animals were minimal and not considered adverse effects. 
Therefore, the no-observed-adverse-effect-level (NOAEL) for administration of TAU to beagle 
dogs for twenty-eight days was determined to be or 660 mg/kg/day uridine (equivalent to 1000 
mg/kg/day TAU). This NOAEL is based on a 40-50% decrease in platelets and histopathologic 
findings in mesenteric lymph nodes and thyroid tissue after twenty-eight days of dosing. 
 
3.3.6 
13 Week Oral Toxicity Study in Dogs Dosed with TAU with a 4-Week Recovery Period 
(HLS 08-3323) 
 
The purpose of this study was to assess the toxicity of uridine when administered twice daily as 
TAU by oral gavage at dose levels 300, 750, or 1500 mg/kg/day to beagle dogs for 13 weeks and 
to assess the reversibility of any adverse effects following a 4-week postdose period. 
 
The study consisted of one control group (five males and five females 0 mg/kg/day) and three 
treatment groups (three males and three females 300 mg/kg/day; three males and three females 
750 mg/kg/day; and five males and five females 1500 mg/kg/day). TAU was administered by oral 
gavage twice daily for thirteen consecutive weeks. The four study groups were 0 mg/kg/day 
(placebo control), 300 mg/kg/day (Low Dose), 750 mg/kg/day (Mid Dose), or 1500 mg/kg/day 
(High Dose) equivalent to 0, 198, 495, or 990 mg/kg/day as uridine, respectively. At the end of 
the treatment period, three animals/sex/group were euthanized and necropsied. At the end of a 
four week recovery period, two animals/sex in the 0 mg/kg/day and 1500 mg/kg/day groups were 
euthanized and necropsied. 
 
Parameters evaluated during the study were: viability, clinical observations, ophthalmology, 
ECGs, body weights, food consumption, clinical pathology (pretest, termination of dosing, and 
end of recovery), toxicokinetics (Days 45 and 90), organ weights, macroscopic observations and 
microscopic pathology. 
 
Clinical pathology findings indicative of slight dehydration were noted in males at 1500 
mg/kg/day. Additionally in the male 1500 mg/kg/day group, hemoglobin, red blood cells, 
hematocrit, serum total protein and albumin were increased at the end of dosing. There were no 
unscheduled deaths during the study and no clinical signs or ophthalmology findings. There was 
no electrocardiographic evidence of test article action or effects on body weights and food 
consumption. There were not test article- related effects on organ weights or macroscopic and 
microscopic findings. 
 
Although there was evidence from clinical pathology of slight dehydration in males at the 1500 
mg/kg/day TAU level, there were no clinical signs, no effects on body weights or food 
consumption, and no microscopic findings. In conclusion, the NOAEL for was 990 mg/kg/day 
uridine (equivalent to 1500 mg/kg/day TAU). 
 
3.3.7 
Bacterial Mutagenicity Assay 
 
The purpose of this study was to evaluate the mutagenic potential of RG2417 by measuring its 
ability to induce reverse mutations at selected loci of several strains of Salmonella and 
Escherichia coli in the presence and absence of metabolic activation. 


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The assay was performed in two phases using the plate incorporation method. The first phase was 
used to establish the dose range for confirmatory mutagenicity assay. The second phase was used 
to evaluate and confirm the mutagenic potential of RG2417. 
 
The dose levels tested were 5.0, 1.58, 0.5, 0.16, 0.05, 0.016 mg per plate. In the initial assay no 
positive mutagenic response was observed. Neither precipitate nor appreciable toxicity was 
observed. Based on the initial findings, the maximum dose plated in the confirmatory assay was 
5.0 mg per plate. In the confirmatory mutagenicity assay, no positive response was observed at 
levels of 5.0, 1.58 and 0.5 mg per plate. As in the initial assay, neither precipitate nor appreciable 
toxicity was observed. Under the conditions of this study, RG2417 was found to be negative in 
the Bacterial Reverse Mutation Assay up to the highest concentration tested (5.0 mg per plate). 
 
3.3.8 
In Vitro Mouse Lymphoma Assay 
 
The purpose of this study was to evaluate the clastogenic or point mutation potential of RG2417 
by measuring its ability to induce forward mutations at the thymidine kinase locus of mouse 
lymphoma LY5178Y cells. 
 
The assay was performed in two phases, a dose range assay and a confirmatory assay. In the first 
phase, eight concentrations of RG2417 were used ranging from 5.0 to 0.0016 mg/ml. No toxicity 
was observed. In the second phase, RG2417 was used at concentrations of 5.0, 1.58, 0.5, and 0.16 
mg/ml under both activating and non-activating conditions. For the non-activated test system 
exposures were for 4 and 28 hours while  for the activated test system the exposure was for 4 
hours. The clastogenic and mutagenic potential of RG2417 was evaluated by its ability to 
increase colonies on the restrictive agent trifluorothymidine. The mutant frequency of RG2417 
was not more than two-fold increased above the corresponding control cultures. Based on the 
findings of this study, RG2417 is considered non-mutagenic. 
 
3.4 
Pharmacokinetics and Toxicokinetics in Animals 
 
Blood levels of uridine are elevated after oral dosing with uridine or prodrugs of uridine. After 
oral dosing TAU is converted by ester hydrolysis to uridine during transit through or absorption 
from the gut. TAU is not detectable in blood at any time point at any dose used in these studies. 
Therefore, observations of elimination and metabolism of uridine after repeated drug exposure in 
animals using TAU aids in assessing the toxicokinetics of uridine. 
 
The toxicokinetics of uridine after TAU dosing were assessed in rats and dogs by measuring 
plasma levels of uridine and uracil. The studies were designed to assess the rate of clearance of 
uridine at increasing dose levels of TAU and any change in the clearance rate of uridine after 
repeat administration of drug. The summary table for toxicokinetics in rats and dogs is shown in 
Table 6. Values obtained were not significantly different after 1 or 28 days of dosing and so only 
those values from the 28 days of dosing are shown. This data will be updated with toxicokinetic 
data from the 13 week studies of RG2417 in rats and dogs when the final reports are available. 
 


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  Table 8: Toxicokinetics of Uridine after TAU Dosing 
 
 
An oral toxicology study in CD rats following TAU administration was conducted. A satellite 
group of animals was assigned for toxicokinetic sampling. A total of seventy- two rats were 
divided into four groups with nine females and nine males in each group. TAU was mixed with 
1% carboxymethylcellulose, methylparaben (0.18%) and propylparaben (0.02 %), and 
homogenized to yield a suspension. Doses for groups 2, 3 and 4 were 150, 500 and 1000 mg/kg, 
respectively, twice a day. This is equivalent to 100, 330, and 660 mg/kg bid of uridine, 
respectively. 
 
Blood was collected at 0, 10, 20, and 40 minutes, and 1, 2, 4, 8 and 24 hours after dosing on day 0 
and day 27 and the plasma analyzed by HPLC analysis. 
 
There was a dose dependent increase in blood uridine Cmax and AUC. There was no significant 
difference in the Cmax of uridine between Day 0 and Day 28. No significant difference in the 
absorption, distribution and metabolism of TAU was observed between males and females. 
 
3.4.2 
Absorption and elimination of uridine in dogs after 1 or 28 days of dosing with TAU 
(HLS 02-3010) 
 
A 28-day oral toxicity study of TAU with a 28-day recovery period was conducted in dogs. Three 
treatment groups were given oral doses of TAU at 150, 500 and 1000  mg/kg, bid. This is 
equivalent to 100, 330, and 660 mg/kg bid of uridine, respectively. All animals were dosed at 5 
ml/kg. Blood samples were collected at 0, 10, 20, 40, 60 and 
90 minutes and 2, 3, 4, 8 and 24 hours after dosing on day 0 and day 27 and plasma was analyzed 
by HPLC analysis. 
 
Plasma uridine Cmax and AUC0-∝ increased in a dose-dependent manner. There was no 
significant difference between Day 1 and Day 28 in terms of Cmax uridine. No significant 
difference was observed between males and females in terms of uridine absorption, distribution 
and metabolism. 
 
Uridine half-life (T1/2) in dogs increased by 6-fold the dose 100 to 660 mg/kg dose (0.24 
± 0.03 hr to 1.55 ± 0.33 hr). This is possibly due to the saturation of uridine metabolism, namely, 
uridine conversion to uracil by uridine phosphorylase. This is supported by data indicating plasma 


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uracil increased linearly with dosing up to 330 mg/kg, and then reached an observed plateau in 
the range from 330 to 660 mg/kg of dose. Saturation of uridine phosphorylase was not observed 
under similar dosing in rats. 
 
4 
EFFECTS IN HUMANS 
 
4.1 
Previous Human Experience with Uridine/RG2417 
 
Uridine/RG2417 has been studied in healthy volunteers and patients with bipolar I disorder. A 
tabular summary of these studies is in Appendix 7.2. 
 
4.1.1 
RG2417-02: Healthy Volunteers 
 
RG2417 was administered to healthy human volunteers in a Phase I trial to compare the 
pharmacokinetics of RG2417 given as tablets or as an oral solution. Twelve subjects were given 
single doses of 1 g, 2 g and 4 g RG2417 and plasma concentrations were sampled at multiple 
times after the doses. PK variables in this study were maximum concentration (Cmax), time to 
Cmax (Tmax), AUC and T1/2. 
 
Mean plasma uridine concentrations (Figure 6) and mean values for Cmax, AUC(0-t), and 
AUC(0-inf) (9) increased in a dose-related manner after oral administration of a single 1 g, 2 g, 
and 4 g dose of RG2417 as tablets or solution. Maximum plasma concentrations occurred at a 
median Tmax of 60 to 105 minutes and the T1/2 ranged from 175 to 
274 minutes (2.9 to 4.6 hours). Neither Tmax nor T1/2 parameter appeared to be dependent on 
either dose or formulation (Table 7). 
 
 
 


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The secondary objective of this study was to determine the safety of RG2417 in healthy 
volunteers.  There were a total of 13 adverse events (AEs) in 5 subjects during this study 
summarized in Table 10. Adverse events includes any untoward medical occurrence in a subject 
administered RG2417 or placebo that does not necessarily have a causal relationship with 
treatment. The majority of AEs were mild in severity (11 AEs) with 1 AE judged by the 
Investigator to be severe (headache) and 1 AE judged by the Investigator to be moderate 
(headache). No AEs were reported to be life-threatening. Only 3 of the AEs (2 events of upper 
abdominal pain and 1 AE of headache) were judged by the Investigator to be possibly related to 
the study medication. Table 11 lists the adverse drug reaction of headache from RG2417. Adverse 
drug reactions include any unintended response(s) related to any dose of RG2417. 
 
 


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There were no deaths, serious adverse events (SAEs) or other clinically-significant AEs reported 
during this study.  No subjects were withdrawn from the study due to an AE. 
 
There were no laboratory differences of significance between the treatment groups.  There were 
no clinically-significant vital sign or physical examination findings. The majority of ECG results 
were normal and any abnormal ECG results were not considered to be clinically significant. 
 
Based on these findings, uridine/RG2417 via oral administration as a tablet or solution was safe 
and well-tolerated in healthy male volunteers when either 1 g, 2 g or 4 g doses were randomly 
given over 3 dosing sessions. 
  
4.1.2 
Uridine/RG2417-01: Bipolar I Depression 
 
A clinical trial in bipolar I depression has been completed, protocol uridine/RG2417-01, entitled, 
“Dose-Escalating, Phase II Study to Assess the Safety and Tolerability of Uridine/RG2417 in the 
Treatment of Bipolar I Depression”. This was a randomized, placebo-controlled parallel arm, 
double-blind multi-center study of the safety and efficacy of uridine/RG2417 as monotherapy in 
subjects with bipolar I disorder and a current depressive phase of longer than 30 days. After a 4 
week period to taper off psychotropic medications, a total of 84 subjects were randomized (44 
placebo, 40 RG2417) for weekly evaluations over a 6 week treatment period. Subjects started on 
placebo or RG2417 at 1 g p.o. bid, which could then be elevated to 2 g p.o. bid depending on 
tolerability and efficacy. The primary safety analysis was recording of adverse events, clinical 
and laboratory information, which was reviewed in two interim safety analyses by an independent 
Data Safety Monitoring Board (DSMB). Primary efficacy analysis was the treatment response, 
measured by the Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global 
Impression of Bipolar Disorder (CGI-BP) compared to placebo. 
 


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Figure 7:  Comparison of the Change from Baseline for Total MADRS Scores 
for RG2417 (Uridine) and Placebo Groups 
 
 
In Figure 7, the average total MADRS score is plotted as the change from study day 1 (baseline) 
for the uridine/RG2417 and placebo groups. The true difference between groups is shown by the 
boxes at each evaluation time point. The solid boxes represent the magnitude of the 
uridine/RG2417 treatment benefit in comparison to placebo. 
 
Uridine RG2417 shows treatment benefit from week 2 to the end of the study, however a strong 
placebo response is observed particularly at weeks 5 and 6.  Uridine/RG2417 treatment resulted 
in an improvement in the MADRS assessments compared to placebo over the 6 week period 
(Figure 7), reaching statistical significance (p = 0.011; mixed effects trend to repeat measures). 
 
The CGI-BP evaluation demonstrated an improvement (p = 0.044) for uridine/RG2417 treatment 
in comparison to placebo. Other clinical measurements included the Young Mania Rating Scale 
(YMRS) and the Hamilton Anxiety score (HAM-A), both of which showed no increase in the 
overall mania or anxiety of bipolar I patients on uridine/RG2417 treatment. 
 
The safety analysis confirmed in this population that uridine/RG2417 is a safe and well-tolerated 
drug. Treatment of bipolar depression with standard antidepressant medications may result in an 
increase in treatment associated affective switch (TAAS) to mania or hypomania. In this study 
there were two hypomanic episodes, 1 from the treatment group and 1 from placebo. Although 
not all patients escalated to the high dose, all subjects taking uridine/RG2417 at 2 g p.o. bid were 
able to tolerate it at this level without any dose reductions.  There were no clinically significant 
abnormalities of clinical laboratories, physical or vital signs, or urinalysis associated with 
uridine/RG2417 treatment. 
 


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In general, adverse events were about as common in the uridine/RG2417 group as placebo. 
Overall, 23 of the 40 (57.5%) subjects who received uridine/RG2417 experienced a total of 109 
adverse events. Twenty nine of the 44 (65.9%) subjects in the placebo group experienced a total 
of 98 adverse events. There is no difference between placebo and uridine/RG2417 in the overall 
severity of AEs, but uridine/RG2417 is slightly more attributable in relationship to AEs. Table 12 
summarizes the adverse event data from study RG2417-01. 
 
. 
 
Table 13 provides a summary of adverse events from the uridine/RG2417 study. Adverse events 
include any untoward medical occurrence in a subject administered uridine/RG2417 or placebo 
that does not necessarily have a causal relationship with treatment.  Gastrointestinal, nervous 
system disorders, and psychiatric disorders were commonly observed and consistent with 
published literature [3, 13].  Although AEs of the nervous system were relatively common (31% 
of total), there was little if any difference between RG2417 and placebo.  There was no greater 
rate of somnolence and sedation in the uridine/RG2417 group compared to Placebo (3 events 
Placebo and 3 events RG2417). There were fewer observed adverse events for anxiety (3 Placebo 
and 1 Uridine/RG2417) and insomnia (5 Placebo and 4 Uridine/RG2417) in the uridine group 
compared to placebo. 
 
 
 


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Table 14 summarizes the most common adverse drug reactions. Adverse drug reactions include 
any unintended response(s) related to any dose of uridine/RG2417. Table 14 shows the number of 
patients with adverse events ≥ 5% of the total for which the rate in the treated group exceeds the 
rate for placebo from study RG2417-01. Specific reactions that were predominant in the uridine 
group included dry mouth (4 events in 4 subjects), fatigue (4 events in 4 subjects), and nausea (4 
events in 4 subjects). The only AE that represented > 10% of total adverse events was headache 
(8 events Uridine/RG2417 and 7 events Placebo) which was similar between groups. 
 
 
 
Table 15 shows less common adverse reactions (number of subjects with adverse reactions < 5% 
of the total are represented and for which the rate of the treated group exceeds the rate for 
placebo). Nervous system disorders, skin and subcutaneous tissue disorders, gastrointestinal 
disorders, and vascular disorders were highest among the less common adverse reactions. 
Hypotension (2 reactions, 1 considered serious) and clumsiness (2 reactions) occurred at the 
highest rates of the less common reactions. 
 
 
 
In reviewing adverse events associated with the bipolar population from study RG2417- 01, rates 
attributable to psychiatric etiology were slightly higher in the Placebo group (10 Placebo and 7 
Uridine RG2417 total events). Bruxism and nightmare were the only psychiatric events 
considered related to uridine/RG2417 which occurred at a higher rate in uridine/RG2417 than 


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Placebo. There were 2 (2.4%) subjects with hypomania, 1 in each treatment group. Cardiac 
disorders were infrequent in both groups with only 1 (1.2%) palpitation event in the study, which 
was not considered related to uridine/RG2417. 
 
 
 
There were two serious adverse events observed during the study, one in the placebo group and 
one in the uridine/RG2417 group. The SAE in the placebo group was unrelated to treatment; the 
uridine SAE was possibly related to treatment (Table 16). The SAE in the uridine group was 
exacerbation of pre-existing hypertension requiring immediate monitoring and work-up. The 
subject in the uridine RG2417 group presented for weekly assessment and noted to have blood 
pressure of 180/100. The subject had pre-existing hypertension, and was taking diuretic 
medication. There were no complaints of dyspnea, shortness of breath or substernal chest pain. 
The subject was immediately referred to their primary care physician who placed the patient in a 
cardiac monitoring unit and ruled out an acute ischemic event. The work- up was negative and the 
subject was allowed to go home with the addition of an angiotensin-converting enzyme inhibitor 
(ACEI) medication. The SAE was considered to be possibly related to study drug. There have 
been no prior reports of SAEs with the phase I experience of uridine/RG2417, or in the published 
literature with uridine or uridine pro-drugs, so this SAE has no clinical context. The assurance 
that this SAE was an isolated event will require confirmation in further clinical studies. 
 
Based on these safety findings, RG2417 as a monotherapy via oral administration up to 4 g was 
safe and well tolerated in Bipolar 1 depression. 
 
4.1.3 
Uridine/RG2417-03: Bipolar I Depression 
 
A clinical trial to further assess the safety and efficacy of uridine/RG2417 in bipolar I depression, 
protocol RG2417-03, entitled, “A Phase II Randomized, Double-Blind, Placebo- Controlled, 
Flexible-Dose Study to Assess the Safety, Tolerability and Efficacy of RG2417 (Uridine) in the 
Treatment of Bipolar I Depression” is currently being conducted. 
 
This study is a randomized, eight-week, double blind, placebo-controlled, phase II study to assess 
the safety and efficacy of RG2417 in bipolar I depression. One hundred and fifty (150) subjects 
of both sexes will be enrolled at up to thirty (30) sites and will be randomized on a 1:1 basis to 
receive either placebo or uridine/RG2417. 
 
Use of psychotropic drugs other than symptomatic use of benzodiazepines and 
sedatives/hypnotics is not permitted during the study. Subjects will be tapered from all such 
medications for up to 28 days prior to Visit 2 (Day 0). This medication taper is necessary in order 
to measure the clinical outcomes of RG2417 as a monotherapy, therefore reducing the possibility 
of a false negative. The duration of the medication taper will be at the discretion of the 


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investigator. However, subjects must be off all psychotropic drugs (excluding fluoxetine) at least 
24 hours prior to Visit 2 (Day 0); subjects must discontinue fluoxetine at least 2 weeks prior to 
Visit 2. During the treatment phase, symptomatic use of small doses of sedatives/hypnotics 
(equivalent to a total daily dose of 12.5 mg zolpidem) will be permitted, at the discretion of the 
investigators for no more than 19 days total as well as benzodiazepines (equivalent to a total daily 
dose of 2 mg lorazepam) for no more than 19 days total. 
 
The clinical impact of treatment will be evaluated by physical examination, recording of adverse 
events, laboratory values, vital signs and clinical rating scales (Montgomery-Asberg Depression 
Rating Scale, Young Mania Rating Scale, Clinical Global Impression of Severity-Bipolar 
Disorder and the Columbia-Suicide Severity and Rating Scale). 
 
4.2 
Anticipated benefits and risks 
 
It is anticipated that administration of uridine/RG2417 to patients with Bipolar Depression will 
result in an improvement in their clinical status, as measured by a decrease from baseline in their 
MADRS and Clinical Global Impression of Severity scores, without induction of mania, as 
measured by the YMRS. The primary risks associated with uridine/RG2417 are likely to be those 
seen with other formulations of uridine, including transient gastrointestinal discomfort, diarrhea, 
headache and hypertension. 
 
4.3 
Marketing Experience 
 
There is no marketing experience with uridine/RG2417. 
 
5 
SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR 
 
5.1 
Investigational Product 
 
Uridine/RG2417 is currently under investigation as a potential treatment for bipolar depression 
and suicidal ideation. 
 
5.2 
Drug Safety 
 
Uridine/RG2417 does not have an effect on the neurobehavioral activity in rats. There is no 
alteration in cardiac function after single doses in minipigs or multiple doses in dogs. RG2417 
does not appear to be genotoxic as measured by the Ames test and in vitro mammalian 
chromosomal aberration test. Repeat dosing for 28 days with the prodrug triacetyluridine (TAU) 
in rats showed microscopic findings in kidney and thyroid tissue. Repeat dosing for 28 days in 
dogs showed microscopic findings in mesenteric lymph nodes and thyroid. 
 
Uracil, the free base of uridine, is demonstrated to be a urinary bladder cancer promoting agent in 
rats, with a TD50 of 671 mg/kg/day (TD50 is the daily dose required to induce tumors in half of 
the animals that would have remained tumor-free at zero dose). Bladder carcinoma in rats is 
associated with the formation of calculi [52]. 
 
Previous experience in man with oral dosing of uridine and uridine based prodrugs have shown 
mild-to moderate side effects at high doses including diarrhea and nausea. 
 


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Uridine/RG2417 in healthy human volunteers at repeated single dosing of 1 g, 2 g and 4 g was 
well tolerated with minimal side effects. 
 
Uridine/RG2417 given as a daily dose of 2 g or 4g day was safe and well tolerated over a 6 week 
period in bipolar depression. 
 
5.3 
Adverse Reactions 
 
Transient gastrointestinal discomfort and diarrhea are the most common adverse events noted in 
conjunction with treatment with uridine and its prodrugs. 
 
In subjects dosed with RG2417, the most common adverse reactions included dizziness, dry 
mouth, nausea, fatigue and headache. (Table 11 and Table 14). Less common adverse reactions 
included dyspepsia, haematochezia, weight decrease, myalgia, clumsiness, dysphasia, bruxism, 
nightmare, pollakiuria, rhinorrhea, increased bruising, rash, and hypertension (Table 15). 
 
There was only one serious adverse event reported that was possibly related to uridine/RG2417. 
This subject, with a co-morbid hypertension experienced a worsening of this pre-existing 
condition and required inpatient monitoring. There were no other ischemic or cardiopulmonary 
sequelae of this event. 
 
5.4 
Method of Administration 
 
Uridine is intended for oral dosing. 
 
5.5 
Contraindications 
 
None known. 
 
5.6 
Special Warning and Special Precautions for Use 
 
There is an increased lactose content in the placebo formulation which may cause clinical 
symptoms in patients that are lactose intolerant. 
 
5.7 
Interactions with Other Medications and Other Forms of Interaction 
 
None known. 
 
5.8 
Undesirable Effects 
 
None known. 
 
5.9 
Overdose 
 
None known. 
 
5.10 
Shelf life 
 
Uridine/RG2417 drug product is expected to remain stable for the duration of clinical studies. All 
lots used in clinical studies will remain on stability testing for the duration of the studies. RG2417 


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drug product lot RCM-05-0001 has remained stable for 2 years when stored at 25°C. The stability 
testing is ongoing. 
 
5.11 
Special Precautions for Storage 
 
Avoid exposure to temperatures < 20°C and > 30°C. 
 
5.12 
Nature and Contents of Container 
 
Tablets are packaged in white HDPE bottles (400cc) with cotton fill. Bottles are induction sealed 
and closed with a childproof cap. 
 
6 
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