Urea for Chronic Hyponatremia

Study Overview
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Brief Summary
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This study is examining how a dietary supplement called urea can be used to treat low blood sodium level. Low blood sodium level is a common problem and some studies show that many patients with low blood sodium level suffer from brain fog and/or loss of balance. Unfortunately, it is unknown at this point what the best treatment is for low blood sodium level. With this pilot research study, the investigators are hoping to learn more about whether urea is safe to take, whether patients can tolerate taking urea for several weeks, whether urea increases blood sodium level, and whether urea can help prevent the brain fog and/or loss of balance that some patients with low blood sodium level suffer from. The information obtained with this study is intended to be used to design a larger study in the future to get a definite answer whether urea is beneficial for patients with low blood sodium level.

Detailed Description
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Hyponatremia is the most common electrolyte disorder encountered clinically. While acute and/or severe hyponatremia is commonly associated with significant symptoms, milder and more chronic forms of hyponatremia remain clinically inconspicuous as the brain effectively adapts to the low extracellular osmolality. However, recent evidence suggests that even mild hyponatremia is associated with subtle neurocognitive deficits, gait disturbances, falls, fractures, and osteoporosis, as well as increased mortality. Current therapeutic interventions for hyponatremia, including fluid restriction and loop diuretics lack clinical trial data to support their efficacy and are commonly associated with poor adherence. The discovery of vasopressin antagonists (vaptans) provided a new drug class targeting the most common mechanism of hyponatremia, i.e., elevated vasopressin. Despite the demonstrated efficacy of vaptans in clinical trials, their use has been limited by high cost as well as safety concerns related to risk of liver injury and the potential for rapid correction of hyponatremia. Thus, despite the significant morbidity and mortality associated with chronic non-severe hyponatremia, there is a paucity of definitively effective, safe, well-tolerated, and reasonably priced treatments. Small European case series have suggested that oral urea is safe and effective for the treatment of hyponatremia. However, urea has not been available for the treatment of hyponatremia in the United States until very recently. This research group recently published the first and only study describing the effectiveness and safety of a new American formulation of oral urea among hospitalized patients with hyponatremia. However, the latter was a retrospective study limited to hospitalized patients. Data from large clinical trials on the efficacy of urea for the prevention of patient-centered outcomes in those with chronic hyponatremia are lacking. The current proposal is a pilot study that seeks to establish the feasibility of recruiting ambulatory patients with chronic hyponatremia into a study of urea, determine the acceptability of urea to patients, and explore the effect of this agent on plasma sodium level (PNa), neurocognitive function, and postural stability. The investigators will recruit 30 ambulatory patients with chronic non-severe hyponatremia and randomize them to oral urea or no drug treatment for a period of 42 days. Following this initial phase, all participants will have a 10-day washout period, followed by a 42-day period in which participants initially randomized to no drug therapy will receive urea and those initially treated with urea will receive no drug therapy. The investigators will collect data regarding the ease of recruitment, participant adherence to urea, and adverse events related to its use. The investigators will monitor participants' PNa, neurocognitive function, and postural stability over the course of the study. The feasibility, acceptability, and proof of concept/efficacy data from this pilot study will confirm the investigator's capacity to conduct, and will inform the design of a large clinical trial that will assess the efficacy of urea for the prevention of serious clinical outcomes of chronic non-severe hyponatremia.

Official Title
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Urea for Chronic Hyponatremia: A Pilot Study

Conditions
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Hyponatremia, Inappropriate ADH Syndrome

Intervention / Treatment
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* Drug: Urea


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Attended ≥1 visit at a University of Pittsburgh Medical Center (UPMC) outpatient clinic within the prior 12 months 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 12 months with most recent PNa ≤ 132 mmol/L prior to screening Patients are ambulatory without the need for any assist device (e.g., cane, walker) Mini-mental state examination (MMSE) score ≥ 25 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 (TSH) level (i.e., TSH between 0.3 to 5 μIU/mL) eGFR >= 45 ml/min/1.73 m2) Exclusion Criteria: Cirrhosis and/or end-stage liver disease Heart failure on diuretics and/or with recorded left ventricular ejection fraction <40 percent Chronic kidney disease with most recent estimated glomerular filtration rate <45 ml/min/1.73m2 Adrenal insufficiency 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 Active infection Neurological disorders with impairment of ambulation or cognition End-stage lung disease with marked impairment in ambulatory capacity Chronic pain with impairment of ambulation 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: On Urea, Then Off Urea<br>Participants assigned to this group will receive oral urea for 42 days (period 1), followed by a 10-day washout period, and then will be off urea for 42 days (period 2). | Drug: Urea<br>* Groups On Urea, Then Off Urea and Off Urea, Then On Urea will receive urea during period 1 and period 2 of the study, respectively. The investigators will use the new American formulation of oral urea (i.e., Ure-Na™), which is packaged as a powder and mixed with 4 ounces. of water for oral consumption. Urea will be started at a dose of 15 grams of urea per mouth once daily. Dose titration will be based on the absolute increase in PNa on days 7 and 14. The urea dosing scheme will involve increasing from the starting dose of 15 grams/day to 30 grams/day (in 2 divided doses) based on the change in and absolute value of PNa, and subsequently, from 30 grams/day to 60 grams/day (in 2 divided doses) when indicated. The maximal dose of urea administered will be 60 g/day.<br>* Other names: Ure-Na;|
| Experimental: Off Urea, Then On Urea<br>Participants assigned to this group will be off urea during for 42 days (period 1), followed by a 10-day washout period, and then on urea for 42 days (period 2) | Drug: Urea<br>* Groups On Urea, Then Off Urea and Off Urea, Then On Urea will receive urea during period 1 and period 2 of the study, respectively. The investigators will use the new American formulation of oral urea (i.e., Ure-Na™), which is packaged as a powder and mixed with 4 ounces. of water for oral consumption. Urea will be started at a dose of 15 grams of urea per mouth once daily. Dose titration will be based on the absolute increase in PNa on days 7 and 14. The urea dosing scheme will involve increasing from the starting dose of 15 grams/day to 30 grams/day (in 2 divided doses) based on the change in and absolute value of PNa, and subsequently, from 30 grams/day to 60 grams/day (in 2 divided doses) when indicated. The maximal dose of urea administered will be 60 g/day.<br>* Other names: Ure-Na;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Proportion of Participants who Met Inclusion/Exclusion Criteria and were Enrolled in the Study | Number and proportion of participants who met inclusion/exclusion criteria and were enrolled in the study. To be assessed by analysis of enrollment data. | 13.5 months | 
| Number and Proportion of Participants Enrolled who Completed the Study | Number and proportion of participants enrolled who completed the study. To be assessed by analysis of enrollment and completion data. | 13.5 months | 
| Monthly Enrollment Rate | Number of participants enrolled in the study every month. To be assessed by analysis of enrollment data | 13.5 months | 
| Number of Prescribed Urea Doses Taken by Participants | Number of prescribed urea doses taken by participants. To be assessed by records in study diary and number of returned medication doses. | Baseline to day 42 while taking urea | 
| Reasons for Non-Adherence to Urea Therapy | Reasons for non-adherence to urea therapy. To be assessed by medication acceptability and medication side effect questionnaires | Baseline to day 42 while taking urea | 
| Change in Plasma Sodium Concentration | Change in plasma sodium concentration from baseline to day 42. Based on plasma sodium assessments on days 0 and 42. | Baseline to day 42 | 
| Change in Percentage Accuracy Action Boundary Selection | Change in percentage accuracy action boundary selection from baseline to day 42. This will be measured by the Perception-Action Coupling Task (PACT) which is 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. | Baseline to day 42 | 
| Change in Overall Score of Sensorimotor Ability Battery | Change in overall score of sensorimotor ability battery from baseline to day 42. This will be measured by the Senaptec Sensory Station™ test battery which examines separate sensorimotor elements including; multiple object tracking, reaction time, perception span, go/no go, depth perception and dynamic visual acuity. The overall score ranges from 0 to 100 where a higher score indicates a better outcome. | Baseline to day 42 | 
| Change in the Sample Entropy of the Center of Pressure Data from the Force Plate | Change in the sample entropy of the center of pressure data from the force plate. The complexity and control of the static representation of postural stability in quiet upright stance will be determined employing non-linear analysis (sample entropy). | Baseline to day 42 | 
| Change in Percentage Angular Deviation of Vestibular Control System using Dynamic Representation of Upright Stance | Change in percentage angular deviation of vestibular control system using dynamic representation of upright stance from baseline to day 42. This will be assessed using the NeuroCom™ Sensory Organization. This test enables both the examination of postural control and stability in response to a direct perturbation of the vestibular control system underlying the maintenance of upright posture, giving insight into the relative contributions and/or any deficits in the vestibular system involved in maintaining upright stance in dynamic situations. | Baseline to day 42 | 
| Change in Percentage Angular Deviation of Somatosensory Control System using Dynamic Representation of Upright Stance | Change in percentage angular deviation of somatosensory control system using dynamic representation of upright stance from baseline to day 42. This will be assessed using the NeuroCom™ Sensory Organization. This test enables both the examination of postural control and stability in response to a direct perturbation of the somatosensory control system underlying the maintenance of upright posture, giving insight into the relative contributions and/or any deficits in the somatosensory system involved in maintaining upright stance in dynamic situations. | Baseline to day 42 | 
| Change in Percentage Angular Deviation of Visual Control System using Dynamic Representation of Upright Stance | Change in percentage angular deviation of visual control system using dynamic representation of upright stance from baseline to day 42. This will be assessed using the NeuroCom™ Sensory Organization. This test enables both the examination of postural control and stability in response to a direct perturbation of the visual control system underlying the maintenance of upright posture, giving insight into the relative contributions and/or any deficits in the visual system involved in maintaining upright stance in dynamic situations. | Baseline to 42 days | 
| Change in Percentage Weight Symmetry using Dynamic Representation of Upright Stance | Change in percentage weight symmetry using dynamic representation of upright stance from baseline to day 42. This will be assessed using the Motor Control Test (MCT). MCT assesses the ability to quickly recover from an unexpected external translation. | Baseline to day 42 | 
| Change in Movement Latency of Posture Control and Stability using Dynamic Representation of Upright Stance | Change in movement latency of posture control and stability using dynamic representation of upright stance from baseline to day 42. This will be assessed using the Motor Control Test (MCT). MCT assesses the ability to quickly recover from an unexpected external translation. | Baseline to day 42 | 
| Change in Amplitude Scaling of Posture Control and Stability using Dynamic Representation of Upright Stance | Change in amplitude scaling of posture control and stability using dynamic representation of upright stance from baseline to day 42. This will be assessed using the Motor Control Test (MCT). MCT assesses the ability to quickly recover from an unexpected external translation. | Baseline to day 42 | 
| Number and Proportion of Participants Enrolled in the Study with Adverse Events Related to the Use of Urea | Number and proportion of participants enrolled in the study with adverse events related to the use of urea from baseline to day 42. To be assessed by medication side effect questionnaire. | Baseline to day 42 while taking urea | 
| Adverse Events Related to Urea | To be assessed by medication side effect questionnaire. A tabulation of counts of participants experiencing specific known side effects of urea as well as their intensity (mild, moderate or severe) will be performed. | Baseline to day 42 while taking urea | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Screened | Number of patients screened. To be assessed by analysis of screening data. | 13.5 months | 
| Number and Proportion of Patients Screened who Met Inclusion/Exclusion Criteria for the Study | Number and proportion of patients screened who met inclusion/exclusion criteria for the study. To be assessed by analysis of screening and enrollment data. | 13.5 months | 
| Number and Proportion of Participants who Took More than 80 Percent of Prescribed Urea Doses | Number and proportion of participants who took more than 80 percent of prescribed urea doses. To be assessed by analysis of study diary and number of returned medication doses. | Baseline to day 42 while taking urea | 
| Number and Proportion of Participants who Thought the Medication was Acceptable | Number and proportion of participants who thought the medication was acceptable. Based on ratings for acceptability in the medication acceptability questionnaire. | Baseline to day 42 while taking urea | 
| Average Ratings for Medication Acceptability | Average ratings using a 5-point Likert scale 19-item medication acceptability questionnaire. in which responders specify their level of agreement to a statement in five points: (1) Strongly disagree; (2) Disagree; (3) Neutral; (4) Agree; (5) Strongly agree; or (1) Very Unhappy; (2) Unhappy; (3) Neutral; (4) Happy; (5) Very Happy. | Baseline to day 42 while taking urea | 
| Change in SF-12 (Health Survey) Mental Component Summary (MCS) | Change in SF-12 (Health Survey) Mental Component Summary (MCS) from baseline to day 42. Based on SF-12 MCS assessments on days 0 and 42. This is computed using the scores of 12 questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Baseline to day 42 | 
| Change in SF-12 (Health Survey) Physical Component Summary (PCS) | Change in SF-12 (Health Survey) Physical Component Summary (PCS) from baseline to day 42. Based on SF-12 PCS assessments on days 0 and 42. This is computed using the scores of 12 questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Baseline to day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyponatremia, SIADH, SIAD, Urea