Urea for Chronic Hyponatremia: A Pilot Study
Phase: PHASE2
Conditions: Hyponatremia, Inappropriate ADH Syndrome
Sponsor: Helbert Rondon Berrios, MD, MS

1 
 
PROTOCOL TITLE: UREA FOR CHRONIC HYPONATREMIA: A PILOT STUDY 
 
VERSION DATE: 8/25/2022 
 
SPONSOR: HELBERT RONDON BERRIOS 
 
IND NUMBER: 150749 
 
 
NCT NUMBER: NCT04588207 
 
PRINCIPAL INVESTIGATOR: HELBERT RONDON BERRIOS, STEVEN D. WEISBORD 
 
SUB-INVESTIGATORS:  
• 
PAUL M. PALEVSKY 
• 
CHRISTOPHER CONNABOY 
• 
JONATHAN G. YABES 
• 
SHAWN FLANAGAN 
 
 
 

2 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS……………………………………………………………………………… 
 
1. 
STUDY OBJECTIVE, SPECIFIC AIMS, BACKGROUND AND SIGNIFICANCE…...... 
 
1.1 OBJECTIVE……………………………………………………………………………….. 
 
1.2 SPECIFIC AIMS…………………………………………………………………………... 
 
1.3 BACKGROUND AND RATIONALE……………………………………………………. 
 
1.4 SIGNIFICANCE…………………………………………………………………………… 
 
2. 
RESEARCH DESIGN AND METHODS……………………………………………………. 
 
2.1 CLASSIFICATION AND METHODOLOGICAL DESIGN…………………………….. 
 
2.2 DETAILED DESCRIPTION OF STUDY DESIGN…………………………………….. 
 
 
2.2.1 TABLE OF STUDY VISITS AND ASSESSMENTS ……………………….. 
2.3 STUDY DRUG(S)………………………………………………………………............... 
 
2.4 STUDY ENDPOINTS…………………………………………………………………….. 
 
2.5 STATISTICAL ANALYSIS……………………………………………………………….. 
 
3. 
HUMAN SUBJECTS………………………………………………………………………….. 
 
3.1 SUBJECT POPULATION………………………………………………………………... 
 
3.2 INCLUSION CRITERIA…………………………………………………………………... 
 
3.3 EXCLUSION CRITERIA………………………………………………………………….. 
 
4. 
IRB APPROVAL AND FDA AMENDMENTS …………………………………………… 
 
5. 
RECRUITMENT AND INFORMED CONSENT PROCEDURES………………………… 
5.1 RECRUITMENT METHODS…………………………………………………………….. 
 
5.2 INFORMED CONSENT PROCEDURES……………………………………………… 
 
6. 
POTENTIAL RISKS AND BENEFITS……………………………………………………… 
 
6.1 POTENTIAL RISKS………………………………………………………………………. 
 
6.2 ALTERNATIVE TREATMENTS…………………………………………………………. 
 
6.3 POTENTIAL BENEFITS…………………………………………………………………. 
 
7. 
RISK MANAGEMENT PROCEDURES…………………………………………………….. 
7.1 PROTECTION AGAINST RISKS……………………………………………………….. 
7.2 PROTECTION AGAINST POTENTIAL RISKS OF EXPERIMENTAL 
INTERVENTION………………………………………………………………………….. 
 
8.  
REPORTABLE EVENTS…………………………………………………………………….. 
 
8.1 REPORTABLE ADVERSE EVENTS…………………………………………………… 
 
8.2 ADVERSE EVENT REPORTING TIMELINES………………………………………… 
 
9. 
DATA SAFETY MONITORING……..……………………………………………………….. 
 
9.1 DATA AND SAFETY MONITORING BOARD…………………………………………. 
 
9.2 DATA AND SAFETY MONITORING PLAN 
 
9.3 PARAMETERS TO BE MONITORED………………………………………………….. 
 
9.4 FREQUENCY OF MONITORING………………………………………………………. 
 
10. 
WITHDRAWAL OF SUBJECTS AND STOPPING CRITERIA…………………………… 
 

3 
 
11. 
COSTS AND PAYMENTS…………………………………………………………………… 
 
11.1 COSTS…………………………………………………………………………………….. 
 
11.2 PAYMENTS……………………………………………………………………………….. 
 
12. 
QUALIFICATIONS AND SOURCE OF SUPPORT……………………………………….. 
 
12.1 QUALIFICATIONS OF THE INVESTIGATORS……………………………………….. 
 
12.2 SOURCE OF SUPPORT………………………………………………………………… 
 
13. 
REFERENCES………………………………………………………………………………… 
 
14.  
APPENDICES ………………………………………………………………………………….. 
 
NEUROCOGNITIVE AND POSTURE STABILITY ASSESSMENTS 
 
 
 
 

4 
 
PROTOCOL SYNOPSIS 
 
Protocol Title: 
Urea for chronic hyponatremia: a pilot study 
Protocol Number: 
STUDY20050035  
NCT Number: 
NCT04588207 
Version # and Date: 
Version #13, 8/25/22 
Clinical Phase: 
2 
Investigational Drugs: 
Urea 
Trial Site: 
University of Pittsburgh Medical Center 
IND Sponsor: 
Helbert Rondon Berrios 
Investigator: 
Helbert Rondon Berrios 
Sub-Investigators: 
Steven Weisbord 
Paul Palevsky 
Christopher Connaboy 
Jonathan Yabes 
Study Monitor: 
DSMB 
Research Facilities: 
1. UPMC Kidney Clinic  
2. University of Pittsburgh Neuromuscular Research 
Laboratory 
3. UPMC Montefiore Clinical and Translational Research 
Center 
Clinical Laboratories: 
UPMC Presbyterian (Falk Medical Building) 
UPMC Magee-Womens 
UPMC Shadyside 
UPMC Mercy 
UPMC Passavant 
UPMC East 
UPMC St Margaret 
UPMC McKeesport 
Study Rationale: 
Hyponatremia, defined as a plasma sodium concentration 
(PNa) <135 mmol/L, is the most common electrolyte disorder 
encountered clinically. Hyponatremia is categorized as mild 
(i.e., PNa 130-134 mmol/L), moderate (i.e., PNa 120-129 
mmol/L), or severe (i.e., PNa<120 mmol/L) and as acute (i.e., 
duration <48 hours), or chronic (i.e., duration ≥48 hours). The 
small proportion of patients with this disorder who present with 
severe and/or acute hyponatremia frequently have overt 
neurological symptoms and require hospitalization and urgent 
treatment. Much more commonly, patients with this condition 
have chronic non-severe hyponatremia that does not typically 
require hospitalization or urgent therapy. While such patients 
are seemingly asymptomatic, a growing body of evidence 
demonstrates that even mild chronic hyponatremia is 
associated with subtle neurocognitive deficits, gait and postural 
disturbances, development of osteoporosis, heightened risk for 

5 
 
falls and fractures, and increased mortality. As a result, there 
has been substantial interest in identifying treatments 
that can be used for the long-term management of patients 
with chronic hyponatremia that are safe, well tolerated, 
and that mitigate the morbidity and mortality associated with 
this condition. 
The most common etiology of chronic hyponatremia is the 
syndrome of inappropriate antidiuretic hormone 
secretion (SIADH), and interventions currently used to treat 
this condition are based on our understanding of its 
pathophysiology. However, some of these treatments, 
including loop diuretics, oral sodium chloride tablets, and 
fluid restriction lack evidence of efficacy from clinical trials, and 
in the case of fluid restriction, pose significant challenges to 
long-term patient compliance. Other therapies such as 
vasopressin receptor antagonists (i.e., vaptans) have been 
shown to improve PNa in clinical trials, yet their widespread 
use is limited by the notable risk for serious side effects, 
including liver injury, as well as very high costs. Consequently, 
at present, there are no treatment interventions available that 
have been shown in clinical trials to be efficacious, safe, easy 
for patients to adhere to, and affordable for long-term use. 
Small case series conducted in Europe have investigated the 
efficacy of increasing urinary solute excretion through the 
administration of oral urea, and found this agent to be safe and 
effective for the treatment of chronic hyponatremia. However, 
these studies were not designed or powered to examine the 
effect of long-term urea therapy on key patient-centered 
clinical outcomes. Moreover, urea has not been available for 
clinical use in the United States until recently when a novel 
commercial formulation was introduced. In the first published 
study of this novel formulation of urea, our group reported it to 
be effective, safe, and well tolerated for the treatment of 
inpatient hyponatremia. However, these findings were derived 
from a retrospective cohort study that focused exclusively on 
short-term inpatient use of urea in a small number of patients. 
To date, there have been no clinical trials that have 
investigated the efficacy and safety of oral urea for the 
treatment of chronic hyponatremia.  
Study Objectives: 
Primary 
1. To determine the number and proportion of patients 
with chronic hyponatremia due to SIADH who met 
inclusion/exclusion criteria and were enrolled in the 
study. 
2. To determine the number and proportion of enrolled 
patients with chronic hyponatremia due to SIADH who 
completed the study. 
3. To determine the monthly enrollment rate of patients 
with chronic hyponatremia due to SIADH who met 
inclusion/exclusion criteria. 

6 
 
4. To determine the number of prescribed urea doses 
taken by patients with chronic hyponatremia due to 
SIADH at completion of the study. 
5. To determine the reasons for non-adherence to urea 
therapy by patients with chronic hyponatremia due to 
SIADH. 
6. To assess the change in percentage accuracy action 
boundary selection in patients with chronic 
hyponatremia due to SIADH from baseline to day 42 of 
urea therapy  
7. To assess the change in overall score of sensorimotor 
ability battery in patients with chronic hyponatremia due 
to SIADH from baseline to day 42 of urea therapy. 
8. To assess the change in the sample entropy of the 
center of pressure data from the force plate in patients 
with chronic hyponatremia due to SIADH from baseline 
to day 42 of urea therapy. 
9. To assess the change in percentage angular deviation 
of vestibular control system using dynamic 
representation of upright stance in patients with chronic 
hyponatremia from SIADH from baseline to day 42 of 
urea therapy. 
10. To assess the change in percentage angular deviation 
of somatosensory control system using dynamic 
representation of upright stance in patients with chronic 
hyponatremia due to SIADH from baseline to day 42 of 
urea therapy. 
11. To assess the change in percentage angular deviation 
of visual control system using dynamic representation 
of upright stance in patients with chronic hyponatremia 
due to SIADH from baseline to day 42 of urea therapy. 
12. To assess the change in percentage weight symmetry 
using dynamic representation of upright stance in 
patients with chronic hyponatremia due to SIADH from 
baseline to day 42 of urea therapy. 
13. To assess the change in movement latency of posture 
control and stability using dynamic representation of 
upright stance in patients with chronic hyponatremia 
due to SIADH from baseline to day 42 of urea therapy. 
14. To assess the change in amplitude scaling of posture 
control and stability using dynamic representation of 
upright stance in patients with chronic hyponatremia 
due to SIADH from baseline to day 42 of urea therapy 
15. To determine the number and proportion of patients 
with chronic hyponatremia due to SIADH enrolled in the 
study with adverse events related to the use of urea 
16. To determine the presence and nature of adverse 
events in patients with chronic hyponatremia due to 
SIADH related to urea therapy. 
Secondary 

7 
 
1. To determine the number of patients screened for the 
study. 
2. To determine the number and proportion of patient 
screened who met inclusion/exclusion criteria for the 
study. 
3. To determine the number and proportion of patients 
enrolled in the study who took more than 80% of 
prescribed urea doses. 
4. To determine the number and proportion of patients 
enrolled in the study who thought urea was acceptable. 
5. To determine the patients’ average ratings for urea 
acceptability. 
6. To assess the change in SF-12 (Health Survey) Mental 
Component Summary (MCS) in patients with chronic 
hyponatremia due to SIADH from baseline to day 42 of 
urea therapy. 
7. To assess the change in SF-12 (Health Survey) 
Physical Component Summary (PCS) in patients with 
chronic hyponatremia due to SIADH from baseline to 
day 42 of urea therapy. 
Study Hypothesis: 
1. We hypothesize that we will be able to recruit at least 
10% of eligible patients with chronic hyponatremia due 
to SIADH.  
2. We hypothesize that we will be able to document at 
least 80% compliance with prescribed urea doses in 
patients with chronic hyponatremia due to SIADH. 
3. We hypothesize that urea will significantly increase the 
plasma sodium concentration at day 42 compared with 
the baseline level in patients with chronic hyponatremia 
due to SIADH.  
4. We hypothesize that urea will significantly improve the 
scores on neurocognitive and posture control and 
stability assessments at day 42 compared with the 
baseline scores in patients with chronic hyponatremia 
due to SIADH. 
5. We hypothesize that adverse events related to the use 
of urea in patients with chronic hyponatremia due to 
SIADH will be very uncommon. 
Study Aims: 
1. To assess  the  feasibility  of  recruiting  patients  with 
chronic hyponatremia due to SIADH into a study of  oral  
urea and to evaluate their adherence to oral urea. 
2. To assess  the  effect  of  oral  urea  on plasma  sodium  
concentration and on neurocognitive function and 
postural control and stability in patients with chronic 
hyponatremia due to SIADH. 
3. To explore the safety of oral urea in patients with 
chronic hyponatremia due to SIADH. 
Study Design: 
The proposed pilot study is designed as a prospective, cross-
over trial. Over a 13.5-month period, we will recruit 30 

8 
 
outpatients with chronic non-severe hyponatremia (PNa 125 to 
132 mmol/L) confirmed to be due to SIADH. Following 
enrollment, patients will be randomly assigned on 1:1 ratio to 
one of two sequence groups. Patients assigned to group “Urea 
ON, then Urea OFF” will receive oral urea for 42 ± 3 days 
(period 1), followed by a 10 ± 4-day period in which patients 
will be off urea (washout period). Patients then will be off urea 
for 42 ± 3 days (period 2). Patients assigned to group “Urea 
OFF, then Urea ON” will be off urea therapy for 42 ± 3 days 
(period 1), and following a 10 ± 4-day washout period then they 
will initiate urea for 42 ± 3 days (period 2). Patients will have 
PNa assessed at baseline and on days 7 ± 2, 14 ± 2, and 42 ± 
3 during periods 1 and 2 of the study and will undergo 
neurocognitive and postural control and stability testing on 
days 0 and 42 of each of the study periods. All patients will be 
advised to restrict their fluid intake to ≤1.2 liters during periods 
1 and 2. 
Planned Sample Size:  
30 patients 
Duration of Treatment: 
42 ± 3 days 
Major Inclusion Criteria:  
1. Age ≥18 years 
2. Attended ≥1 visit at a UPMC outpatient clinic within the 
prior 12 months 
3. Chronic hyponatremia with a history of ≥ 2 sequential 
plasma sodium concentration (PNa) between 125 
mmol/L and 132 mmol/L performed ≥ 14 days apart 
within the last 18 months with most recent PNa ≤ 132 
mmol/L prior to screening 
4. Patients are ambulatory without the need for any assist 
device (e.g., cane, walker) 
5. Mini-mental state examination (MMSE) score ≥ 25 
6. Diagnosis of SIADH established by the Bartter and 
Schwartz criteria as follows: 
a. Hyponatremia with a PNa between 125 mmol/L and 
132 mmol/L 
b. Plasma osmolality < 275 mOsm/kg 
c. Clinical euvolemia 
d. Urine osmolality > 100 mosm/kg 
e. Urine Na ≥ 20 mmol/L 
f. Intact adrenal function (i.e., morning plasma cortisol 
value ≥15 μg/dL, or negative corticotropin 
stimulation test) 
g. Normal thyroid stimulating hormone level (i.e., TSH 
between 0.3 to 5 μIU/mL) 
h. eGFR ≥ 45 ml/min/1.73 m2) 
7. Nephrology patients who meet eligibility for the study 
including a nadir serum sodium of no less than125 
mmol/L and have already started urea and treating 
physician agrees to discontinuing prescribed urea. 

9 
 
Major Exclusion 
Criteria: 
1. Cirrhosis and/or end-stage liver disease 
2. Heart failure on diuretics and/or with recorded left 
ventricular ejection fraction <40% 
3. Chronic kidney disease with most recent estimated 
glomerular filtration rate < 45 ml/min/1.73m2 
4. Adrenal insufficiency 
5. Untreated hypothyroidism 
6. Urinary tract obstruction within the prior 2 months 
7. Uncontrolled hyperglycemia (most recent random 
plasma glucose ≥ 200 mg/dL) 
8. Ongoing drug treatment for hyponatremia with vaptans 
or combination of loop diuretics and salt tablets. 
9. Active malignancy (not on remission) 
10. Active infection 
11. Neurological disorders with impairment of ambulation 
and/or cognition 
12. End-stage lung disease with marked impairment in 
ambulatory capacity 
13. Chronic pain with impairment of ambulation and/or 
cognition 
14. Chronic nausea 
15. Hypersensitivity to urea 
16. Women who are pregnant, breast feeding, or of 
childbearing potential who are not using contraception 
17. Patient is unable to consent for himself/herself 
Study Endpoints: 
Primary Endpoints: 
1. Number and proportion of patients who met 
inclusion/exclusion criteria and were enrolled in the 
study 
2. Number and proportion of patients enrolled who 
completed the study 
3. Monthly enrollment rate 
4. Number of prescribed urea doses taken by patients 
5. Reasons for non-adherence to urea therapy 
6. Change in plasma sodium concentration 
7. Change in percentage accuracy action boundary 
selection 
8. Change in overall score of sensorimotor ability battery 
9. Change in the sample entropy of the center of pressure 
data from the force plate 
10. Change in percentage angular deviation of vestibular 
control system using dynamic representation of upright 
stance 
11. Change in percentage angular deviation of 
somatosensory control system using dynamic 
representation of upright stance 
12. Change in percentage angular deviation of visual 
control system using dynamic representation of upright 
stance 
13. Change in percentage weight symmetry using dynamic 
representation of upright stance 

10 
 
14. Change in movement latency of posture control and 
stability using dynamic representation of upright stance 
15. Change in amplitude scaling of posture control and 
stability using dynamic representation of upright stance 
16. Number and proportion of patients enrolled in the study 
with adverse events related to the use of urea 
17. Adverse events related to urea 
Secondary Endpoints: 
1. Number of patients screened 
2. Number and proportion of patient screened who met 
inclusion/exclusion criteria for the study 
3. Number and proportion of patients who took more than 
80% of prescribed urea doses 
4. Number and proportion of patients who thought the 
medication was acceptable 
5. Average ratings for medication acceptability 
6. Change in SF-12 (Health Survey) Mental Component 
Summary (MCS) 
7. Change in SF-12 (Health Survey) Physical Component 
Summary (PCS) 
1. 
OBJECTIVE, SPECIFIC AIMS, BACKGROUND, AND SIGNIFICANCE 
 
1.1 OBJECTIVE 
 
Primary: 
 
a. To determine the number and proportion of patients with chronic hyponatremia due to 
SIADH who met inclusion/exclusion criteria and were enrolled in the study. 
b. To determine the number and proportion of enrolled patients with chronic hyponatremia 
due to SIADH who completed the study. 
c. To determine the monthly enrollment rate of patients with chronic hyponatremia due to 
SIADH who met inclusion/exclusion criteria. 
d. To determine the number of prescribed urea doses taken by patients with chronic 
hyponatremia due to SIADH at completion of the study. 
e. To determine the reasons for non-adherence to urea therapy by patients with chronic 
hyponatremia due to SIADH. 
f. To assess the change in percentage accuracy action boundary selection in patients with 
chronic hyponatremia due to SIADH from baseline to day 42 of urea therapy  
g. To assess the change in overall score of sensorimotor ability battery in patients with 
chronic hyponatremia due to SIADH from baseline to day 42 of urea therapy. 
h. To assess the change in the sample entropy of the center of pressure data from the 
force plate in patients with chronic hyponatremia due to SIADH from baseline to day 42 
of urea therapy. 
i. 
To assess the change in percentage angular deviation of vestibular control system using 
dynamic representation of upright stance in patients with chronic hyponatremia from 
SIADH from baseline to day 42 of urea therapy. 
j. 
To assess the change in percentage angular deviation of somatosensory control system 
using dynamic representation of upright stance in patients with chronic hyponatremia 
due to SIADH from baseline to day 42 of urea therapy. 

11 
 
k. To assess the change in percentage angular deviation of visual control system using 
dynamic representation of upright stance in patients with chronic hyponatremia due to 
SIADH from baseline to day 42 of urea therapy. 
l. 
To assess the change in percentage weight symmetry using dynamic representation of 
upright stance in patients with chronic hyponatremia due to SIADH from baseline to day 
42 of urea therapy. 
m. To assess the change in movement latency of posture control and stability using 
dynamic representation of upright stance in patients with chronic hyponatremia due to 
SIADH from baseline to day 42 of urea therapy. 
n. To assess the change in amplitude scaling of posture control and stability using dynamic 
representation of upright stance in patients with chronic hyponatremia due to SIADH 
from baseline to day 42 of urea therapy 
o. To determine the number and proportion of patients with chronic hyponatremia due to 
SIADH enrolled in the study with adverse events related to the use of urea 
p. To determine the presence and nature of adverse events in patients with chronic 
hyponatremia due to SIADH related to urea therapy. 
 
 
Secondary: 
 
a. To determine the number of patients screened for the study. 
b. To determine the number and proportion of patient screened who met 
inclusion/exclusion criteria for the study. 
c. To determine the number and proportion of patients enrolled in the study who took more 
than 80% of prescribed urea doses. 
d. To determine the number and proportion of patients enrolled in the study who thought 
urea was acceptable. 
e. To determine the patients’ average ratings for urea acceptability. 
f. To assess the change in SF-12 (Health Survey) Mental Component Summary (MCS) in 
patients with chronic hyponatremia due to SIADH from baseline to day 42 of urea 
therapy. 
g. To assess the change in SF-12 (Health Survey) Physical Component Summary (PCS) in 
patients with chronic hyponatremia due to SIADH from baseline to day 42 of urea 
therapy. 
 
1.2 SPECIFIC AIMS 
 
Hypotheses:  
 
a. We hypothesize that we will be able to recruit at least 10% of eligible patients with chronic 
hyponatremia due to SIADH.  
b. We hypothesize that we will be able to document at least 80% compliance with 
prescribed urea doses in patients with chronic hyponatremia due to SIADH. 
c. We hypothesize that urea will significantly increase the plasma sodium concentration at 
day 42 compared with the baseline level in patients with chronic hyponatremia due to 
SIADH.  
d. We hypothesize that urea will significantly improve the scores on neurocognitive and 
posture control and stability assessments at day 42 compared with the baseline scores 
in patients with chronic hyponatremia due to SIADH. 
e. We hypothesize that adverse events related to the use of urea in patients with chronic 
hyponatremia due to SIADH will be very uncommon. 

12 
 
 
Specific Aims: 
 
Primary:  
 
1. To assess  the  feasibility of recruiting patients with chronic hyponatremia due to SIADH 
into a study of oral urea and to evaluate their adherence to oral urea. 
2. To assess  the  effect of oral urea  on plasma  sodium  concentration and on 
neurocognitive function and postural control and stability in patients with chronic 
hyponatremia due to SIADH. 
3. To explore the safety of oral urea in patients with chronic hyponatremia due to SIADH. 
 
1.3. BACKGROUND and RATIONALE 
 
Introduction 
Hyponatremia, defined as a plasma sodium concentration (PNa) <135 mmol/L, is the most 
common electrolyte disorder encountered clinically. Hyponatremia is categorized as mild (i.e., 
PNa 130-134 mmol/L), moderate (i.e., PNa 120-129 mmol/L), or severe (i.e., PNa<120 mmol/L) 
and as acute (i.e., duration <48 hours), or chronic (i.e., duration ≥48 hours). The small 
proportion of patients with this disorder who present with severe and/or acute hyponatremia 
frequently have overt neurological symptoms and require hospitalization and urgent 
treatment. Much more commonly, patients with this condition have chronic non-severe 
hyponatremia that does not typically require hospitalization or urgent therapy. While such 
patients are seemingly asymptomatic, a growing body of evidence demonstrates that even mild 
chronic hyponatremia is associated with subtle neurocognitive deficits, gait and postural 
disturbances, development of osteoporosis, heightened risk for falls and fractures, and 
increased mortality.(1) As a result, there has been substantial interest in identifying treatments 
that can be used for the long-term management of patients with chronic hyponatremia that are 
safe, well-tolerated, and that mitigate the morbidity and mortality associated with this condition. 
The most common etiology of chronic hyponatremia is the syndrome of inappropriate 
antidiuretic hormone secretion (SIADH), and interventions currently used to treat this condition 
are based on our understanding of its pathophysiology. However, some of these treatments, 
including loop diuretics, oral sodium chloride tablets, and fluid restriction lack evidence of 
efficacy from clinical trials, and in the case of fluid restriction, pose significant challenges to 
long-term patient compliance. Other therapies such as vasopressin receptor antagonists (i.e., 
vaptans) have been shown to improve PNa in clinical trials (2), yet their widespread use is 
limited by the notable risk for serious side effects, including liver injury, as well as very high 
costs. Consequently, at present, there are no treatment interventions available that have been 
shown in clinical trials to be efficacious, safe, easy for patients to adhere to, and affordable for 
long-term use. Small case series conducted in Europe have investigated the efficacy of 
increasing urinary solute excretion through the administration of oral urea, and found this agent 
to be safe and effective for the treatment of chronic hyponatremia.(3) However, these studies 
were not designed or powered to examine the effect of long-term urea therapy on key patient-
centered clinical outcomes. Moreover, urea has not been available for clinical use in the United 
States until recently when Ure-Na™, a novel commercial formulation was introduced. In the first 
published study of this novel formulation of urea, our group reported it to be effective, safe, and 
well tolerated for the treatment of inpatient hyponatremia.(4) However, these findings were 
derived from a retrospective cohort study that focused exclusively on short-term inpatient use of 
urea in a small number of patients. To date, there have been no clinical trials that have 
investigated the efficacy and safety of oral urea for the treatment of chronic hyponatremia. 
 

13 
 
Prevalence and costs of chronic non-severe hyponatremia in the ambulatory setting 
While the prevalence of chronic non-severe hyponatremia has not been extensively 
investigated, existing data suggest this condition is quite common. Gankam-Kengne et al. (5) 
demonstrated that 6.3% of ambulatory patients in Dallas, Texas had hyponatremia (median 
PNa=133 mmol/L). Using data from the University of Pittsburgh Medical Center (UPMC), our 
group found that among 413,000 adult patients seen at UPMC outpatient clinics over a 1-year 
period, 4,941 (1.2%) had a PNa between 125 and 132 mmol/L. While this represents a small 
proportion of the overall population, extrapolating 1.2% to all American adults suggests that 
approximately 3 million Americans have chronic non-severe hyponatremia. In fact, a study from 
Boscoe et al.(6) suggested that the overall treatment costs associated with hyponatremia in the 
United States exceed $3.5 billion annually. 
 
Clinical significance of chronic non-severe hyponatremia 
Chronic non-severe hyponatremia, even if seemingly asymptomatic, is associated with serious 
adverse outcomes.(7) Renneboog et al.(8) performed neurocognitive testing in 16 patients with 
chronic hyponatremia and found that patients with PNa 123-132 mmol/L manifested deficits in 
attention and gait (postural stability). Chronic non-severe hyponatremia is also associated with 
an increased risk of osteoporosis. Using NHANES III data, Verbalis et al.(9) found that mild 
hyponatremia (mean PNa=133 mmol/L) was independently associated with an increased risk of 
osteoporosis (OR, 2.85; 95%CI, 1.03-7.86; p<0.01). Kruse et al.(10) demonstrated that mild 
hyponatremia (mean PNa=132 mmol/L) was associated with decreased bone mineral density, 
bone mineral content, and T-score on DEXA scan. The clinical significance of impaired 
attention, postural instability, and osteoporosis in patients with chronic non-severe hyponatremia 
relates to the increased risk for falls and fractures in these patients. Renneboog et al.(8) found 
that 26 of 122 patients (21.3%) with apparently asymptomatic, chronic hyponatremia (mean 
PNa 126 mmol/L), seen in an Emergency Department had been evaluated for falls compared 
with 13 of 244 (5.3%) age-matched normonatremic controls (OR, 67.43; 95%CI, 7.48-607.42; 
p<0.001). The threshold PNa below which fall risk significantly increased was 134 mmol/L. Most 
recently, Jamal et al.(11) demonstrated in a study of 5,122 men that mild hyponatremia (mean 
PNa=132 mmol/L) was associated with an increased risk of hip fractures (HR, 3.48; 95%CI, 
1.76-6.87), as well as a higher risk for prevalent (HR, 2.78; 95%CI, 1.46-5.30) and incident (HR, 
3.36; 95%CI, 1.36-8.27) morphometric fractures (i.e., fractures identified by x-ray rather than 
from symptoms) compared with patients with normal PNa. Chronic non-severe hyponatremia is 
also associated with increased mortality. In a prospective cohort study of 5,208 elderly patients, 
Hoorn et al.(12) demonstrated that mild hyponatremia (mean PNa=133 mmol/L) was associated 
with an increased risk of death after adjusting for demographic characteristics and clinical 
comorbidities (HR, 1.21; 95%CI, 1.03-1.43; p=0.02). Similarly, in a study that used the NHANES 
database, Mohan et al.(13) found that mild hyponatremia (mean PNa=132 mmol/L) was 
independently associated with an increased risk of death over 7 years of follow up (HR, 3.61; 
95%CI, 2.31-5.63; p<0.001). While the precise mechanism(s) linking hyponatremia with 
mortality has not been definitively established, these and other studies underscore the potential 
seriousness of chronic non-severe hyponatremia. In summary, chronic non-severe 
hyponatremia is associated with impairments in attention, gait disturbances, and increased risk 
for osteoporosis, falls, fractures, and death; findings that highlight the clear need to identify 
treatments that not only increase PNa, but mitigate risk for these serious, adverse outcomes. 
 
Paucity of effective, safe, well-tolerated, and affordable therapies. 
At present, there are several interventions that are available for the treatment of chronic non-
severe hyponatremia. However, each has important limitations that preclude its routine use. A 
key pathophysiological process underlying the development of hyponatremia is water intake in 
excess of urinary free water excretory capacity. Hence, one treatment approach is restriction of 

14 
 
oral fluid intake. However, data documenting the effectiveness of and patient adherence to this 
treatment are lacking. In a recent study of over 3,000 subjects with hyponatremia, the increase 
in PNa observed with fluid restriction in the first 24 hours was not significantly different from that 
observed in untreated patients.(14) It is estimated that as many as 70% of patients with SIADH 
will not respond to fluid restriction alone.(15) Furthermore, widespread and long-term use of 
fluid restriction is limited by patient non-compliance, particularly in the outpatient setting. 
Another available treatment is oral loop diuretics in combination with NaCl tablets. Loop 
diuretics impair the formation of an osmotic gradient necessary for water reabsorption in the 
kidneys, while oral NaCl helps prevent negative sodium balance from the diuretic. 
This treatment combination has been shown to raise PNa in small case series, yet its effect on 
patient-centered outcomes and tolerability to patients are unknown.(16-18) 
Vasopressin antagonists (vaptans) block the action of vasopressin at the V2 receptor in the 
collecting duct resulting in increased renal free water excretion. Randomized clinical trials have 
demonstrated the efficacy of vaptans to treat hyponatremia. The SALT-1 and SALT-2 trials (2) 
enrolled 448 hyponatremic patients (i.e., PNa<135 mmol/L) to receive tolvaptan or placebo and 
demonstrated that patients who received tolvaptan had a larger increase in PNa at 30 days 
(6.2±4.1 mmol/L vs. 1.7±3.6 mmol/L in SALT1; and 6.2±3.9 mmol/L vs. 1.8±3.8 mmol/L in 
SALT2). Subsequently, 5 meta-analyses that included between 11 and 18 studies comprising 
1,000 to 5,000 patients confirmed the efficacy of vaptans in raising PNa.(19-23) In 2009, the 
Food and Drug Administration (FDA) approved tolvaptan for the treatment of hyponatremia. 
However, the use of this agent has been greatly limited due to safety concerns related to liver 
damage in a study of polycystic kidney disease(24), which led the FDA to issue a drug safety 
communication restricting the use of tolvaptan to 30 days and avoiding its use in patients with 
underlying liver disease.(25) In addition to these safety issues, the cost of tolvaptan (i.e., $438 
per single 15 mg tablet) is an important barrier to its routine use. In fact, certain clinical practice 
guidelines on the management of hyponatremia recommend against the use of tolvaptan for this 
indication.(26) In summary, currently available treatments for chronic hyponatremia lack data on 
efficacy and/or have important limitations related to patient non-adherence, adverse side 
effects, and/or significant costs. Consequently, there is a clear need for investigation of 
alternative treatments for this common condition. 
 
Preliminary studies of urea 
Urea, also known as Carbamide, it is an organic compound with formula CH4N2O. This amide 
has two amino groups (-NH2) joined by a carbonyl (C=O) functional group. Urea is an 
endogenous product of protein and amino acid catabolism.  Oral urea works as an osmotic 
diuretic that increases urinary water excretion and has been available for use in Europe for the 
treatment of hyponatremia for many years. Preliminary evidence of the potential efficacy of urea 
derives from small European case series.(1) Decaux et al.(3) studied 7 patients with chronic 
hyponatremia and found that treatment with urea over a period of up to 9 months resulted in an 
increase in mean PNa from 116 to 136 mmol/L and was not associated with any major side 
effects. Another study by Decaux et al.(27) of 50 patients with mild to moderate hyponatremia 
(PNa 120 to 134 mmol/L) found that 2 days of treatment with urea increased PNa by 7±4 
mmol/L. Collectively, these and other small studies demonstrated that urea increases PNa. 
However, these studies were retrospective, lacked a control group, included small numbers of 
patients, used a formulation of urea that is not available in the United States, and did not 
examine whether the effect of urea on raising PNa translates into a reduction in morbidity and/or 
mortality. In 2016, Ure-Na™, a novel formulation of oral urea became available in the United 
States. The FDA considers urea to be a medical food, and therefore, does not require a medical 
prescription for its use. Our group published the first study on the efficacy of this agent for the 
treatment of hyponatremia in the United States.(4) We identified patients hospitalized at UPMC 
with PNa <135 mmol/L who received urea, including a subgroup with SIADH who received urea 

15 
 
as the sole drug therapy for hyponatremia (‘urea-only’ patients). Overall, 58 patients received 
urea (7.5-90 g/day) over a median of 4.5 days and demonstrated an increase in PNa from 124 
to 131 mmol/L (p<0.001). Among 12 ‘urea-only’ treated patients, PNa increased from 125 to 131 
mmol/L (p=0.001) with a larger increase in PNa by 24 h (2.5 mmol/L [IQR 0-4.5] vs. -0.5 mmol/L 
[IQR -2.5 to 1.5], p=0.04) and more patients normalized PNa (33% vs. 8%, p=0.08) compared to 
a control group. No patients experienced overly rapid correction of PNa and no serious adverse 
events were reported. While our study was retrospective and limited to hospitalized patients, the 
findings support the potential efficacy and safety of this agent. After the publication of our study, 
two other observational studies were published supporting the efficacy, safety, and tolerability of 
oral urea in hyponatremia.(28, 29) Just one past study compared urea to other therapies for 
hyponatremia. Soupart et al. compared urea to vasopressin antagonists in 13 patients with 
chronic SIADH.(30) Patients were treated with vaptans (satavaptan and tolvaptan) for 1 year, 
during which PNa increased from 125±3 mmol/L to 135±3 mmol/L. Vaptans were then 
discontinued, leading to recurrent hyponatremia. After an 8-day washout period, oral urea was 
prescribed for 1 year with normalization of PNa in all patients (mean PNa 135±2 mmol/L). 
Patients tolerated urea well with no significant side effects. To date, there have been no studies 
comparing urea to fluid restriction. 
 
Effect of therapy for chronic hyponatremia on patient-centered outcomes 
Prior studies suggest that treatment of chronic hyponatremia may improve key patient-centered 
outcomes. A meta-analysis by Corona et al comprising 15 studies and 13,186 patients found 
that treatment of hyponatremia was associated with reduced mortality (OR=0.57 [0.40-0.81], 
p=0.002).(31) Vandergheynst et al. prospectively studied 11 elderly patients with mild 
hyponatremia (PNa 127.7±2.5 mmol/L) due to SIADH and found a significant improvement in 
mobility measured by ‘Up and Go’ test times after PNa normalization with fluid restriction and 
urea.(32) Peripheral nerve conduction velocities also improved significantly with correction of 
hyponatremia, but muscle strength did not change. Finally, in a study of 19 patients with 
hyponatremia, treatment that included salt tablets, fluid restriction, and/or discontinuation of the 
offending medication was associated with correction in PNa from 128.8±3.9 mmol/L to 
133.5±3.5 mmol/L and improved clinical symptoms and neurocognition.(33) Collectively, these 
studies suggest that correction of chronic hyponatremia results in improvements in patient 
centered outcomes; yet they underscore the clear need for further investigation of this issue. 
 
Summary 
Chronic non-severe hyponatremia is prevalent, and while seemingly asymptomatic, is 
associated with significant morbidity and mortality. Current therapies have important limitations 
that preclude their widespread use. Our group demonstrated that a novel formulation of urea 
with a cost of $3.70 per 15-g dose appears to be effective in raising PNa. However, evidence of 
its efficacy for the prevention of serious, adverse events related to hyponatremia is lacking. Past 
studies suggest that correcting chronic hyponatremia could potentially have beneficial effects on 
patient-centered outcomes. This pilot proposal seeks to assess the feasibility of recruitment, 
acceptability of urea to ambulatory patients, and proof of concept on the efficacy and safety of 
urea that are necessary to justify and inform the design of an adequately powered, randomized, 
placebo-controlled clinical trial of urea for the prevention of serious, patient-centered outcomes 
related to chronic non-severe hyponatremia. 
 
1.4 SIGNIFICANCE 
 
By demonstrating the feasibility of recruiting patients, documenting patient adherence, and 
establishing a signal of efficacy to increase PNa and potentially improve neurocognitive function 
and postural control and stability, this pilot study will generate the data needed to justify and 

16 
 
inform the design of an adequately powered, multi-center, randomized, placebo-controlled 
clinical trial to investigate whether therapy with urea decreases morbidity, mortality, and costs. 
This proposal will bring together a multi-disciplinary group of investigators with expertise in the 
diagnosis and treatment of hyponatremia (Drs. Rondon and Sterns), assessment of 
neurocognition and posture control/stability (Dr. Connaboy and Dr. Flanagan), clinical trial 
design and implementation (Drs. Weisbord and Palevsky), and biostatistics (Dr. Yabes). 
Establishing a track record of collaboration among this group of investigators will greatly 
strengthen future efforts to extend this line of investigation to a much larger numbers of patients. 
Assuming that as many as 1.2% of the overall adult population has chronic hyponatremia and 
that half or more of these patients could be treated with urea, as many as 2 million patients 
nationwide could  
ultimately benefit from this novel and inexpensive intervention. 
 
2.   RESEARCH DESIGN AND METHODS 
 
2.1 CLASSIFICATION AND METHODOLOGICAL DESIGNS 
 
The proposed pilot study is designed as a prospective, cross-over trial. Over a 13.5-month 
period, we will recruit 30 outpatients with chronic non-severe hyponatremia (PNa 125 to 132 
mmol/L) confirmed to be due to SIADH. Subjects will not be withdrawn from any known effective 
therapy for chronic hyponatremia for the purpose of participating in this study. Following 
enrollment, patients will be randomly assigned on 1:1 ratio to one of two sequence groups. 
Patients assigned to group “Urea ON, then Urea OFF” will receive oral urea for 42 ± 3 days 
(period 1), followed by a 10 ± 4-day period in which all patients will be off urea (washout period). 
Patients then will be off urea for 42 ± 3 days (period 2). Patients assigned to group “Urea OFF, 
then Urea ON” will be off urea therapy for 42 ± 3 days (period 1), and following a 10 ± 4-day 
washout period then they will initiate urea for 42 ± 3 days (period 2). Patients will have PNa 
assessed at baseline and on days 7 ± 2, 14 ± 2, and 42 ± 3 during periods 1 and 2 of the study 
and will undergo neurocognitive and postural control and stability testing on days 0 and 42 of 
each of the study periods. All patients will be advised to restrict their fluid intake to ≤1.2 liters 
during periods 1 and 2.  
 
2.2 DETAILED DESCRIPTION OF STUDY DESIGN 
 
 
Table 1 – Study assessments 
Assessment 
Day 
0 
Day 
7 
Day 
14 
Day 
42 
Phone interview 
 
X 
X 
 
In person clinic assessment: 
X 
 
 
X 
SF-12 
X 
 
 
X 
Neurocognitive assessment 
X 
 
 
X 
Postural stability assessment 
X 
 
 
X 
BMP 
X 
X 
X 
X 
Plasma osmolality, uric acid 
X 
 
 
X 
24h urine Cr, volume, urea nitrogen, 
uric acid, osmolality, Na, K 
X 
 
 
X 
  
Baseline (day 0) assessments: 
 

17 
 
The baseline study visit will take place at the University of Pittsburgh Neuromuscular Research 
Laboratory. All patients will provide a blood sample to measure a basic metabolic panel, plasma 
osmolality, and plasma uric acid. The 24h urine collection (started the day before) will be sent 
for measurement of volume, creatinine, urea nitrogen, uric acid, osmolality, sodium, and 
potassium. Patients will complete the short form 12 (SF-12) to assess health-related quality of 
life. They will then undergo assessments of neurocognition and postural control and stability 
(See Appendix). Specifically, the neurocognition assessment will involve the Perception-Action 
Coupling Task (PACT), an affordance-based assessment conducted on an iPad, which uses 
matched pairs of ‘virtual’ balls and ‘virtual’ holes to assess patients’ ability to accurately assess 
their action boundaries. Additional neurocognitive testing will involve administration of six 
measures from the Senaptec Sensory Station™ test battery to examine separate sensorimotor 
elements including; multiple object tracking, reaction time, perception span, go/no go, depth 
perception and dynamic visual acuity. Postural control and stability will be determined using 
both static and dynamic representations of upright stance. Employing non-linear analysis 
(sample entropy), the complexity and control of the static representation of postural stability in 
quiet upright stance will be determined. In addition, dynamic postural stability will be assessed 
using the NeuroCom™ Sensory Organization and Motor Control Tests. These tests enable both 
the examination of postural control and stability in response to a direct perturbation of the 
control systems underlying the maintenance of upright posture (vestibular, somatosensory, and 
visual), giving insight into the relative contributions and/or any deficits in the sensorimotor 
systems involved in maintaining upright stance in dynamic situations. 
 
Randomization: 
 
Patients will be randomized to either group “Urea ON, then Urea OFF” or “Urea OFF, then Urea 
ON” in a 1:1 allocation scheme. We will generate a randomization list using permuted blocks of 
random block sizes of 4 and 6. Our systems analyst will load the list into the web-based data 
management structure to preserve allocation concealment for consecutively enrolled 
participants.  
 
Intervention (oral urea) and study period 1:  
Patients randomized to study group “Urea ON, then Urea OFF” (N=15) will begin 42 ± 3 days of 
urea therapy, while those randomized to study group “Urea OFF, then Urea ON” (N=15) will not 
receive urea during this period. All patients will be asked to restrict their fluid intake to ≤1.2 
L/day during period 1. We will provide participants with a protocol for recording their daily fluid 
intake which includes carefully measuring all ingested fluids with a measuring cup and recording 
them on a study diary during the entire study period. We will use the new American formulation 
of oral urea (i.e., Ure-Na™), which is packaged as a powder that is mixed with 4 oz. of water for 
oral consumption. Group “Urea ON, then Urea OFF” patients will be given 48 powder pouches 
of Ure-Na (15 g of urea per pouch) and will be instructed to start at a dose of 15 g once daily. 
Dose titration will be based on the absolute increase in PNa on days 7 ± 2 and 14 ± 2  as 
follows: 
 
• 
Day 7: If PNa increases ≥3 mmol/L from baseline, then continue same urea 
dose. If PNa increases <3 mmol/L from baseline, then increase urea to next 
dose.  
• 
Day 14: If PNa increases ≥ 6 mmol/L from baseline, or PNa increases <6 mmol/L 
from baseline and PNa ≥135 mmol/ L, then continue same urea dose. If PNa 
increases <6 mmol/L from baseline and PNa <135 mmo/L, then increase urea to 
next dose. 
 

18 
 
The dosing scheme for urea will involve increasing when appropriate, from the starting dose of 
15 g/day, to 30 g/day in 2 divided doses, and subsequently, when appropriate, from 30 g/day to 
60 g/day (in 2 divided doses). The maximal dose of urea administered will be 60 g/day. Patients 
will undergo a PNa check approximately 7 ± 2 days after a urea dose adjustment to less than 
the maximal dose of urea allowed. Patients will record the doses of urea they consume each 
day during treatment period 1 in the study diary. 
 
Follow-up research assessments: 
 
All patients in group “Urea ON, then Urea OFF” will have scheduled follow up assessments on 
days 7, 14, and 42 as follows: 
 
• 
Day 7: Phone interview and basic metabolic panel (BMP).  
• 
Day 14: Phone interview and BMP. More boxes of Ure-Na will be mailed if 
needed to complete the study. 
• 
Day 42: same assessment as in the baseline study visit 
 
The phone interviews visits will focus on assessing side effects, tolerability, and adherence to 
urea and as appropriate, dose titration of urea. Side effects and tolerability will be assessed with 
questionnaires (See Medication Side Effects Questionnaire and Medication Acceptability 
Questionnaire). Patient also will be asked to bring their study diary to the in-person clinic visits 
to track their adherence to fluid restriction and urea. Visits at day 0 and day 42 will take place in 
the Neuromuscular Research Laboratory at the University of Pittsburgh. BMP assessment on 
days 7, 14 will take place at the UPMC clinical laboratory of patient’s choice. At the 42-day visit, 
patients will be asked to return their study diary and any urea doses they did not consume. 
During period 1 of the study, patients randomized to group “Urea OFF, then Urea ON” will 
undergo same assessments as outlined for group “Urea ON, then Urea OFF”, although they will 
not be asked about tolerability or adherence to urea as they will not be on this treatment during 
this period. 
 
Crossover and study period 2: 
 
Upon completion of period 1, all patients (groups “Urea ON, then Urea OFF” and “Urea OFF, 
then Urea ON”) will enter a 10 ± 4-day washout period during which they will not take urea. 
Patients will be advised that they do not need to restrict their fluid intake during this 10 ± 4-day 
period. Subsequently, all patients will start the second 42 ± 3-day phase of the study (period 2). 
Patients in group “Urea OFF, then Urea ON” will be started on urea for 42 ± 3 days using the 
same titration protocol as described for group “Urea ON, then Urea OFF” during period 1. 
Patients in group “Urea ON, then Urea OFF” will continue off urea for the duration of period 2 
and will complete the same plasma and urine assessments and clinic visits as group “Urea 
OFF, then Urea ON”. All patients will be instructed to limit fluid intake to ≤1.2 liters per day 
during this final study period. At the conclusion of the study, all patients will be offered the 
opportunity to visit the UPMC Kidney Clinic for continuation of urea therapy. 
 
Research activities 
 
Screening visit 
 
• 
Patient will come in person to the UPMC Kidney Clinic. 

19 
 
• 
For Nephrology inpatients who meet eligibility for the study and have not started urea 
in the hospital, we will obtain informed consent during their hospitalization and 
schedule them for a screening visit within approximately 5-7 days after discharge. 
For Nephrology inpatients who meet eligibility for the study including a nadir serum 
sodium of no less than 125 mmol/L and have already started urea in the hospital, we 
will obtain informed consent during hospitalization, discuss with the nephrologist 
and/or hospitalist, we will ask them if the patient can come off urea and if so, to 
discontinue urea. We will then schedule these patient for a screening visit within 5-7 
days after discharge. Screening visit for subjects enrolled from inpatient will take 
place at UPMC Kidney Clinic. 
• 
For Nephrology outpatients who meet eligibility for the study including a nadir serum 
sodium of no less than 125 mmol/L and are already on urea, we will obtain informed 
consent, discuss with the nephrologist, we will ask them if the patient can come off 
urea and if so, to discontinue urea. We will then schedule these patients for a 
screening visit within 5-7 days after urea discontinuation. Screening visit for subjects 
enrolled from the outpatient setting will take place at UPMC Kidney Clinic. 
• 
The principal investigator will obtain informed consent from the patient to be enrolled 
in the study.  
• 
Patient will undergo a physical examination by principal investigator which involves: 
assessment of patient's ability to walk normally without help, assessment of patient's 
cognition with the use of the Mini-Mental State Examination test, and assessment of 
volume status 
• 
The research coordinator will draw approximately 14 mL of patient's blood and send 
the specimen promptly to the UPMC Presbyterian clinical laboratory for processing 
and analysis of the following: basic metabolic panel, plasma cortisol, thyroid 
stimulating hormone, and plasma osmolality.. 
• 
The research coordinator will ask the patient to provide a urine sample. The research 
coordinator will send the specimen promptly to the UPMC Presbyterian clinical 
laboratory for processing and analysis of the following: urine osmolality, urine 
sodium, and urine pregnancy test when indicated. 
• 
After the principal investigator analyzes the results of the physical exam and 
laboratory test results and determines patient eligibility for the study, the research 
coordinator will call the patient to inform him/her whether he/she is eligible to 
participate in the study. 
• 
For patients with serum cortisol level less than 15 mcg/dL in the screening visit then 
we will proceed to schedule a corticotropin stimulation test (cosyntropin stimulation 
test) at the UPMC Montefiore Clinical and Translational Research Center. 
• 
If patient is eligible to participate in the study then the research coordinator will give 
the patient instructions about the first study visit as well as mail him/her a container 
with instructions to collect urine for 24 hours prior to first study visit. 
• 
If patient is not eligible to participate in the study then the principal investigator will 
give the patient the choice to follow up in the UPMC Kidney Clinic for the 
management of his/her hyponatremia. 
• 
This visit will last approximately 1.5 hours. 
 
First study visit (Day 0 of Period 1) 
 
• 
Patient will come in person to the University of Pittsburgh Neuromuscular Research 
Laboratory located at 3860 S Water St, Pittsburgh, PA 15203. 

20 
 
• 
Patient will bring the container with the 24-hour urine collection he/she started the 
day prior. The research coordinator will send the specimen promptly to the UPMC 
Presbyterian clinical laboratory for processing and analysis of the following: 
creatinine, urea nitrogen, uric acid, osmolality, sodium, and potassium. 
• 
The research coordinator will draw approximately 14 mL of patient's blood and send 
the specimen promptly to the UPMC Presbyterian clinical laboratory for processing 
and analysis of the following: basic metabolic panel, plasma osmolality, and plasma 
uric acid. 
• 
Patient will complete SF-12 survey with pen and paper.  
• 
A co-investigator will test patients' reactions and decision making using specialized 
software on a tablet computer. 
• 
A co-investigator will test patients' balance while standing on a specialized piece of 
equipment. Patient will be asked to stand on both legs on top of a platform in a 
dynamic moving environment. Patient will go through six conditions, with three trials 
per condition, lasting about 20 seconds each. Patient will be asked to look forward, 
and stand as motionless as possible with your arms at your sides. The six conditions 
include the possibility of moving surroundings or moving base of support. If patient 
move or lose his/her balance during the procedures, patient will be asked to repeat 
that part again. Patient will be supported by means of a harness in the equipment to 
make sure he/she cannot fall over while performing the tests. 
• 
The research coordinator will instruct the patient to restrict his/her fluid intake to no 
more 1200 mL/day for the next 42 ± 3 days. The research coordinator will provide 
the patient with a diary to record daily fluid intake. 
• 
Patients will be randomized prior to or at the first study visit (Period 1 Day 0) 
following completion of baseline assessments. Our biostatistician will generate the 
randomization list using permuted blocks of random block sizes of 4 and 6 and our 
systems analyst will load the list into RedCAP. To preserve allocation concealment 
for consecutively enrolled participants, we will use the randomization module in 
RedCAP to assign each participant 1:1 to either On-to-Off Urea sequence or Off-to-
On Urea sequence. 
• 
If patient is randomized to take On-to-Off Urea sequence then the research 
coordinator will give the patient 48 urea powder pouches with instructions on how to 
take the urea every day. The research coordinator will provide the patient with a 
diary to record patient's daily urea intake. 
• 
This visit will last approximately 2.5 hours. 
 
Second study visit (Day 7 of Period 1) 
 
• 
The research coordinator will call the patient on the phone to ask some questions 
about any new symptoms patient might have experienced since his/her last visit. 
• 
The research coordinator will direct the patient to go the UPMC clinical laboratory of 
the patient's choice that day to have his blood drawn for analysis of a basic 
metabolic panel. 
• 
If patient is taking urea, we might call the participant on the phone again to ask to 
change the dose of urea depending on the sodium level results. 
• 
This visit will last approximately 20 minutes. 
 
Third study visit (Day 14 of Period 1) 
 

21 
 
• 
The research coordinator will call the patient on the phone to ask some questions 
about any new symptoms patient might have experienced since his/her last visit. 
• 
The research coordinator will direct the patient to go the UPMC clinical laboratory of 
the patient's choice that day to have his blood drawn for analysis of a basic 
metabolic panel. 
• 
The research coordinator will instruct the patient to bring his fluid and urea intake 
diaries to the next study visit. 
• 
The research coordinator will give or mail the patient a container with instructions to 
collect urine for 24 hours prior to next study visit. 
• 
If patient is taking urea then research coordinator will give and/or mail the patient 
enough urea powder pouches to complete his/her participation in this period of the 
study. 
• 
If patient is taking urea, we might call the participant on the phone to ask to change 
the dose of urea depending on the sodium level results. 
• 
If urea dose is adjusted to less than the maximum allowed dose, research 
coordinator will direct the patient to go the UPMC clinical laboratory of the patient's 
choice in approximately 7 days to have his/her blood drawn for analysis of a basic 
metabolic panel. 
• 
This visit will last approximately 30 minutes. 
 
Reminder telephone call 
 
• 
The research coordinator will call the patient on the phone 48-72 hours before the 
next study visit to remind him/her of the upcoming study visit. 
 
Fourth study visit (Day 42 of Period 1) 
 
• 
Patient will come in person to the University of Pittsburgh Neuromuscular Research 
Laboratory located at 3860 S Water St, Pittsburgh, PA 15203. 
• 
The research coordinator will collect the patient's fluid and urea intake diaries. 
• 
The research coordinator will ask the patient some questions about any new 
symptoms patient might have experienced since his/her last visit. 
• 
If patient is taking urea then the research coordinator will ask patient some questions 
related to acceptability of urea. 
• 
Patient will bring the container with the 24-hour urine collection he/she started the 
day prior. The research coordinator will send the specimen promptly to the UPMC 
Presbyterian clinical laboratory for processing and analysis of the following: 
creatinine, urea nitrogen, uric acid, osmolality, sodium, and potassium  
• 
The research coordinator will draw approximately 14 mL of patient's blood and send 
the specimen promptly to the UPMC Presbyterian clinical laboratory for processing 
and analysis of the following: basic metabolic panel, plasma osmolality, and plasma 
uric acid. 
• 
Patient will complete the SF-12 survey with pen and paper.  
• 
A co-investigator will test patients' reactions and decision making using specialized 
software on a tablet computer. 
• 
A co-investigator will test patients' balance while standing on a specialized piece of 
equipment. Patient will be asked to stand on both legs on top of a platform in a 
dynamic moving environment. Patient will go through six conditions, with three trials 
per condition, lasting about 20 seconds each. Patient will be asked to look forward, 
and stand as motionless as possible with your arms at your sides. The six conditions 

22 
 
include the possibility of moving surroundings or moving base of support. If patient 
move or lose his/her balance during the procedures, patient will be asked to repeat 
that part again. Patient will be supported by means of a harness in the equipment to 
make sure he/she cannot fall over while performing the tests. 
• 
The research coordinator will ask patient to stop fluid restriction. 
• 
If patient is taking urea then the research coordinator will instruct the patient to stop 
taking urea and return all the urea pouches he/she did not use to the research 
coordinator. 
• 
The research coordinator will provide the patient with a container with instructions to 
collect urine for 24 hours prior to next study visit. 
• 
This visit will last approximately 2.5 hours. 
 
Reminder telephone call 
 
• 
The research coordinator will call the patient on the phone 48-72 hours before the 
next study visit to remind him/her of the upcoming study visit. 
 
Fifth study visit (Day 0 of Period 2) 
 
• 
Patient will come in person to the University of Pittsburgh Neuromuscular Research 
Laboratory located at 3860 S Water St, Pittsburgh, PA 15203. 
• 
Patient will bring the container with the 24-hour urine collection he/she started the 
day prior. The research coordinator will send the specimen promptly to the UPMC 
Presbyterian clinical laboratory for processing and analysis of the following: 
creatinine, urea nitrogen, uric acid, osmolality, sodium, and potassium. 
• 
The research coordinator will draw approximately 14 mL of patient's blood and send 
the specimen promptly to the UPMC Presbyterian clinical laboratory for processing 
and analysis of the following: basic metabolic panel, plasma osmolality, and plasma 
uric acid. 
• 
Patient will be given the SF-12 survey to complete with pen and paper.  
• 
A co-investigator will test patients' reactions and decision making using specialized 
software on a tablet computer. 
• 
A co-investigator will test patients' balance while standing on a specialized piece of 
equipment. Patient will be asked to stand on both legs on top of a platform in a 
dynamic moving environment. Patient will go through six conditions, with three trials 
per condition, lasting about 20 seconds each. Patient will be asked to look forward, 
and stand as motionless as possible with your arms at your sides. The six conditions 
include the possibility of moving surroundings or moving base of support. If patient 
move or lose his/her balance during the procedures, patient will be asked to repeat 
that part again. Patient will be supported by means of a harness in the equipment to 
make sure he/she cannot fall over while performing the tests. 
• 
The research coordinator will instruct the patient again to restrict his/her fluid intake 
to no more 1200 mL/day for the next 42 ± 3 days. The research coordinator will 
provide the patient with a new diary to record daily fluid intake. 
• 
If patient was randomized to take Off-to-On Urea sequence then the research 
coordinator will give the patient 48 urea powder pouches with instructions on how to 
take the urea every day. The research coordinator will provide the patient with a new 
diary to record patient's daily urea intake. 
• 
This visit will last approximately 2.5 hours. 
 

23 
 
Sixth study visit (Day 7 of Period 2) 
 
• 
The research coordinator will call the patient on the phone to ask some questions 
about any new symptoms patient might have experienced since his/her last visit. 
• 
The research coordinator will direct the patient to go the UPMC clinical laboratory of 
the patient's choice that day to have his/her blood drawn for analysis of a basic 
metabolic panel. 
• 
If patient is taking urea, we might call the participant on the phone again to ask to 
change the dose of urea depending on the sodium level results. 
• 
This visit will last approximately 20 min. 
 
Seventh study visit (Day 14 of Period 2) 
 
• 
The research coordinator will call the patient on the phone to ask some questions 
about any new symptoms patient might have experienced since his/her last visit. 
• 
The research coordinator will direct the patient to go the UPMC clinical laboratory of 
the patient's choice that day to have his blood drawn for analysis of a basic 
metabolic panel. 
• 
The research coordinator will instruct the patient to bring his fluid and urea intake 
diaries to the next study visit. 
• 
The research coordinator will give or mail the patient a container with instructions to 
collect urine for 24 hours prior to next study visit. 
• 
If patient is taking urea then research coordinator will give and/or mail the patient 
enough urea powder pouches to complete his/her participation in this period of the 
study. 
• 
If patient is taking urea, we might call the participant on the phone to ask to change 
the dose of urea depending on the sodium level results. 
• 
If urea dose is adjusted to less than the maximum allowed dose, research 
coordinator will direct the patient to go the UPMC clinical laboratory of the patient's 
choice in approximately 7 days to have his/her blood drawn for analysis of a basic 
metabolic panel. 
• 
This visit will last approximately 30 minutes. 
 
Reminder telephone call 
 
• 
The research coordinator will call the patient on the phone 48-72 hours before the 
next study visit to remind him/her of the upcoming study visit. 
 
Eighth study visit (Day 42 of Period 2) 
 
• 
Patient will come in person to the University of Pittsburgh Neuromuscular Research 
Laboratory located at 3860 S Water St, Pittsburgh, PA 15203. 
• 
The research coordinator will collect the patient's fluid and urea intake diaries. 
• 
The research coordinator will ask the patient some questions about any new 
symptoms patient might have experienced since his/her last visit. 
• 
If patient is taking urea then the research coordinator will ask patient some questions 
related to acceptability of urea. 
• 
Patient will bring the container with the 24-hour urine collection he/she started the 
day prior. The research coordinator will send the specimen promptly to the UPMC 

24 
 
Presbyterian clinical laboratory for processing and analysis of the following: 
creatinine, urea nitrogen, uric acid, osmolality, sodium, and potassium.  
• 
The research coordinator will draw approximately 14 mL of patient's blood and send 
the specimen promptly to the UPMC Presbyterian clinical laboratory for processing 
and analysis of the following: basic metabolic panel, plasma osmolality, and plasma 
uric acid. 
• 
Patient will be given the SF-12 survey to complete with pen and paper.  
• 
A co-investigator will test patients' reactions and decision making using specialized 
software on a tablet computer. 
• 
A co-investigator will test patients' balance while standing on a specialized piece of 
equipment. Patient will be asked to stand on both legs on top of a platform in a 
dynamic moving environment. Patient will go through six conditions, with three trials 
per condition, lasting about 20 seconds each. Patient will be asked to look forward, 
and stand as motionless as possible with your arms at your sides. The six conditions 
include the possibility of moving surroundings or moving base of support. If patient 
move or lose his/her balance during the procedures, patient will be asked to repeat 
that part again. Patient will be supported by means of a harness in the equipment to 
make sure he/she cannot fall over while performing the tests. 
• 
The research coordinator will instruct patient to stop fluid restriction. 
• 
If patient is taking urea then the research coordinator will instruct the patient to stop 
taking urea and return all the urea pouches he/she did not use to the research 
coordinator. 
• 
The principal investigator will give the patient the choice to follow up in the UPMC 
Kidney Clinic to continue the management of his/her hyponatremia. 
• 
This visit will last approximately 2.5 hours. 
 
2.3 STUDY DRUG 
 
The drug to be administered is urea (brand name Ure-Na™). Urea is a medical food or 
dietary supplement considered by the FDA under the GRAS (Generally Regarded As Safe) 
category. Patients will be instructed to start urea at a dose of 15 g once daily. Dose titration 
then will occur based on the absolute increase in PNa on days 7 and 14  as follows: 
 
• 
Day 7: If PNa increases ≥3 mmol/L from baseline, then continue same urea 
dose. If PNa increases <3 mmol/L from baseline, then increase urea to next 
dose. 
• 
Day 14: If PNa increases ≥ 6 mmol/L from baseline, or PNa increases <6 mmol/L 
from baseline and PNa ≥135 mmol/ L, then continue same urea dose. If PNa 
increases <6 mmol/L from baseline and PNa <135 mmo/L, then increase urea to 
next dose. 
 
The dosing scheme for urea will involve increasing when appropriate, from the starting dose 
of 15 g/day, to 30 g/day in 2 divided doses, and subsequently, when appropriate, from 30 
g/day to 60 g/day (in 2 divided doses). The maximal dose of urea administered will be 60 
g/day. The route of administration will be oral and the total duration of administration will be 
42 ± 3 days.  
 
Oral urea use is occasionally associated with the onset of nausea, vomiting, diarrhea and 
headaches. If these symptoms appear then they will be initially managed by asking patients 
to monitor their symptoms and report to the research coordinator if symptoms persist after 

25 
 
24h. If symptoms persist, urea dose will be reduced by 50%. If symptoms persist 72h after 
reducing the dose of urea, urea will be discontinued. 
 
Subjects will be seen at the UPMC kidney clinic immediately after the completion of their 
participation in the study for consideration of continuation of urea therapy.  
 
 
2.3.1. Study Drug Preparation and Dispensing 
 
The study drug will be donated by Nephcentric, the manufacturer of Ure-Na™. Ure-Na™ 
is formulated as a powder packaged in a 21-g pouch or sachet. Each pouch of Ure-Na™ 
contains 15 g of pharmaceutical grade urea and 6 g of other ingredients including natural 
flavors, citric acid, maltodextrin, calcium silicate, and sucralose. The powder is then 
mixed with 3 to 4 oz. of water or juice for oral consumption. No on-site preparation of the 
study drug will be performed. Patients will be given 6 boxes of Ure-Na™ each containing 
eight pouches (total of 48 pouches) and instructed to take the study drug at home as 
indicated. Some more pouches of Ure-Na™ will be given at day 14 as necessary to 
complete their participation in the study. 
 
2.3.2. Drug Administration 
 
During the study visit at day 0, patients will be given six boxes of Ure-Na™ each 
containing eight pouches (total of 48 pouches) to take home. Some more pouches of 
Ure-Na™ will be given at day 14 as necessary to complete their participation in the 
study. Subjects will be instructed to take 1 pouch (15 g of urea) per mouth once daily. 
Subjects will be instructed to carefully open the pouch, pour all the content of the pouch 
into a glass or cup, add 3 to 4 oz of water, stir, and drink after a meal to decrease 
gastrointestinal intolerance. Subjects will be told that the dose of urea will be titrated 
throughout the study based on plasma sodium levels and/or the appearance of side 
effects and this will be communicated during the study assessments by the research 
coordinator. In addition, subjects will be instructed to store the study drug at home at 
room temperature, in a dry place, out of direct sun-light. 
 
2.3.3. Dose Selection 
 
Urea, also known as Carbamide, it is an organic compound with formula CH4N2O. This 
amide has two amino groups (-NH2) joined by a carbonyl (C=O) functional group. Urea 
is an endogenous product of protein and amino acid catabolism.  Oral urea works as an 
osmotic diuretic that increases urinary water excretion and has been available for use in 
Europe for the treatment of hyponatremia for many years. Preliminary evidence of the 
potential efficacy of urea derives from small European case series.(1) Decaux et al.(3) 
studied 7 patients with chronic hyponatremia and found that treatment with urea over a 
period of up to 9 months resulted in an increase in mean PNa from 116 to 136 mmol/L 
and was not associated with any major side effects. Another study by Decaux et al.(27) 
of 50 patients with mild to moderate hyponatremia (PNa 120 to 134 mmol/L) found that 2 
days of treatment with urea increased PNa by 7±4 mmol/L. Collectively, these and other 
small studies demonstrated that urea increases PNa. However, these studies were 
retrospective, lacked a control group, included small numbers of patients, used a 
formulation of urea that is not available in the United States, and did not examine 
whether the effect of urea on raising PNa translates into a reduction in morbidity and/or 
mortality. In 2016, Ure-Na™, a novel formulation of oral urea became available in the 
United States. The FDA considers urea to be a medical food, and therefore, does not 

26 
 
require a medical prescription for its use. Our group published the first study on the 
efficacy of this agent for the treatment of hyponatremia in the United States.(4) We 
identified patients hospitalized at UPMC with PNa <135 mmol/L who received urea, 
including a subgroup with SIADH who received urea as the sole drug therapy for 
hyponatremia (‘urea-only’ patients). Overall, 58 patients received urea (7.5-90 g/day) 
over a median of 4.5 days and demonstrated an increase in PNa from 124 to 131 
mmol/L (p<0.001). Among 12 ‘urea-only’ treated patients, PNa increased from 125 to 
131 mmol/L (p=0.001) with a larger increase in PNa by 24 h (2.5 mmol/L [IQR 0-4.5] vs. 
-0.5 mmol/L [IQR -2.5 to 1.5], p=0.04) and more patients normalized PNa (33% vs. 8%, 
p=0.08) compared to a control group. No patients experienced overly rapid correction of 
PNa and no serious adverse events were reported. While our study was retrospective 
and limited to hospitalized patients, the findings support the potential efficacy and safety 
of this agent. After the publication of our study, two other observational studies were 
published supporting the efficacy, safety, and tolerability of oral urea in 
hyponatremia.(28, 29) Just one past study compared urea to other therapies for 
hyponatremia. Soupart et al. compared urea to vasopressin antagonists in 13 patients 
with chronic SIADH.(30) Patients were treated with vaptans (satavaptan and tolvaptan) 
for 1 year, during which PNa increased from 125±3 mmol/L to 135±3 mmol/L. Vaptans 
were then discontinued, leading to recurrent hyponatremia. After an 8-day washout 
period, oral urea was prescribed for 1 year with normalization of PNa in all patients 
(mean PNa 135±2 mmol/L). Patients tolerated urea well with no significant side effects. 
To date, there have been no studies comparing urea to fluid restriction. 
 
Our study propose to use the oral route for urea administration. Pharmacological urea 
currently exist in topical and oral formulations. The oral formulation allows for systemic 
absorption and renal excretion causing the desired pharmacological effect (i.e. osmotic 
diuresis). The initial dose of urea to be administered during our study will be 15 g/day but 
this can be titrated in subsequent study visits based on efficacy and safety. The next 
dose in our titration algorithm is 30 g/day (in 2 divided doses), and the next and maximal 
dose allowed will be 60 g day (in 2 divided doses). The European Clinical practice 
guideline on diagnosis and treatment of hyponatraemia(26) recommended a urea dose 
of 0.25 – 0.5 g/kg/day which for a 60 kg person constitutes between 15 and 30 g of urea 
per day. Our study using Ure-Na™ at the University of Pittsburgh Medical Center(4) 
showed that patients were treated with doses ranging from 7.5 g/day up to 90 g/day, 
however most patients required doses between 15 and 30 g. The rationale behind the 
divided doses with doses of 30 or 60 g/day of urea is double. Urea’s half-life is 2.5 h and 
a single dose of urea is completely eliminated via the kidneys within 12 h. Also, higher 
doses of urea are more likely to cause gastrointestinal side effects. Therefore, to achieve 
a sustained effect while minimizing adverse reactions a twice daily dose of urea will be 
more appropriate. While past observational studies demonstrated a potential benefit of 
increasing plasma sodium on neurocognitive outcomes within 1 week (8, 32, 33), we 
have increased the treatment duration to 42 ± 3 days to ensure a longer period of 
plasma sodium normalization that captures the potential beneficial effects of urea on 
these outcomes.  
 
For a summary of the information related to the human pharmacokinetics and human 
safety profile of urea, as well as findings from non-clinical studies that support the 
evaluation of urea in humans, please, refer to: Toxicological Review of Urea by the United 
Stated Environmental Protection Agency (EPA). 
 
2.3.4. Treatment Period 

27 
 
 
 
 
42 ± 3 days 
 
2.3.5. Breaking the Blind  
 
The proposed clinical study will not be blinded. 
 
2.3.6. Medication Compliance 
 
Patients will record the doses of urea they consume each day during treatment period in 
a study diary which will be reviewed during study visits. 
 
We will be assessing patient compliance with urea as described above so patients will 
not be withdrawn due to non-compliance with the study drug. If patients are non-
compliant with serum sodium checks such that the PIs believe the patient should not 
continue to take urea, we will formally discuss the case with the study team and if it is 
agreed by all members of the study team that the patient be withdrawn, they will be 
asked to stop study drug, return remaining doses, and will be formally withdrawn from 
the study 
 
Subjects withdrawn from the study will be replaced. We will continue recruitment until the 
target number of patients are enrolled. 
 
2.3.7. Medication Storage and Accountability 
 
The UPMC Investigational Drug Services (IDS) will be utilized in this study. They are a 
separate pharmacy who only handles investigational drugs. Each drug is stored in a 
separately labeled bin in a temperature controlled environment. All files and drug are 
kept in a locked pharmacy and only IDS staff has access. Only PI’s and Co-I’s that we 
list on the order form are able to prescribe the investigational product.  
 
IDS creates a study binder to maintain accountability. The IDS staff will log every time 
there is a dispense or they receive medication. The IDS staff will maintain patient 
accountability keeping a separate tab in the binder for each patient enrolled. The IDS 
staff will file all invoices for the investigational product. 
 
At the end of the study, all the unused investigational product shall be transferred to the 
IDS accountability and destruction. The investigational product returns will be accounted 
for by both the study team and pharmacy. The study team will provide the first count 
followed by a second count performed by the IDS staff. The IDS staff will reconcile the 
count returned with the research coordinator and document in the accountability log. 
After reconciliation the investigational product will be immediately discarded into the 
appropriate waste stream containers. 
 
2.3.8 Concomitant Medications 
 
During their participation in the study, subjects will not be allowed to take the following 
medications: 
 
- Vasopressin antagonists: tolvaptan, conivaptan 

28 
 
- Thiazide and thiazide-like diuretics: hydrochlorothiazide, chlorothiazide, 
bendroflumethiazide, chlorthalidone, indapamide, metolazone 
- Osmotic diuretics: mannitol 
- Carbonic anhydrase inhibitors: acetazolamide, topiramate 
- Desmopressin 
- Demeclocycline 
 
Subjects’ medical history will be reviewed during every subject’s study visit looking for 
changes in health status, hospitalizations, and new prescription drugs. In addition, 
subjects will be asked about the use of any new medication (prescription or non-
prescription) during every study visit including the ones listed above. 
 
2.3.9 Rescue Medications 
 
No rescue medications will be used during this study. 
 
2.4 STUDY ENDPOINTS 
 
2.5 STATISTICAL ANALYSIS 
 
 
2.5.1 Sample Size Determination 
 
This pilot study aims to assess the feasibility of conducting a future clinical trial. Thus, 
the sample size of 30 patients was determined based on clinical and logistical reasons 
rather than statistical requirements. For Aim 1, we anticipate identifying approximately 
300 potentially eligible patients during the 13.5 months of recruitment (~22 per month). A 
95% confidence interval (CI) for the randomization rate provides a 3% margin of error 
(MoE) assuming the true rate was 10% (~3 per month). If the underlying dropout and 
adherence rates were 80%, a sample size of 30 provides 14% MoE for 95% CIs. For 
Aim 2, our sample size provides 83% power to detect a standardized mean difference of 
0.65 for our efficacy outcomes. We are not powered to detect smaller effect sizes. 
However, since this is a proof-of-concept study, detecting a moderate-to-large effect size 
increases our confidence in the potential efficacy of urea. For Aim 3, underlying adverse 
events rates of 5% to 10%, 95% CIs will provide 8% to 11% MoE, respectively. 
 
2.5.2 Study Conduct Analysis 
 
At the conclusion of the study, we will assess the achievement of our aims including the 
target number of patients. 
 
 
2.5.3 Efficacy Analysis 
 
This study is not powered to establish the efficacy of urea on increasing PNa or 
improving neurocognition and/or postural control/stability. However, to justify a future 
large, randomized clinical trial of urea, we need proof of concept data that urea has 
potential benefits for these outcomes. We will summarize patient demographics and 
clinical characteristics by study group. For the primary outcomes (PNa, neurocognition 
scores, postural control/stability scores) and secondary exploratory outcome (SF-12 
scores), we will calculate change from baseline to day 42 in each treatment period. We 
will analyze these data using a linear mixed effects model with patient-specific random 
effects to account for within-patient correlations. Model predictors will include treatment, 

29 
 
period and treatment period interaction. Coefficients and 95% CIs will be used to 
quantify the treatment effect. We will also use this model to assess period effect and 
carryover effects (treatment period interaction). 
 
 
2.5.4  Safety Analysis 
 
This pilot study is not designed to comprehensively identify low frequency adverse 
events. Nonetheless, we will report all adverse events/side effects during urea therapy. 
We will report to the sponsor the seriousness and severity of each event and whether 
the event was potentially related to urea. We recognize that osmotic demyelination 
syndrome is a complication of overly rapid correction of PNa (increase in PNa >8 
mmol/L/24h) in patients with severe hyponatremia (PNa ≤120 mmol/L). However, we do 
not believe this is a concern in our study as patients with PNa ≥125 mmol/L who do not 
have serious liver disease (an exclusion criterion for our study) have a negligible risk of 
osmotic demyelination syndrome if overly rapid correction of hyponatremia occurs. 
 
 
2.5.5  Handling Missing Data 
 
The extent and reasons that data are missing will be described. A comparison of 
baseline characteristics and intermediate outcomes between those who complete the 
study and those who do not will be conducted. We will investigate the randomness of 
missing data using available information on patient characteristics to help discern 
patterns in the missing data and to identify the possible covert missing data 
mechanisms. The primary efficacy analytic approach (mixed models) can handle data 
that are ignorable missing (i.e., either missing completely at random or missing at 
random). However, strategies to handle missing data (single/multiple imputation, 
selection models, pattern-mixture models, etc.) and sensitivity analyses to encompass 
different scenarios of assumptions will be considered as appropriate 
 
 
2.5.6  Data Management 
 
Standardized clinical data collection protocols will be in place for the clinical trial as 
documented in a study manual of procedures (MOP). The Principal Investigator (PI) will 
ensure that the study is conducted according to the protocol and will be responsible for 
carrying out the Data Safety and Monitoring Plan (DSMP). Regular study team meetings 
will be used to ensure that all data quality and IRB policies and procedures are being 
followed. The CRHC-DC will help the PIs develop the forms and setting up the study 
options in REDCap (Research Electronic Data Capture) then support it for the life of the 
study. Access will be restricted to certain study staff members.  
  
Data collection and form development 
Each case report form (CRF) will be developed by CRHC-DC in conjunction with the 
clinical study team. In order to make sure that all data elements are collected, CRFs will 
be considered across the following categories: 1) screening & baseline information; 2) 
follow up visits, tests, and procedures; 3) adherence to study treatment; 4) adverse 
experiences; 5) clinical endpoints; and 6) subject treatment and follow up. This allows 
discussions on CRF development to center around each of the categories and prevents 
particular forms from being missed. To minimize missing data, all of the study forms will 
have certain key fields that are required before form submission. Pop-up messages will 
also be used to remind the study coordinator or data entry personnel that particular fields 

30 
 
are empty upon form submission and give reasons as to why incomplete data was 
submitted.  
  
Data entry 
Data will be entered electronically via The REDCap password-protected web-based data 
entry system, but paper versions of forms will be provided for manual entry in case of 
technical issues. The data will be stored on University of Pittsburgh Clinical and 
Translational Science Institute (CTSI) REDCap servers.  
  
Participant eligibility, & randomization 
The data entry process will begin during the online participant enrollment into the clinical 
trial. The study coordinator will have the ability to generate a participant ID upon 
initiation. The data capture system will utilize an “eligibility checklist” which is pre-
populated with information from all questions that directly relate to inclusion and 
exclusion criteria. By not having a separate form with checkboxes for each criterion, this 
will prevent any data entry errors which may result in ineligible randomizations. Once the 
eligibility criteria are met and confirmed, the study coordinator will submit the 
randomization form for the subject, and the REDCap randomization module will return 
the participant’s study group assignment (“Urea ON, then Urea OFF” versus “Urea OFF, 
then Urea ON” sequence). 
  
Data quality control 
The CHRC-DC has several systems programmers and data managers who will design 
and maintain the data entry/checking in REDCap, generate reports, and provide 
technical support for data entry personnel. REDCap validation rules such as setting 
acceptable range of values will be used to ensure data entry quality. Audit trails for 
tracking data manipulation will be used to ensure data integrity.  
  
Data management, security, and confidentiality 
Study data will be collected and managed using REDCap electronic data capture tools 
hosted at The University of Pittsburgh. REDCap is a secure, web-based software 
platform designed to support data capture for research studies, providing 1) an intuitive 
interface for validated data capture; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to 
common statistical packages; and 4) procedures for data integration and interoperability. 
 
Access to data will be controlled through password and authentication policies. Only 
approved individuals will have access to data. The CRHC-DC biostatistical group uses 
current versions of SAS, R, and Stata for all data manipulation, statistical analyses, and 
reporting with set guidelines for code documentation and reproducibility. In addition, the 
statisticians use M-Plus and StatXact for specific types of analyses or simulations. 
 
3.  HUMAN SUBJECTS 
 
3.1 SUBJECT POPULATION 
 
3.1.1 Inclusion of Women and Minorities 
 
For the proposed study, there are no exclusions based on gender, race, ethnicity, 
socioeconomic status, religion or sexual orientation. All patients with chronic non-severe 
hyponatremia who are seen at UPMC ambulatory clinics will be eligible for enrollment. 

31 
 
We will include both men and women, as well as all minority populations in this pilot 
study as they present to ambulatory clinics. However, it is expected that among these 
patients, we will have higher participation among women given the slightly higher 
prevalence of hyponatremia among women. By virtue of recruiting from an 
urban/suburban population in/around Pittsburgh, we anticipate that our study population 
will mirror the demographic population of the greater Pittsburgh area. Overall, it is 
anticipated that approximately 17 subjects will be female, based on prior studies of 
hyponatremia. Likewise, based on prior studies and considering the population of the 
greater Pittsburgh area, we predict that approximately 20 subjects will be White, 5 will be 
African American, and 5 will be of Hispanic ethnicity. 
 
3.1.2 Inclusion of Children 
 
This pilot study will provide preliminary data on the effectiveness, safety and tolerability 
of urea for the treatment of chronic hyponatremia in patients’ age 18 years old and older. 
No patients less than age 18 will be studied for several reasons. First, there is very 
limited data available on clinical outcomes of pediatric hyponatremia or the safety of 
urea in children with hyponatremia. Second, no one under the age of 18 receives care at 
the sites of enrollment. Third, the waiver of HIPPA needed to screen adult patients would 
not be approved by the Institutional Review Boards at the University of Pittsburgh due to 
the special status of minors as a vulnerable population, deemed to require a higher level 
of protection than adults in similar circumstances. Finally, the Principal Investigators and 
co-Investigator Dr. Palevsky are adult nephrologists and do not care for patients less 
than age 18. For these reasons, the use of urea in pediatric hyponatremia should be 
studied separately and is beyond the scope of the current proposal. 
 
3.1.3 Inclusion of Prisoners 
 
 
No prisoners will be included in this study.  
 
3.2 INCLUSION CRITERIA 
 
a. Age ≥18 years 
b. Attended ≥1 visit at a UPMC outpatient clinic within the prior 12 months 
c. Chronic hyponatremia with a history of ≥ 2 sequential plasma sodium concentration (PNa) 
between 125 mmol/L and 132 mmol/L performed ≥ 14 days apart within the last 18 months 
with most recent PNa ≤ 132 mmol/L prior to screening 
d. Patients are ambulatory without the need for any assist device (e.g., cane, walker) 
e. Mini-mental state examination (MMSE) score ≥ 25 
f. Diagnosis of SIADH established by the Bartter and Schwartz criteria as follows: 
• 
Hyponatremia with a PNa between 125 mmol/L and 132 mmol/L 
• 
Plasma osmolality < 275 mOsm/kg 
• 
Clinical euvolemia 
• 
Urine osmolality > 100 mosm/kg 
• 
Urine Na ≥ 20 mmol/L 
• 
Intact adrenal function (i.e., morning plasma cortisol value ≥15 μg/dL, or negative 
corticotropin stimulation test) 
• 
Normal thyroid stimulating hormone level (i.e., TSH between 0.3 to 5 μIU/mL) 
• 
eGFR ≥ 45 ml/min/1.73 m2) 

32 
 
g. Nephrology patients who meet eligibility for the study including a nadir serum sodium of 
no less than125 mmol/L and have already started urea and treating physician agrees to 
discontinuing prescribed urea. 
 
3.3 EXCLUSION CRITERIA 
 
a. Cirrhosis and/or end-stage liver disease 
b. Heart failure on diuretics and/or with recorded left ventricular ejection fraction <40% 
c. Chronic kidney disease with most recent estimated glomerular filtration rate < 45 
ml/min/1.73m2 
d. Adrenal insufficiency 
e. Untreated hypothyroidism 
f. Urinary tract obstruction within the prior 2 months 
g. Uncontrolled hyperglycemia (most recent random plasma glucose ≥ 200 mg/dL) 
h. Ongoing drug treatment for hyponatremia with vaptans or combination of loop diuretics 
and salt tablets. 
i. 
Active malignancy (not on remission) 
j. 
Active infection 
k. Neurological disorders with impairment of ambulation and/or cognition 
l. 
End-stage lung disease with marked impairment in ambulatory capacity  
m. Chronic pain with impairment of ambulation and/or cognition 
n. Chronic nausea 
o. Hypersensitivity to urea 
p. Women who are pregnant, breast feeding, or of childbearing potential who are not using 
contraception 
q. Patient is unable to consent for himself/herself 
 
4.   IRB APPROVAL AND FDA AMENDMENTS 
 
The Investigator will obtain, from the University of Pittsburgh Institutional Review Board 
(IRB), prospective approval of the clinical protocol and corresponding informed consent 
form(s); modifications to the clinical protocol and corresponding informed consent forms, 
and advertisements (i.e., directed at potential research subjects) for study recruitment.    
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s).  In such circumstances, 
the Investigator will promptly notify the University of Pittsburgh IRB of the deviation. The 
Investigator should also notify the sponsor of this event.   
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR 
Parts 50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice (CGP).  
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, 
substantial changes to a clinical protocol submitted under an FDA-accepted IND application, 
or in the event of the Investigator’s decision to modify the previously accepted clinical 
protocol: 
 
• 
for a Phase 1 clinical study: The Sponsor will submit (i.e., in advance of implementing 
the change) a Protocol Amendment to the IND describing any change to the Phase 1 

33 
 
clinical protocol that significantly affects the safety of the subjects.  For changes that do 
not affect critical safety assessments, the revisions to the clinical protocol will be 
addressed in the Annual Report to the IND.  
 
• 
for Phase 2 and 3 clinical studies:  The Sponsor will submit (i.e., in advance of 
implementing the change) a Protocol Amendment to the IND describing any change to a 
Phase 2 or Phase 3 protocol that significantly affects the safety of subjects, the scope of 
the investigation, or the scientific quality of the study.  Examples of Phase 2 and 3 
clinical protocol changes requiring the submission of a Protocol Amendment include: 
 
o Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any 
significant increase in the number of subjects under study. 
 
o Any significant change in the design of the protocol (such as the addition or 
deletion of a control group). 
 
o The addition of a new test or procedure that is intended to improve monitoring 
for, or reduce the risk of, a side effect or adverse event; or the dropping of a test 
intended to monitor the safety of the investigational drug. 
 
5. RECRUITMENT AND INFORMED CONSENT PROCEDURES 
 
5.1 RECRUITMENT METHODS:  
 
To identify study patients, we will conduct three sequential processes. 
 
First stage: after obtaining IRB approval, we will use a University of Pittsburgh Health Records 
Research Request service patient-generated list, the Pitt+Me University of Pittsburgh research 
registry, self-referrals, direct patient referrals from other physicians, and review of medical 
records of Nephrology outpatients at the UPMC Kidney Clinic and Nephrology inpatients at 
UPMC Presbyterian hospital, UPMC Shadyside hospital, UPMC Magee-Womens hospital, and 
UPMC Mercy hospital to identify patients who meet the following criteria: 
 
• 
Age ≥18 years 
• 
Attended ≥1 visit at a UPMC outpatient clinic within the prior 12 months 
• 
Evidence of chronic hyponatremia defined by ≥2 sequential PNa measurement 
between 125 mmol/L and 132 mmol/L performed ≥ 14 days apart within the prior 18 
months. 
• 
Most recent PNa measurement ≤132 mmol/L 
 
Second stage: this will involve electronic medical record reviews of patients identified above to 
confirm that the aforementioned inclusion criteria were met and to exclude those patients with 
any of the following: 
 
• 
Cirrhosis and/or end-stage liver disease 
• 
Heart failure on diuretics and/or with recorded left ventricular ejection fraction <40% 
• 
Chronic kidney disease with most recent estimated glomerular filtration rate < 45 
ml/min/1.73m2 
• 
Adrenal insufficiency 

34 
 
• 
Untreated hypothyroidism 
• 
Urinary tract obstruction within the prior 2 months 
• 
Uncontrolled hyperglycemia (most recent random plasma glucose≥200 mg/dL) 
• 
Ongoing drug treatment for hyponatremia with vaptans or combination of loop 
diuretics and salt tablets 
• 
Active malignancy (not on remission) 
• 
Active infection 
• 
Neurological disorders with impairment of ambulation and/or cognition 
• 
End-stage lung disease with marked impairment in ambulatory capacity 
• 
Chronic pain with impairment of ambulation and/or cognition 
• 
Chronic nausea 
• 
Hypersensitivity to urea 
• 
Women who are pregnant, breast feeding, or of childbearing potential who are not 
using contraception 
• 
Patient is unable to consent for himself/herself 
 
For all patients meeting these inclusion and exclusion criteria, we will contact their primary care 
provider (PCP) to discuss the study and their patients’ potential eligibility. We will ask PCPs for 
permission to mail a letter to their patient on the PCP’s behalf that introduces the study and 
describes how the patient can contact our study team if they are interested in participating. The 
letter will also state that if patients do not contact our team within 2 weeks, we will call them to 
inquire about their interest in participating in the study. This process of identifying and 
contacting potential study subjects has been deemed acceptable by the UPMC Institutional 
Review Board. 
 
For Nephrology outpatients and inpatients, if the patient is not known to a study team clinician, 
the study team will request a clinician known to the subject ask the subject if a research team 
member may approach. Upon confirmation from the clinician that the subject is interested, the 
study team will approach. 
 
Third stage: For patients who are interested in potentially participating, we will proceed with the 
third step. This will involve an in-person visit to obtain written informed consent from the patient 
to perform a physical examination and laboratory testing to confirm the presence of 
hyponatremia and to establish the etiology as SIADH. This informed consent will also cover 
patient participation in the study (patients who fail this screening testing will have their consent 
to participate withdrawn).  
 
For Nephrology inpatients who meet eligibility for the study and have not started urea in the 
hospital, we will obtain informed consent during their hospitalization and schedule them for a 
screening visit within approximately 5-7 days after discharge. For Nephrology inpatients who 
meet eligibility for the study including a nadir serum sodium of no less than 125 mmol/L and 
have already started urea in the hospital, we will obtain informed consent during hospitalization, 
discuss with the nephrologist and/or hospitalist, we will ask them if the patient can come off urea 
and if so, to discontinue urea. We will then schedule these patient for a screening visit within 5-7 
days after discharge. This will ensure that if urea is discontinued, that the process is approved 
and implemented by the treating physician and that the patient will have a follow up plasma 
sodium checked within approximately 5-7 days after urea discontinuation. We are specifically 
limiting the inclusion of Nephrology inpatients, including those who are on urea in the hospital, 
to those with plasma sodium levels no less than 125 mmol/L to avoid enrolling patients with 
plasma sodium levels that are more severely reduced.  

35 
 
 
For Nephrology outpatients who meet eligibility for the study including a nadir serum sodium of 
no less than 125 mmol/L and are already on urea, we will obtain informed consent, discuss with 
the nephrologist, we will ask them if the patient can come off urea and if so, to discontinue urea. 
We will then schedule these patients for a screening visit within 5-7 days after urea 
discontinuation. Screening visit for subjects enrolled from the outpatient setting will take place at 
UPMC Kidney Clinic. 
 
The screening physical examination will confirm that patients: 1) are ambulatory without the 
need for any assist device (e.g., cane, walker) in order to comply with study postural control and 
stability assessments; 2) have intact cognition based on a mini-mental state examination 
(MMSE) score ≥25 in order to comply with neurocognitive assessment and; 3) are euvolemic in 
order to meet diagnostic criteria for SIADH. For ambulatory, cognitively intact, euvolemic 
patients, we will then check a basic metabolic panel, plasma osmolality, plasma uric acid, 
thyroid stimulating hormone, morning plasma cortisol; and urine osmolality and urine sodium. 
Patients with a morning plasma cortisol value <15 μg/dL will be considered to have an equivocal 
result and will need to undergo a standard-dose (250 μg) corticotropin stimulation test to rule out 
adrenal insufficiency in the UPMC Montefiore Clinical and Translational Research Center. 
Patients determined to have hyponatremia due to SIADH based on the following laboratory 
criteria will be eligible to participate:  
 
• 
PNa between 125 mmol/L and 132 mmol/L 
• 
Plasma osmolality <275 mOsm/kg 
• 
Urine osmolality >100 mOsm/kg 
• 
Urine Na ≥ 20 mmol/L 
• 
Intact adrenal function (i.e., morning plasma cortisol value ≥15 μg/dL, or negative 
corticotropin stimulation test) 
• 
Normal thyroid stimulating hormone level (i.e.,TSH 0.3-5 μIU/mL) 
• 
Normal kidney function based on eGFR ≥ 45 ml/min/1.73 m2 
 
Patients deemed eligible to participate based on this testing will be notified by the study team 
and sent a 24-hour urine collection container with instructions to return the sample at the time of 
the baseline study visit. The study team will also notify patients who do not meet criteria for 
SIADH that they will not be eligible to participate in the study and will offer them follow up in the 
UPMC Kidney Clinic for routine clinical care of their hyponatremia. 
 
5.2 INFORMED CONSENT PROCEDURES  
 
After IRB is approved then we will identify patients that meet inclusion criteria (see first stage 
above) from the University of Pittsburgh Health Records Research Request patient-generated 
list, the Pitt+Me University of Pittsburgh research registry, direct patient referrals from other 
physicians, andreview of medical records of Nephrology outpatients at the UPMC Kidney Clinic 
and Nephrology inpatients at UPMC Presbyterian hospital, UPMC Shadyside hospital, UPMC 
Magee-Womens hospital, and UPMC Mercy hospital.The electronic medical records of these 
patients will be reviewed to confirm inclusion criteria and select patients who do not meet 
exclusion criteria (see second screening stage above). For all patients meeting these inclusion 
and exclusion criteria, we will contact their primary care provider (PCP) to discuss the study and 
their patients’ potential eligibility as well as ask for permission to mail a letter to their patient on 
the PCP’s behalf that introduces the study and describes how the patient can contact our study 
team if they are interested in participating. The letter will also state that if patients do not contact 

36 
 
our team within 2 weeks, we will call them to inquire about their interest in participating in the 
study. This process of identifying and contacting potential study subjects has been deemed 
acceptable by the UPMC Institutional Review Board. For Nephrology outpatients and inpatients, 
if the patient is not known to a study team clinician, the study team will obtain permission from a 
clinical caregiver known to the subject to approach about study participation.  
For patients who are interested in potentially participating, we will ask them to come for an in-
person visit and the PI will obtain written informed consent from the patients to perform 
screening tests, including a physical examination, as well as laboratory testing (see third 
screening stage above). For Nephrology inpatients who meet eligibility for the study and have 
not started urea in the hospital, we will obtain informed consent during their hospitalization and 
schedule them for a screening visit within approximately 5-7 days after discharge. For 
Nephrology inpatients who meet eligibility for the study including a nadir serum sodium of no 
less than 125 mmol/L and have already started urea in the hospital, we will obtain informed 
consent during hospitalization, discuss with the nephrologist and/or hospitalist, we will ask them 
if the patient can come off urea and if so, to discontinue urea. We will then schedule these 
patient for a screening visit within 5-7 days after discharge. This will ensure that if urea is 
discontinued, that the process is approved and implemented by the treating physician and that 
the patient will have a follow up plasma sodium checked within approximately 5-7 days after 
urea discontinuation. We are specifically limiting the inclusion of Nephrology inpatients, 
including those who are on urea in the hospital, to those with plasma sodium levels no less than 
125 mmol/L to avoid enrolling patients with plasma sodium levels that are more severely 
reduced.  
 
This informed consent will also cover patient participation in the study. The information 
communicated as part of the patient participation in the study will include:  
 
- 
Name of the study  
- 
Name of the Principal Investigators  
- 
Explanation that the study involves research  
- 
Explanation of the purpose of the study  
- 
Explanation of the treatment procedures  
- 
Description of randomization  
- 
Description of the risks and benefits of participation in the study  
- 
Description of alternatives to participation in the study  
- 
Explanation that all records will be kept confidential, but that records may be 
examined by representatives of the NIH and/or the FDA  
- 
Whom to contact for questions about the research and about subjects' rights  
- 
Whom to contact in the event of a research-related injury  
- 
A statement that participation in the study is voluntary and that a decision not to 
participate or to withdraw from the study after initially agreeing involves no penalty, 
loss of benefits, or reduction in access to medical care  
- 
A statement that the treatments provided as part of this study are free 
- 
Payments offered for their participation 
 
There will be no waiting period between informing the prospective participant and obtaining 
consent. If participants are unable to consent for themselves then they won’t be included in the 
study as this constitutes an exclusion criteria. Patients deemed eligible to participate based on 
this testing will be notified by the study team within 2 business days. Patients who fail this 
screening testing will have their consent to participate withdrawn and the study team will notify 
them and offer them follow up in the UPMC Kidney Clinic for routine clinical care of their 

37 
 
hyponatremia. Subjects will not be informed of the outcome of the research unless they request 
so in writing. 
 
6.  POTENTIAL RISKS AND BENEFITS 
 
6.1 POTENTIAL RISKS 
 
6.1.1 Risk of Experimental Drug Intervention 
 
Overall, this is a low risk study. 
 
Physical risks 
 
Urea is a dietary supplement considered by the US Food and Drug administration under the 
GRAS (Generally Regarded As Safe) category. Urea is now available for the treatment of 
hyponatremia in the United States and evidence from case series in Europe and from a 
recent study by our group suggests that urea is safe and well-tolerated. Nevertheless, some 
patients might experience distaste, nausea, vomiting, diarrhea, and/or headaches 
associated with the use of urea. Osmotic demyelination syndrome is a complication of overly 
rapid correction of PNa (increase in PNa >8 mmol/L/24 hours) in patients with severe 
hyponatremia (PNa < 120 mmol/L). However, this is not a concern in our study population 
as patients with a PNa ≥125 mmol/L who do not have serious liver disease (an exclusion 
criterion for our study) have a negligible risk of osmotic demyelination syndrome if 
overcorrection of hyponatremia occurs. 
 
Psychological risks 
There are no anticipated psychological risks. 
 
No social, cultural, financial or legal risks for the study participants are anticipated. Pregnant 
women are excluded from this study. However, no birth defect have been observed and 
currently there is inadequate information to conclude whether urea is mutagenic.  
 
7.1.2 Risk of Study Procedures 
 
• 
Blood draws: It may cause pain and bruise. Some people may become light-headed 
(dizzy) or faint after blood drawing. There is also a rare risk of infection at the site of 
the blood draw 
• 
Fluid restriction: it may cause thirst. 
• 
Neurocognition assessment: no known risks are associated with this study procedure. 
• 
Posture stability assessment: There is a risk of falling while undertaking the balance 
testing, and this is heighted with increased age. All participants will use a safety 
harness during posture stability assessment. 
• 
Collection and storing of PHI and Bio specimens: low risk of breach of confidentiality 
• 
Discontinuing clinically prescribed urea in the hospital: This might cause the blood 
sodium level to decrease. To minimize this risk, we will first obtain approval from the 
participant’s treating physician in the hospital to make sure is safe to do so and 
schedule participants for the screening visit within 5-7 days of hospital discharge to 
ensure a blood sodium level will be checked after urea discontinuation. In addition, 
we are only enrolling participants with a blood sodium level no lower of 125 mmol/L 
where the risk of experiencing any symptoms related to low blood sodium is very low. 

38 
 
 
6.2 ALTERNATIVE TREATMENTS 
 
Alternative treatments include fluid restriction alone, loop diuretics with salt tablets, and 
tolvaptan.  
 
6.3 POTENTIAL BENEFITS 
 
There is no direct benefit to study participants. The results will provide proof of concept data and 
inform the design of a future randomized controlled trial which may profoundly impact the 
treatment of patients with chronic hyponatremia. However, the study interventions convey a very 
low risk in relationship to the therapeutic benefits for future patients with chronic hyponatremia. 
All patients will be offered the opportunity to be seen in the UPMC kidney clinic after completion 
of the study for consideration of continuation of urea therapy as part of their routine clinical care. 
 
7. RISKS MANAGEMENT PROCEDURES 
 
7.1 PROTECTION AGAINST RISKS   
 
General Risks of Study Protocol and Procedures 
All research interventions/activities will be conducted in private patient care areas. The collection 
of sensitive information about subjects is limited to the amount necessary to achieve the aims of 
the research, so that no unneeded sensitive information is being collected. All demographic and 
clinical information about the subject will be stored in an electronic password-guarded study 
database under the supervision of the Investigator for this protocol. 
 
The data will be stripped of individual identifiers and stored anonymously with a subject number. 
Information linking subject identifiers with the coded subject number will be stored under 
password protection on computers in locked areas, with access only to the database manager. 
All staff will sign confidentiality statements. Access to the database will be limited to the data 
manager and staff under the supervision of the Investigator. 
 
All staff involved in this study are properly credentialed and instructed in the areas of testing, 
confidentiality, and safety.  
 
The investigators will retain the data for the entire period of this study and will retain the 
specified records and reports for up to two years after the marketing application is approved for 
the investigational drug; or, if a marketing application is not submitted or approved for the 
investigational drug, until two years after investigations under the IND have been discontinued 
and the FDA so notified. The investigators may continue to use and disclose subjects’ de-
identified information for the purpose of this study for a minimum of seven years after final 
reporting or publication of the study. If the subject and/or legal representative decide to withdraw 
or be withdrawn from study participation, they may request that the study data be destroyed. 
Subject names or other directly identifiable information will not appear on any reports, 
publications, or other disclosures of clinical study outcomes. 
 
Clinical study data that will be recorded directly on the electronic database include patient 
demographics, medications, comorbidities, and laboratory data whereupon the electronic data is 
to be considered Source Data. Source Data are the clinical findings and observations, 
laboratory and test data, and other information contained in Source Documents. Source 
documents may include, but are not limited to, hospital records, clinical and office charts, 

39 
 
laboratory notes, memoranda, subjects’ diaries or evaluation, checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm, or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and 
at the medico-technical departments involved in the clinical trial. When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents.   
 
We will account for any missed, unused, and/or spurious data as follows: the extent and 
reasons that data are missing will be described. A comparison of baseline characteristics and 
intermediate outcomes between those who complete the study and those who do not will be 
conducted. We will investigate the randomness of missing data using available information on 
patient characteristics to help discern patterns in the missing data and to identify the possible 
covert missing data mechanisms. The primary efficacy analytic approach (mixed models) can 
handle data that are ignorable missing (i.e., either missing completely at random or missing at 
random). However, strategies to handle missing data (single/multiple imputation, selection 
models, pattern-mixture models, etc.) and sensitivity analyses to encompass different scenarios 
of assumptions will be considered as appropriate. 
 
7.2 PROTECTION AGAINST POTENTIAL RISKS OF EXPERIMENTAL INTERVENTION 
 
• 
Involvement of trained staff / investigators with experience in the administration of the 
study drug 
 
• 
Continuous monitoring by the Data and Safety Monitoring Board 
 
• 
Required Education in the Protection of Human Research Participants (CITI Good Clinical 
Practice Module) 
 
8.0 ADVERSE EVENTS  
 
The proposed study will use the FDA definition of adverse events (AE) and serious adverse 
events (SAE). Any SAE, which is unexpected and related to study intervention, will be reported 
immediately to the IRB and FDA and will include all known details regarding the nature of the 
SAE. In the event that a participant either withdraws from the study or the investigators decide 
to discontinue a participant due to a SAE, the participant will be monitored by the PI and treating 
investigator until (a) a resolution is reached (e.g., the problem has resolved or stabilized with no 
further change expected), (b) the SAE is determined to be clearly unrelated to the study 
intervention, or (c) the SAE results in death. Outcomes of SAEs not previously reported will be 
reported to the sponsor, IRB and FDA via a follow-up report.  A summary of the SAEs that 
occurred during the previous year will be included in the FDA annual progress report as well as 
in the annual IRB renewal. 
 
The severity of adverse changes in physical signs or symptoms will be classified as follows: 
 
• 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observation 
only; intervention not indicated. 
 
• 
Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-
appropriate ADL (Activities of Daily Living). 
 

40 
 
• 
Grade 3 (Severe): medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care/ADL. 
 
• 
Grade 4 (Life-threatening): consequences; urgent intervention indicated. 
 
• 
Grade 5 (Death): event is a direct cause of death.  
 
8.1 REPORTABLE ADVERSE EVENTS 
 
For this study, a serious adverse event is any untoward clinical event that is thought by either 
the investigator or the sponsor to be unexpected and at least possibly related to the study and 
results in any of the following: 
 
1. Death 
2. A life-threatening adverse event 
3. Inpatient hospitalization or prolongation of an existing hospitalization 
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5. A congenital anomaly or birth defect 
6. Important medical events that may not result in death, be life threatening, or require 
7. Hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient, or subject, and may require medical, or 
surgical intervention to prevent one of the serious outcomes listed above. 
 
If clinically important and unexpected adverse experiences or clinically important study-related 
adverse experiences occur, they will be recorded on the adverse event case report form.    
 
8.2 ADVERSE EVENTS REPORTING TIMELINES 
 
Life-threatening or fatal unexpected adverse events associated with the use of the study drug or 
procedures must be reported to the IRB within 24 hours of discovery of the incident with 
subsequent follow-up submission of a detailed written report. 
 
The FDA will be notified by telephone or facsimile transmission of a human adverse event that 
is fatal or life-threatening no later than 7 calendar days after receiving the respective human 
adverse event information, followed by the subsequent submission of a written IND Safety 
Report. 
 
Serious and unexpected adverse events associated with the use of the study drug or 
procedures will be reported to the IRB with subsequent follow-up submission of a detailed 
written report in accordance with the respective policies and procedures of the IRB. Written IND 
Safety Reports will be submitted to the FDA as soon as possible and, in no event, later than 15 
calendar days following the investigator-sponsor’s receipt of the respective adverse event 
information. 
 
A summary report of the findings will be prepared and submitted to the regulatory agencies as 
required. 
 
9. DATA SAFETY MONITORING  
 

41 
 
9.1 DATA SAFETY MONITORING BOARD 
 
A Data Safety Monitoring Board (DSMB) will be appointed for this study. The DSMB will be 
composed of 3 members to be named.  
 
9.2 DATA SAFETY MONITORING PLAN 
 
Monitoring of safety and data quality in the proposed study will be the responsibility of all 
personnel on the project, with primary responsibility and supervision by the Investigator.  The 
Institutional Review Board will approve the Statement of Informed Consent for the study and 
provide institutional oversight of data and safety issues. The study protocol will be approved 
prior to recruiting or obtaining consent from any participants. Moreover, the study will be 
reviewed at a minimum of annual basis (or more frequently as deemed necessary) by the IRB 
committee. Each participant will sign the Informed Consent Form described above prior to 
participating in the study. To ensure participant safety, once participants are enrolled in the 
study, study staff will immediately report all adverse and serious adverse events to one of the 
Investigators. The Investigator will, per institutional requirements, report them to the IRB for their 
review. These events should also be communicated to the sponsor of the IND.  With regard to 
monitoring of data quality and protected health information, all required personnel proposed for 
this project will have the required human subjects and confidentiality training, which includes 
information about maintaining data integrity and security. Confidentiality will be guarded using 
established procedures such as storing data in locked cabinets within locked offices or locked 
data rooms, coding by study identification numbers rather than any personally identifying 
information to avoid revealing the identity of subjects, and aggregating data across participants. 
The key linking names and study identification numbers will be kept separately from the data 
sets with limited access by study personnel. Only study personnel will have access to the data 
sets on protected servers. In order to maintain the highest standard of data entry quality, all data 
will be double-entered, with discrepancies highlighted so that they can be reviewed by the 
project coordinator. Oversight of all aspects of data management will occur with the Investigator. 
 
9.3 PARAMETERS TO BE MONITORED 
 
The following progress will be monitored throughout the course of the research to ensure the 
safety of subjects as well as the integrity and confidentiality of their data. 
 
• 
An evaluation of the progress of the research study, including subject recruitment 
and retention, and an assessment of the timeliness and quality of the data. 
 
• 
A review of collected data (including adverse events, unanticipated problems 
requiring reporting and those captured on the non-compliance log, and subject 
withdrawals) to determine whether there is a change to the anticipated benefit-to-
risk assessment of study participation and whether the study should continue as 
originally designed, should be changed, or should be terminated. 
 
• 
An assessment of external factors or relevant information (e.g. pertinent scientific 
literature reports or therapeutic development, results of related studies) that may 
have an impact on the safety and study participants or the ethics of the research 
study. 
 

42 
 
• 
A review of study procedures designed to protect the privacy of the research 
subjects and the confidentiality of their research data. 
 
9.4 FREQUENCY OF MONITORING 
 
The Investigator will review subject safety data as it is generated. The Investigator, sub-
investigators, and the research staff will meet on a 4-week interval to re-evaluate study goals, 
subject recruitment, data coding and retention, documentation and identification of adverse 
events, complaints and confidentiality of subjects. There will be an evaluation of the progress of 
the research study, including assessments of data quality, timelines, participant recruitment, 
accrual, and retention. The Investigator will also review the outcome and adverse event data to 
determine whether there is any change to the anticipated benefit-to-risk ratio of study 
participation and whether the study should continue as originally designed or should it be re-
evaluated and changed. 
 
10. WITHDRAWAL OF SUBJECTS AND STOPPING CRITERIA: 
 
 
Adverse Events: Oral urea use is occasionally associated with the onset of nausea, vomiting, 
diarrhea and headaches. If these symptoms appear then they will be initially managed by asking 
patients to monitor their symptoms and report to the research coordinator if symptoms persist 
after 24h. If symptoms persist, urea dose will be reduced by 50%. If symptoms persist 72h after 
reducing the dose of urea, urea will be discontinued. Participant will be asked to return 
remaining urea doses, and after consultation with all the members of the research team, 
participant will be formally withdrawn from the study. Data no longer will be collected from the 
withdrawn subject and subject will be referred to the UPMC kidney clinic for follow up. Subjects 
withdrawn from the study will be replaced using the regular procedures described for 
recruitment. We will continue recruitment until the target number of patients are enrolled. 
 
Other Criteria: None 
 
Discontinuation of the Clinical Trial: This does not apply to this study as this is a pilot study 
that is not designed to assess either efficacy or futility. 
 
11.  COSTS AND PAYMENTS 
 
11.1 COSTS 
 
The total budget for the study is $234,750.00. 
 
11.2 PAYMENTS 
 
Patient’s time compensation will be $20 per patient per visit. In addition, participants will receive 
free validated parking during study visits.  
 
12.  QUALIFICATIONS AND SOURCE OF SUPPORT 
 
12.1 QUALIFICATIONS OF THE INVESTIGATORS 
 
Helbert Rondon Berrios, MD, MS, FACP, FASN, FNKF (Principal Investigator) 
 

43 
 
Dr. Rondon Berrios is an Associate Professor of Medicine at the University of Pittsburgh School 
of Medicine and Program Director of the Nephrology Fellowship Training Program at UPMC 
Medical Education. Dr. Rondon Berrios is a physician trained in Internal Medicine and 
Nephrology with over 10 years of clinical experience in both private practice and academia. 
Within the field of nephrology, Dr. Rondon Berrios has a special interest in fluid, electrolytes, 
and acid-base disorders with an emphasis on the diagnosis, management, and outcomes of 
chronic non-severe hyponatremia. Dr. Rondon Berrios has authored several peer-reviewed 
publications and book chapters on the topic of hyponatremia and has given invited talks on this 
topic at regional and national meetings. Dr. Rondon Berrios recently served as the primary 
investigator and author on a retrospective observational study describing the use of urea for the 
treatment of hyponatremia among hospitalized patients. This was the first study describing the 
use of this therapy in the United States. In association with Dr. Steven Weisbord who is co-
Principal Investigator on this proposal and who has extensive experience conducting clinical 
trials in the field of nephrology, Dr. Rondon Berrios is uniquely positioned to successfully carry 
out the proposed research project. In close collaboration with Dr. Weisbord, Dr. Rondon Berrios 
will oversee all aspects of this study including, obtaining IRB approval, hiring and training the 
study coordinator, enrolling patient participants, ensuring compliance with the study protocol, 
overseeing data collection and analysis, and dissemination of study results. 
 
Steven D. Weisbord, MD, MSc, FASN (Co-Principal Investigator) 
 
Dr. Weisbord is a Professor of Medicine (with Tenure) and Clinical and Translational Sciences 
at the University of Pittsburgh School of Medicine and Staff Nephrologist and clinical 
investigator at the VA Pittsburgh Healthcare System. Dr. Weisbord has conducted two 
multicenter clinical trials. Most recently, Dr. Weisbord was the Study Chairman and Principal 
Investigator of the Prevention of Serious Adverse Events Following Angiography (PRESERVE) 
study, a multicenter, randomized, VA clinical trial that compared interventions for the prevention 
of serious adverse outcomes among high-risk Veterans undergoing angiography. Dr. Weisbord 
was also Principal Investigator of the NIH-supported Biomarker Collection and Analysis in the 
PRESERVE Trial Cohort study, which involved the collection and banking of blood and urine 
specimens from PRESERVE trial participants for analyses of specific kidney biomarkers. With 
Dr. Weisbord’s experience as a Principal Investigator on prior clinical trials, he is uniquely 
positioned to assist Dr. Rondon Berrios conduct the proposed pilot study. Specifically, Dr. 
Weisbord will assist Dr. Rondon Berrios on all aspects of the proposed research, including 
patient screening and recruitment, data collection, data analysis, presentation of study results, 
and dissemination of study findings. 
 
Paul M. Palevsky, MD, FASN (Co-Investigator) 
 
Dr. Palevsky is a Professor of Medicine (with Tenure) and Clinical and Translational Sciences at 
the University of Pittsburgh School of Medicine and chief of the Renal Section and clinical 
investigator at the VA Pittsburgh Healthcare System. Dr. Palevsky’s primary research interests 
are in the areas of acute kidney injury, critical care nephrology, chronic kidney disease and 
acute and chronic dialysis. Dr. Palevsky has helped design and conduct multiple large, 
multicenter, randomized controlled trials including the VA/NIH Acute renal failure Trial Network 
(ATN) study (VA CSP #530; NCT000769219) for which he was the study chair; the VA 
Nephropathy in Diabetes (NEPHRON-D) study (VA CSP #565; NCT00555217) for which he 
was on the planning and executive committees; the EUPHRATES trial, evaluating the safety 
and efficacy of polymyxin B hemoperfusion in patients with endotoxemia and septic shock 
(NCT01046669) for which he was a member of the study executive committee; the Prevention 
of Serious Adverse Events Following Angiography (PRESERVE) trial (VA CSP #578; 

44 
 
NCT01467466) for which he was the co-principal investigator and study co-chair; and the 
ongoing Stop GOUT (Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat; VA CSP 
#594; NCT02579096) for which he was a member of the planning committee and is a member 
of the study executive committee. Dr. Palevsky has also been a co-investigator for the 
Protocolized Goaldirected Resuscitation of Septic Shock to prevent AKI (ProGReSS-AKI) study 
(1R01DK083961), an ancillary study to the recently completed Protocolized Care for Early 
Septic Shock (ProCESS) trial (NCT00510835), which evaluated the effect of protocolized goal-
directed therapy in sepsis on the development and long-term outcomes of AKI and he is one of 
three principal investigator for Phenotyping Renal Cases In Sepsis and surgery for Early Acute 
Kidney Injury (PReCISE AKI), the Pittsburgh AKI recruitment site for the NIDDK Kidney 
Precision Medicine Project (1UG3 DK114861-01). Among other research roles, he is a member 
of the OSMB for the Chronic Renal Insufficiency Cohort (CRIC) study, served as the chair of the 
DSMB for the NIDDK’s Hemodialysis Novel Therapies (HDNT) Consortium, is a member of the 
DSMB for the Optimal Management of HIV Positive Adults at Risk for Kidney Disease in Nigeria 
study and is a member of the EPP for the United States Renal Data System. With his 
experience as a Principal Investigator on prior clinical trials, Dr. Palevsky is uniquely positioned 
to assist Dr. Rondon Berrios and Dr. Weisbord conduct the proposed project. 
 
Christopher Connaboy, PhD (Co-Investigator) 
 
Dr. Connaboy is an Assistant Professor in the Department of Sport Medicine and Nutrition, 
working within the Neuromuscular Research Laboratory and Warrior Human Performance 
Research Center. Dr. Connaboy completed his PhD in Biomechanics and Motor Control and his 
MSc in Biomechanics at the University of Edinburgh. Prior to coming to the University of 
Pittsburgh, Dr. Connaboy worked at the University of Houston, TX and Edinburgh Napier 
University, Scotland. During Dr. Connaboy's time at Edinburgh Napier University, he led the 
successful development of a collaborative, interdisciplinary research group: The Military and 
Veterans Health Research Consortium (MVHRC). The MVHRC is a network of academic 
partners from around Scotland, the UK, and USA. During his tenure as Director of MHVRC, Dr. 
Connaboy oversaw the inclusion of the MVHRC as a preferred supplier on the Ministry of 
Defense/Defense Science and Technology Laboratories Human Capabilities Research 
Program, from which they were successful in receiving over £1,000,000+ of research funding. 
Prior to undertaking his academic career Dr. Connaboy was an enlisted soldier in the Black 
Watch, Royal Highland Regiment in the UK Armed Forces. As a researcher, he has expertise in 
human performance optimization with a specific focus on movement, coordination and the 
perceptuo-motor processes involved in performing skilled actions in occupational settings, and 
for both elite warfighters and athletes. Dr. Connaboy has received funding from the U.S. 
Department of Defense (ARMY, NAVY, AIR FORCE and MARINES), NASA, and the UK 
Ministry of Defense. Therefore, Dr. Connaboy is well positioned to provide Dr. Rondon Berrios 
and Dr. Weisbord the expertise in the measurement of neurocognition and postural stability for 
the proposed project. 
 
Shawn Flanagan, PhD (Co-investigator) 
 
Dr. Flanagan is an Assistant Professor of Sports Medicine and Nutrition, and his overall 
research agenda emphasizes neural contributions and adaptations related to human 
performance, resilience, and injury. He has a broad background in neuroscience and physiology 
with specific training in brain stimulation, imaging, endocrinology, and physical exercise. I use 
multimodal and complementary neuroimaging, perturbational, biochemical, and 
electrophysiological techniques combined with ethologically-relevant behavioral assays to better 
understand and improve human brain-body interactions in health and disease. His research is 

45 
 
interdisciplinary in nature and has involved collaborations with physiologists, biomechanists, 
neuroscientists, psychologists, biochemists, mathematicians, psychiatrists, nutritionists, and 
neurologists. As a PI or co-Investigator on several federally-funded grants, his current work 
includes efforts to better understand psychological and physiological resilience, novel 
techniques to optimize human performance, the influence of injury on the brain, and biomarkers 
for performance adaptations and injury. In this capacity, he has successfully administered the 
projects, cultivated strong collaborations, produced several peer-reviewed publications in 
leading journals, and developed communication and management practices that facilitate 
realistic research plans, timelines, and budgets. In summary, He has the expertise, resources, 
and leadership needed to successfully complete the proposed research, which represents a 
logical extension of his prior work. 
 
Jonathan G. Yabes, PhD (Co-Investigator) 
 
Dr. Yabes is an Assistant Professor of Medicine at the University of Pittsburgh School of 
Medicine and a biostatistician at the University of Pittsburgh Center for Research on Health 
Care Data Center (CRHC-DC), where he works with various investigators in different clinical 
research projects. Dr. Yabes has been collaborating with the Nephrology division on several 
projects. Dr. Yabes is currently a co-investigator and biostatistician in several other randomized 
trials studying interventions for patients on hemodialysis, with chronic kidney disease, insomnia, 
lower respiratory tract infection, and diabetes. Dr. Yabes also work on health services research 
projects on urologic oncology using large administrative datasets. Dr. Yabes was a member of 
the Multidisciplinary Clinical Research Scholars Program advisory committee where he 
collaborated with junior faculties working on career development proposals. As the study 
biostatistician, Dr. Yabes will work closely with the study team in overseeing and executing the 
statistical aspects of trial including randomization, report generation for data monitoring and 
dissemination, and implementation of the statistical analyses plan. Dr. Yabes has worked with 
Dr. Rondon Berrios and Dr. Weisbord in developing the study design and statistical aspects of 
this proposed work. In summary, Dr. Yabes’ research experience and rigorous statistical training 
are well-suited for the biostatistical needs of the proposed work.  
 
12.2 SOURCES OF SUPPORT 
 
This study is supported by NIH/NIDDK grant 1 R21 DK122023-01A1 
 
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14. APPENDICES 
 
NEUROCOGNITIVE AND POSTURAL STABILITY ASSESSMENT 
 
Neurocognition assessment  
 
Perception-Action Coupling Task (PACT)  
The PACT assesses perception-action coupling behavior; specifically, the accuracy of action-
boundary perception. The PACT uses matched pairs of ‘virtual’ balls and ‘virtual’ holes to assess 
the subject’s ability to accurately and quickly determine if a ball will fit inside a hole, when 
presented on an iPad screen. Subjects are presented with a series of virtual balls of different sizes 
and a corresponding virtual hole, also varying in size. The objective of the task is to accurately 
and quickly judge if the ball will fit into the hole, or not. Subject are seated, with an iPad held in 
both hands and forearms resting on their thighs and the thumb of their preferred hand resting on 
the green (home) button on the iPad screen (figure 3). Subjects will be presented with randomly 

49 
 
occurring series of virtual ball: virtual hole parings (see figure 1) over a 15-minute period. Time 
between the presentation of the virtual ball: virtual hole parings is also random. On presentation 
of a virtual ball: virtual hole paring, subjects react by moving their thumb from the home button to 
the blue joystick button. If they perceive the hole aperture (white circle) to be large enough to 
accommodate the ball (yellow circle) the subjects move the joystick forward towards the hole. If 
the subject perceives the hole to be too small compared to the size of the ball they move the 
joystick down, away from the ball. The ball will move in correspondence with the movement of the 
joystick. After completing the move, subject return their thumb to the home button and await the 
appearance of the next pairing. This is repeated for a total of 15 minutes. Subject are required to 
perform 1 cycle trial of the PACT protocol to establish familiarization with the task. 
The figure below shows a zoomed in version of the test on a tablet (left), while the right-side photo 
shows a subject performing the test. The PACT produces multiple scores including: (1) initiation 
time (IT), (2) within-participant IT variability, (3) movement time, (4) within-participant MT 
variability, (5) percentage correct responses, (6) aperture ratio, (7) mean IT for correct and 
incorrect responses, (8) percentage perceived as afforded action, (9) percentage perceived as 
un-afforded action. Visual representation of the PACT as seen on the tablet screen (left) and a 
subject performing the test (right) 
 
 
Senaptec™ Sensory test battery  
A total of seven measures from the Senaptec Sensory Station™ test battery will be used 
to assess sensorimotor abilities. Measures to be assessed include: multiple object 
tracking (perception span), reaction time (Hand response time), perception span, go/no 
go, depth perception and dynamic visual acuity (near far quickness). 

50 
 
  
 
 
 
 
 
Multiple object tracking task  
It is used to measure the ability to attentively select and successfully track several moving 
objects. For the first 5 trials, 6 black dots are presented on a white background. Three dots are 
targets and each target is paired with a corresponding distractor dot. The three target-distractor 
pairs are located around a cross in the center of a 13.3” tablet display.  The user is instructed to 
track the 3 target dots, which were cued in red for 1 second, then the pairs of the target-distractor 
pair rotate around each other. The pairs rotate for 5 seconds with 2 reversals at random points in 
that time span. After the rotation stops, the user selects one dot from each target-distractor pair 
by using the tablet touchscreen interface. After each of the first 4 trials, the speed is adjusted 
based on the accuracy of the identification of the targets. The starting rotational speed for the first 
trial is 500 deg/sec and for the following trials can reach from 120 to 900 deg/sec after gradual 
adjustments.  The threshold speed is defined as the final speed including the adjustment after the 
5th trial. The first trial of the last 5 trials starts with 4 pairs with the rotational speed set at 80% of 
the threshold speed determined from the first 5 trials. Identifying all targets correctly for each trial 
results in adding another pair of dots for the following trial. If the user does not get all targets 
correct, a pair is removed for the next trial. The maximum number of pairs for the last 5 trials is 8 
pairs and the minimum is 2 pairs. 
 
Reaction time test (Hand response Test) 
Subjects will keep an arm’s length from the 13’3” tablet computer. Two annular patterns 
appear on the screen with centers 14.5 cm apart; each annulus consists of 2 concentric circles, 
6.4 cm and 3.1 cm in diameter. Automated instructions direct the subject to place the fingertips of 
both hands on the inner circles of the annulus. If the hand was aligned correctly, the outer circles 
of both annuli would change color to blue-green. After a randomized delay of 2, 3, or 4 seconds, 
one of the annuli turns blue-green, and the subject removes the hand on that annulus as quickly 
as possible. Animation examples are shown, followed by 2 practice trials. Ten trials are conducted 
per subject to calculate average reaction and response times – 5 dominant, and 5 non-dominant 
trials presented in random order. Reaction Time is measured as the elapsed time between onset 
of the test annulus and release of the control annulus.  After 10 trials, the computer calculates the 
averages and standard deviations for the reaction and response times. If any single measure 
differed from the mean by more than 2 standard deviations in either direction, another trial was 
conducted to replace the outlying measure for that trial. 

51 
 
 
 
 
Perception Span test 
Subject seated with the 13’3” tablet computer located at arm’s length. The subject is 
instructed to focus on a shrinking white dot in the center of a grid pattern of 30 circles arranged 
into a grid pattern. The disappearance of the white dot triggers the appearance of a pattern of 
yellow dots which simultaneously flash for 100 milliseconds. The subject is then required to 
recreate and identify the pattern of yellow dots by pressing on their locations on the touch screen 
tablet screen. If a pass rate of greater than 75% is achieved the grid pattern is increased, with 
additional number of potential locations – Levels 1-2: 6 circles in the grid with 2-3 dots, Levels 3-
8: 18 circles with 3 to 7 dots, Levels 9-12: 30 circles with 7 to 10 dots presented. The dot pattern 
at each level is pseudorandomized, to maintain spatial organization/distribution and prevent 
clustering of dots into recognizable patterns. Examples are shown, followed by two practices 
trails. The score representing this measures is based on the cumulative number of correct 
responses, with missed responses and extra (superfluous identifications) subtracted from the 
cumulative score.  Subjects were allowed two attempts to pass each level, if two attempts were 
taken on the values from the passing score were added to the cumulative score. If the subject 
fails the second attempt the test is terminated and total calculated.  
  
Go/No Go test 
Subjects are presented with a grid of 8 (rows) x 6 (columns) equally spaced circles on the 
tablet computer. A series of yellow-green or red dots are presented in a pseudorandomized order 
to maintain spatial distribution and prevent clustering and recognizable patterns of dot 
presentation. The dots, either yellow-green or red, are presented at random locations on the grid 
for only 450 milliseconds, and with no time gap between presentations. If a yellow-green dot is 
presented the subject should touch the screen, if a red dot is presented the subject is instructed 
not to touch it. If a yellow-green dot is touched a point is awarded, if a yellow-green dot is not 
touched a point is subtracted, and if a red dot is touched a point is subtracted. Subjects are 
instructed to touch as many yellow-green dots as possible in the time allotted.  Examples are 
presented prior to taking the assessment, but no practice trials are given. A total of 96 are 
resented (64 yellow-green, 32 red). The overall score is calculated as the total number of points 
scored. 
  
Depth perception 
Subjects wear a pair of red/blue glasses, creating simulated depth in 1 of 4 black rings 
presented on an off-white background on the tablet computer. This gives the illusion of one of the 
rings appearing to float above the screen. The 4 rings are presented simultaneously at 1) 12 
o’clock, 2) 3 o’clock, 3) 6 o’clock and 4) 9 o’clock, with one of the rings appear to float. Subjects 
are instructed to swipe across the screen in the direction of the ‘floating ring’ as quickly as 
possible. Examples are shown to the subjects and then 3 practice trials are allowed. Average 
response time for the testing is used to represent performance.  
Dynamic visual acuity (Target Capture): Subjects are instructed to fixate a central white 
dot on the tablet computer screen until the appearance of a yellow ‘Landolt’ ring (a circular ring 
with a missing section) appears briefly in 1 of the 4 corners of the screen. Subjects are required 
to indicate the location of the missing section of the Landolt ring by swiping across the tablet 
screen in the direction of the missing section. Examples of the test procedure are given followed 
by 3 practice trials. If subjects cannot judge the direction of the missing segment of the ring, 
guessing is encouraged. The Landolt ring is initially presented for 500 milliseconds, the 
presentation time reducing with successive correct responses. A staircase reversal algorithm is 

52 
 
used to discern the threshold exposure duration; and is recorded as the output measure for the 
dynamic visual acuity.      
 
 
Near-Far Quickness (accommodative-vergence facility) 
In alternating style, a 20/80-equivalent black Landolt ring is 
presented in a box on the handheld screen, and a black 
Landolt ring 0.1 log unit above the threshold determined with 
the Visual Clarity assessment is presented on the far screen. 
The subject is instructed to swipe the screen of the handheld 
screen in the perceived direction of the gap in the ring 
presented on each display; incorrect responses would not 
change the target presentation. The assessment begins with 
3 practice trials. The first Landolt ring was always presented 
on the far screen. After the correct response is recorded, the 
Landolt ring appears on the handheld screen.  The subject 
then continually switches focus between far and near for 30 seconds, trying to correctly identify 
as many rings as possible. The number of correct responses determines the score.  
 
Posture stability assessment 
 
Force Plate Center of Pressure Analysis 
To further assess postural stability and control, static balance in 
single leg and bipedal stance can be recorded for 30 seconds on 
a Kistler force platform (see figure below). The center of pressure 
(COP) data is recorded from the force platform in both eyes open 
and eyes closed conditions. The data produced is analyzed for the 
min-max excursions in the mediolateral and anteroposterior 
directions, the total path length, and velocity of the COP trace. In 
addition the sample entropy of the COP data is examined to 
determine the signal complexity, providing insight into factors 
related to postural control.    
 
 
 
NeuroCom Smart Balance Master System  

53 
 
Postural control and stability will be assessed through the 
use of the Sensory Organization Test and Motor Control 
Test on the (NeuroCom International, Inc., Clackamas, 
OR).  The NeuroCom (pictured) has been developed to 
provide an objective assessment of postural stability 
under static and dynamic test conditions. A variety of tests 
using the NeuroCom have been developed to objectively 
test sensory and motor impairments as well as functional 
limitations. The NeuroCom allows for the unique ability to 
safely assess each individual sensory system input cues 
(visual, vestibular, and somatosensory). The NeuroCom 
tests requires individuals to determine which sensory 
system cues are appropriate and inappropriate by 
manipulating the visual surround, support surface, and 
applying 
external 
perturbations. 
Traditional 
tests 
assessing postural stability using force plates are unable 
to determine which sensory system input cues are being 
used and/or suppressed. These traditional tests are only 
capable of identifying if impairment exists, but is unable to 
provide information regarding why there is impairment. While traditional measures of postural 
stability using force plates are frequently reported in the literature the underlying sensory systems 
being utilized to maintain postural stability cannot be identified, whereas, the NeuroCom has the 
ability to isolate the three sensory sources (somatosensory, vestibular, vision) . 
 
Sensory Organization Test (SOT)  
The SOT consists of 6 testing conditions 
designed to systematically test the visual, 
vestibular and somatosensory systems. 
The 6 test conditions consist of the 
following: 
  
Condition 1: Eyes open, support surface 
stable; 
Condition 2: Eyes closed, support surface 
stable;  
Condition 3: Visual surround moves, 
support surface stable;  
Condition 4: Eyes open, support surface 
moves; 
Condition 5: Eyes closed, support surface 
moves; 
Condition 6: Visual surround moves, 
support surface moves. 
 
Subject positioning on the NeuroCom as well as subject instructions will follow the manufacturer’s 
guidelines. During each test condition subjects will wear a harness (designed to prevent fall, but 
not impede or assist balance) and assume a two-legged stance with feet shoulder width apart on 
the support surface with their arms hanging down at their side. The verbal cues provided by the 
manufacturer for each test condition will be provided, for example: during this test (Condition 1) 
you are to keep your eyes open looking forward with arms hanging down by your side. After 
subjects verbally state that they understand the test condition and are ready to begin the test will 

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start.  A practice trial will be provided to ensure subjects are comfortable with the test procedures. 
Each test condition lasts 20 seconds. A 1 minute rest period will be provided between practice 
trials and test trials. A 30 second rest period will be provided between trials. A total of 3 test trials 
will be collected for each test condition and averaged for analyses.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Motor Control Test (MCT)  
The MCT assesses the ability to quickly 
recover 
from 
an 
unexpected 
external 
translation. The translations occur in the 
forward and backward directions. During each 
test condition subjects will wear a harness 
(designed to prevent fall, but not impede or 
assist balance) and assume a two-legged 
stance with feet shoulder width apart on the 
support surface with their arms hanging down 
at their side. For each direction (forward and 
backward) there are 3 translations: small (2.8 
degrees/second), 
medium 
(6.0 
degrees/second) 
and 
large 
(8.0 
degrees/second). The verbal cues provided by 
the manufacturer for each test condition will be 
provided, for example: during this test condition 
you are to keep your eyes open looking 
forward, arms hanging down by your side, and 
the support surface will translate either forward or backward. After subjects verbally state that 
they understand the test condition and are ready to begin the test will start.  A practice trial will be 
provided to ensure subjects are comfortable with the test procedures. A 1 minute rest period will 
be provided between practice trials and test trials. A 30 second rest period will be provided 
between test conditions (forward and backward). A total of 3 test trials will be collected for each 
speed (small, medium, large) in both directions (forward, backward) and averaged for analyses. 
 

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