HyponatremiaPhase 2NCT04588207
Urea for Chronic Hyponatremia
A Phase 2 study testing Urea in people with Hyponatremia and Inappropriate ADH Syndrome, run by Helbert Rondon Berrios, MD, MS at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hyponatremia, Inappropriate ADH Syndrome
- What is being tested?
- Urea
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteUnited States
- Study dates
- 28 Dec 2021to 29 Sep 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
Show all 14Show fewer
- 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)
Who cannot join
- 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
Show all 17Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15261
About this study
Official title: Urea for Chronic Hyponatremia: A Pilot Study
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.
Read the detailed description
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.
- Conditions
- Hyponatremia, Inappropriate ADH Syndrome
- Being tested
- Urea
- Keywords
- Hyponatremia, SIADH, SIAD, Urea
- Medical subject headings
- Hyponatremia, Inappropriate ADH Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
UreaDrug
Also called Ure-Na
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.
| Study group | Role | What they receive |
|---|---|---|
| On Urea, Then Off Urea | Experimental | 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). Receives: Drug: Urea |
| Off Urea, Then On Urea | Experimental | 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) Receives: Drug: Urea |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number and Percentage of Participants Who Met Inclusion/Exclusion Criteria and Were Enrolled in the Study
Number and percentage of participants who met inclusion/exclusion criteria and were enrolled in the study. To be assessed by analysis of enrollment data.
Measured: 9 months
Number and Percentage of Participants Enrolled Who Completed the Study
Number and percentage of participants enrolled who completed the study. To be assessed by analysis of enrollment and completion data.
Measured: 9 months
Monthly Enrollment Rate
Number of participants enrolled in the study every month. To be assessed by analysis of enrollment data
Measured: 9 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.
Measured: 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
Measured: 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.
Measured: 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. Accuracy of affordance perception is measured. Scores goes from 0% to 100% with higher score representing increased accuracy
Measured: 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. Score goes from 0 to1500 with higher scores representing better sensorimotor ability
Measured: Baseline to day 42
Change in the Sample Entropy of the Center of Pressure Data From the Force Plate
Measure the 'structure' of the noise in the oscillations of the center of mass of the individual. The measurement represent the percentage of displacement from the center of pressure. No reference ranges are available as these vary according to the population studied
Measured: 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 was 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. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in vestibular balance control.
Measured: 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. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in somatosensory balance control.
Measured: 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. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in visual balance control.
Measured: 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. Weight symmetry indicates weight distribution under the left and right legs prior to perturbation onset. A score of 100 indicates perfect between-limb symmetry. Larger deviations away (higher or Lower) from 100 indicate asymmetry. Scores goes from -100 to +100 closer to 100 is optimal.
Measured: 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. Latency scores measure the time lapse between force plate translation on postural response for healthy, elderly populations, with previously reported mean latency values ranging from 126.80-131.40. Higher/Larger scores indicate poorer balance control.
Measured: 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. It is scored in units of angular momentum and normalized to body height and weight. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in ability to recover from an unexpected external translation reflecting better balance.
Measured: 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.
Measured: 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.
Measured: Baseline to day 42 while taking urea
Secondary outcomes (7)
Number of Patients Screened
Number of patients screened. To be assessed by analysis of screening data.
Measured: 9 months
Number and Percentage of Patients Screened Who Met Inclusion/Exclusion Criteria for the Study
Number and percentage of patients screened who met inclusion/exclusion criteria for the study.
To be assessed by analysis of screening and enrollment data.
Measured: 9 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.
Measured: 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.
Measured: Baseline to day 42 while taking urea
Average Ratings for Medication Acceptability
Average ratings using a 5-point Likert scale 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. A higher overall score represents more acceptability
Measured: 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.
Measured: 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.
Measured: Baseline to day 42
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2020
- Study start28 Dec 2021
- Primary completion29 Sep 2022
- Study completion29 Sep 2022
Why it stopped: Unable to recruit participants
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (41)Papers the sponsor has linked to this study.
- Other trials for HyponatremiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Helbert Rondon Berrios, MD, MS
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Helbert Rondon Berrios, MD, MS, University of Pittsburgh
- Investigators
- Helbert Rondon Berrios, MD. MS, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04588207
- Sponsor's protocol ID
- STUDY20050035
- Other IDs
- R21DK122023
- Status last verified
- Apr 2024
- First submitted
- 7 Oct 2020
- Last updated
- 20 May 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The investigators will share all collected IPD
Publications
Rondon-Berrios H, Berl T. Mild Chronic Hyponatremia in the Ambulatory Setting: Significance and Management. Clin J Am Soc Nephrol. 2015 Dec 7;10(12):2268-78. doi: 10.2215/CJN.00170115. Epub 2015 Jun 24.
PubMed 26109207Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112. doi: 10.1056/NEJMoa065181. Epub 2006 Nov 14.
PubMed 17105757Decaux G, Genette F. Urea for long-term treatment of syndrome of inappropriate secretion of antidiuretic hormone. Br Med J (Clin Res Ed). 1981 Oct 24;283(6299):1081-3. doi: 10.1136/bmj.283.6299.1081.
PubMed 6794768Rondon-Berrios H, Tandukar S, Mor MK, Ray EC, Bender FH, Kleyman TR, Weisbord SD. Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol. 2018 Nov 7;13(11):1627-1632. doi: 10.2215/CJN.04020318. Epub 2018 Sep 4.
PubMed 30181129Gankam-Kengne F, Ayers C, Khera A, de Lemos J, Maalouf NM. Mild hyponatremia is associated with an increased risk of death in an ambulatory setting. Kidney Int. 2013 Apr;83(4):700-6. doi: 10.1038/ki.2012.459. Epub 2013 Jan 16.
PubMed 23325088Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Eff Resour Alloc. 2006 May 31;4:10. doi: 10.1186/1478-7547-4-10.
PubMed 16737547Decaux G. Is asymptomatic hyponatremia really asymptomatic? Am J Med. 2006 Jul;119(7 Suppl 1):S79-82. doi: 10.1016/j.amjmed.2006.05.013.
PubMed 16843090Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006 Jan;119(1):71.e1-8. doi: 10.1016/j.amjmed.2005.09.026.
PubMed 16431193Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, Resnick HE. Hyponatremia-induced osteoporosis. J Bone Miner Res. 2010 Mar;25(3):554-63. doi: 10.1359/jbmr.090827.
PubMed 19751154Kruse C, Eiken P, Vestergaard P. Hyponatremia and osteoporosis: insights from the Danish National Patient Registry. Osteoporos Int. 2015 Mar;26(3):1005-16. doi: 10.1007/s00198-014-2973-1. Epub 2014 Dec 3.
PubMed 25466529Jamal SA, Arampatzis S, Harrison SL, Bucur RC, Ensrud K, Orwoll ES, Bauer DC. Hyponatremia and Fractures: Findings From the MrOS Study. J Bone Miner Res. 2015 Jun;30(6):970-5. doi: 10.1002/jbmr.2383.
PubMed 25294595Hoorn EJ, Rivadeneira F, van Meurs JB, Ziere G, Stricker BH, Hofman A, Pols HA, Zietse R, Uitterlinden AG, Zillikens MC. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. J Bone Miner Res. 2011 Aug;26(8):1822-8. doi: 10.1002/jbmr.380.
PubMed 21381111Mohan S, Gu S, Parikh A, Radhakrishnan J. Prevalence of hyponatremia and association with mortality: results from NHANES. Am J Med. 2013 Dec;126(12):1127-37.e1. doi: 10.1016/j.amjmed.2013.07.021.
PubMed 24262726Greenberg A, Verbalis JG, Amin AN, Burst VR, Chiodo JA 3rd, Chiong JR, Dasta JF, Friend KE, Hauptman PJ, Peri A, Sigal SH. Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney Int. 2015 Jul;88(1):167-77. doi: 10.1038/ki.2015.4. Epub 2015 Feb 11.
PubMed 25671764Decaux G, Gankam Kengne F, Couturier B, Musch W, Soupart A, Vandergheynst F. Mild water restriction with or without urea for the longterm treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH): Can urine osmolality help the choice? Eur J Intern Med. 2018 Feb;48:89-93. doi: 10.1016/j.ejim.2017.09.024. Epub 2017 Oct 7.
PubMed 29017746
Study at a glance
From the registry record, last updated by the sponsor on 20 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Urea for Chronic Hyponatremia: A Pilot Study
- ClinicalTrials.gov ID
- NCT04588207
- Acronym / sponsor ID
- STUDY20050035
- Conditions
- Hyponatremia, Inappropriate ADH Syndrome
- Keywords
- Hyponatremia, SIADH, SIAD, Urea
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Unable to recruit participants
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Helbert Rondon Berrios, MD, MSUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- 28 Dec 2021 (actual)
- Primary completion
- 29 Sep 2022 (actual)
- Study completion
- 29 Sep 2022 (actual)
- First posted
- 19 Oct 2020 (actual)
- Results
- Posted 20 May 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| On Urea, Then Off Urea | Experimental | Drug: UreaParticipants 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). |
| Off Urea, Then On Urea | Experimental | Drug: UreaParticipants 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) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| UreaAlso: Ure-NaGroups "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. | Drug | Off Urea, Then On Urea, On Urea, Then Off Urea |
Primary outcome
Number and Percentage of Participants Who Met Inclusion/Exclusion Criteria and Were Enrolled in the Study
Time frame: 9 months
Number and percentage of participants who met inclusion/exclusion criteria and were enrolled in the study. To be assessed by analysis of enrollment data.
Number and Percentage of Participants Enrolled Who Completed the Study
Time frame: 9 months
Number and percentage of participants enrolled who completed the study. To be assessed by analysis of enrollment and completion data.
Monthly Enrollment Rate
Time frame: 9 months
Number of participants enrolled in the study every month. To be assessed by analysis of enrollment data
Number of Prescribed Urea Doses Taken by Participants
Time frame: Baseline to day 42 while taking urea
Number of prescribed urea doses taken by participants. To be assessed by records in study diary and number of returned medication doses.
Reasons for Non-Adherence to Urea Therapy
Time frame: Baseline to day 42 while taking urea
Reasons for non-adherence to urea therapy. To be assessed by medication acceptability and medication side effect questionnaires
Change in Plasma Sodium Concentration
Time frame: Baseline to day 42
Change in plasma sodium concentration from baseline to day 42. Based on plasma sodium assessments on days 0 and 42.
Change in Percentage Accuracy Action Boundary Selection
Time frame: Baseline to day 42
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. Accuracy of affordance perception is measured. Scores goes from 0% to 100% with higher score representing increased accuracy
Change in Overall Score of Sensorimotor Ability Battery
Time frame: Baseline to day 42
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. Score goes from 0 to1500 with higher scores representing better sensorimotor ability
Change in the Sample Entropy of the Center of Pressure Data From the Force Plate
Time frame: Baseline to day 42
Measure the 'structure' of the noise in the oscillations of the center of mass of the individual. The measurement represent the percentage of displacement from the center of pressure. No reference ranges are available as these vary according to the population studied
Change in Percentage Angular Deviation of Vestibular Control System Using Dynamic Representation of Upright Stance
Time frame: Baseline to day 42
Change in percentage angular deviation of vestibular control system using dynamic representation of upright stance from baseline to day 42. This was 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. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in vestibular balance control.
Change in Percentage Angular Deviation of Somatosensory Control System Using Dynamic Representation of Upright Stance
Time frame: Baseline to day 42
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. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in somatosensory balance control.
Change in Percentage Angular Deviation of Visual Control System Using Dynamic Representation of Upright Stance
Time frame: Baseline to 42 days
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. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in visual balance control.
Change in Percentage Weight Symmetry Using Dynamic Representation of Upright Stance
Time frame: Baseline to day 42
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. Weight symmetry indicates weight distribution under the left and right legs prior to perturbation onset. A score of 100 indicates perfect between-limb symmetry. Larger deviations away (higher or Lower) from 100 indicate asymmetry. Scores goes from -100 to +100 closer to 100 is optimal.
Change in Movement Latency of Posture Control and Stability Using Dynamic Representation of Upright Stance
Time frame: Baseline to day 42
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. Latency scores measure the time lapse between force plate translation on postural response for healthy, elderly populations, with previously reported mean latency values ranging from 126.80-131.40. Higher/Larger scores indicate poorer balance control.
Change in Amplitude Scaling of Posture Control and Stability Using Dynamic Representation of Upright Stance
Time frame: Baseline to day 42
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. It is scored in units of angular momentum and normalized to body height and weight. No reference range for changes in percentage exist which vary with the population studied. Larger positive changes indicate significant improvement in ability to recover from an unexpected external translation reflecting better balance.
Number and Proportion of Participants Enrolled in the Study With Adverse Events Related to the Use of Urea
Time frame: Baseline to day 42 while taking 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.
Adverse Events Related to Urea
Time frame: Baseline to day 42 while taking 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.
7 secondary outcomes
Number of Patients Screened
Time frame: 9 months
Number and Percentage of Patients Screened Who Met Inclusion/Exclusion Criteria for the Study
Time frame: 9 months
Number and Proportion of Participants Who Took More Than 80 Percent of Prescribed Urea Doses
Time frame: Baseline to day 42 while taking urea
Number and Proportion of Participants Who Thought the Medication Was Acceptable
Time frame: Baseline to day 42 while taking urea
Average Ratings for Medication Acceptability
Time frame: Baseline to day 42 while taking urea
Change in SF-12 (Health Survey) Mental Component Summary (MCS)
Time frame: Baseline to day 42
Change in SF-12 (Health Survey) Physical Component Summary (PCS)
Time frame: Baseline to day 42
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 May 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26109207Rondon-Berrios H, Berl T. Mild Chronic Hyponatremia in the Ambulatory Setting: Significance and Management. Clin J Am Soc Nephrol. 2015 Dec 7;10(12):2268-78. doi: 10.2215/CJN.00170115. Epub 2015 Jun 24.
- Background: PubMed 17105757Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112. doi: 10.1056/NEJMoa065181. Epub 2006 Nov 14.
- Background: PubMed 6794768Decaux G, Genette F. Urea for long-term treatment of syndrome of inappropriate secretion of antidiuretic hormone. Br Med J (Clin Res Ed). 1981 Oct 24;283(6299):1081-3. doi: 10.1136/bmj.283.6299.1081.
- Background: PubMed 30181129Rondon-Berrios H, Tandukar S, Mor MK, Ray EC, Bender FH, Kleyman TR, Weisbord SD. Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol. 2018 Nov 7;13(11):1627-1632. doi: 10.2215/CJN.04020318. Epub 2018 Sep 4.
- Background: PubMed 23325088Gankam-Kengne F, Ayers C, Khera A, de Lemos J, Maalouf NM. Mild hyponatremia is associated with an increased risk of death in an ambulatory setting. Kidney Int. 2013 Apr;83(4):700-6. doi: 10.1038/ki.2012.459. Epub 2013 Jan 16.
- Background: PubMed 16737547Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Eff Resour Alloc. 2006 May 31;4:10. doi: 10.1186/1478-7547-4-10.
- Background: PubMed 16843090Decaux G. Is asymptomatic hyponatremia really asymptomatic? Am J Med. 2006 Jul;119(7 Suppl 1):S79-82. doi: 10.1016/j.amjmed.2006.05.013.
- Background: PubMed 16431193Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006 Jan;119(1):71.e1-8. doi: 10.1016/j.amjmed.2005.09.026.
- Background: PubMed 19751154Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, Resnick HE. Hyponatremia-induced osteoporosis. J Bone Miner Res. 2010 Mar;25(3):554-63. doi: 10.1359/jbmr.090827.
- Background: PubMed 25466529Kruse C, Eiken P, Vestergaard P. Hyponatremia and osteoporosis: insights from the Danish National Patient Registry. Osteoporos Int. 2015 Mar;26(3):1005-16. doi: 10.1007/s00198-014-2973-1. Epub 2014 Dec 3.
- Background: PubMed 25294595Jamal SA, Arampatzis S, Harrison SL, Bucur RC, Ensrud K, Orwoll ES, Bauer DC. Hyponatremia and Fractures: Findings From the MrOS Study. J Bone Miner Res. 2015 Jun;30(6):970-5. doi: 10.1002/jbmr.2383.
- Background: PubMed 21381111Hoorn EJ, Rivadeneira F, van Meurs JB, Ziere G, Stricker BH, Hofman A, Pols HA, Zietse R, Uitterlinden AG, Zillikens MC. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. J Bone Miner Res. 2011 Aug;26(8):1822-8. doi: 10.1002/jbmr.380.
- Individual participant dataSharing planned: Yes. The investigators will share all collected IPD
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Helbert Rondon Berrios, MD. MS principal investigator
University of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Urea in people with Hyponatremia and Inappropriate ADH Syndrome, run by Helbert Rondon Berrios, MD, MS at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number and Percentage of Participants Who Met Inclusion/Exclusion Criteria and Were Enrolled in the Study (time frame: 9 months). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04588207, which also lists 41 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 May 2024.