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| ID | Type | Description | Link |
|---|---|---|---|
| R21DK122023 | U.S. NIH Grant/Contract | View source |
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Unable to recruit participants
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
|
| 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Urea | Drug | 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-Naâ„¢), 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 9 months |
| Monthly Enrollment Rate | Number of participants enrolled in the study every month. To be assessed by analysis of enrollment data | 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. | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients Screened | Number of patients screened. To be assessed by analysis of screening data. | 9 months |
| Number and Percentage of Patients Screened Who Met Inclusion/Exclusion Criteria for the Study |
Not provided
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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Helbert Rondon Berrios, MD. MS | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | 15261 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26109207 | Background | 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. | |
| 17105757 | Background | Schrier 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. |
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The investigators will share all collected IPD
12 months after publication of primary manuscript
Request in writing addressed to the principal investigator
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| ID | Title | Description |
|---|---|---|
| FG000 | On Urea, Then Off Urea | 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). Urea: 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-Naâ„¢), 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. |
| FG001 | Off Urea, Then On Urea | 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) Urea: 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-Naâ„¢), 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
| |||||||||||||
| Washout Period |
| |||||||||||||
| Period 2 |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | On Urea, Then Off Urea | 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). Urea: 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-Naâ„¢), 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Count of Participants | Participants | 9 months |
|
94 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Urea | Participants assigned to this group will receive oral urea for 42 days | 0 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
Study was terminated because of inability to recruit. Only two participants were recruited of the estimated 30 participants.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Helbert Rondon Berrios, Professor of Medicine | University of Pittsburgh School of Medicine | 4126473120 | rondonberriosh@upmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 25, 2022 | Feb 9, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 21, 2022 | Feb 9, 2024 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D007010 | Hyponatremia |
| D007177 | Inappropriate ADH Syndrome |
| ID | Term |
|---|---|
| D014883 | Water-Electrolyte Imbalance |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D010900 | Pituitary Diseases |
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| ID | Term |
|---|---|
| D014508 | Urea |
| ID | Term |
|---|---|
| D000577 | Amides |
| D009930 | Organic Chemicals |
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|
|
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 |
| 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 Stationâ„¢ 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 | 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 | 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 NeuroComâ„¢ 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. | 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 NeuroComâ„¢ 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. | 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 NeuroComâ„¢ 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. | 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. | 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. | 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. | 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 |
Number and percentage of patients screened who met inclusion/exclusion criteria for the study.
To be assessed by analysis of screening and enrollment data.
| 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. | 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 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 | 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 |
| 6794768 | Background | Decaux 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. |
| 30181129 | Background | Rondon-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. |
| 23325088 | Background | Gankam-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. |
| 16737547 | Background | Boscoe 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. |
| 16843090 | Background | Decaux 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. |
| 16431193 | Background | Renneboog 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. |
| 19751154 | Background | Verbalis 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. |
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| 21381111 | Background | Hoorn 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. |
| 24262726 | Background | Mohan 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. |
| 25671764 | Background | Greenberg 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. |
| 29017746 | Background | Decaux 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. |
| 6621759 | Background | Decaux G. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by long loop diuretics. Nephron. 1983;35(2):82-8. doi: 10.1159/000183052. No abstract available. |
| 6805839 | Background | Decaux G, Waterlot Y, Genette F, Hallemans R, Demanet JC. Inappropriate secretion of antidiuretic hormone treated with frusemide. Br Med J (Clin Res Ed). 1982 Jul 10;285(6335):89-90. doi: 10.1136/bmj.285.6335.89. |
| 7442772 | Background | Decaux G, Waterlot Y, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. N Engl J Med. 1981 Feb 5;304(6):329-30. doi: 10.1056/NEJM198102053040605. No abstract available. |
| 28214374 | Background | Bhandari S, Peri A, Cranston I, McCool R, Shaw A, Glanville J, Petrakova L, O'Reilly K. A systematic review of known interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia and a meta-analysis of the vaptans. Clin Endocrinol (Oxf). 2017 Jun;86(6):761-771. doi: 10.1111/cen.13315. Epub 2017 Mar 27. |
| 21962320 | Background | Jaber BL, Almarzouqi L, Borgi L, Seabra VF, Balk EM, Madias NE. Short-term efficacy and safety of vasopressin receptor antagonists for treatment of hyponatremia. Am J Med. 2011 Oct;124(10):977.e1-9. doi: 10.1016/j.amjmed.2011.04.028. |
| 27766511 | Background | Li B, Fang D, Qian C, Feng H, Wang Y. The Efficacy and Safety of Tolvaptan in Patients with Hyponatremia: A Meta-Analysis of Randomized Controlled Trials. Clin Drug Investig. 2017 Apr;37(4):327-342. doi: 10.1007/s40261-016-0470-3. |
| 20538391 | Background | Rozen-Zvi B, Yahav D, Gheorghiade M, Korzets A, Leibovici L, Gafter U. Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis. 2010 Aug;56(2):325-37. doi: 10.1053/j.ajkd.2010.01.013. Epub 2010 Jun 9. |
| 27082573 | Background | Zhang X, Zhao M, Du W, Zu D, Sun Y, Xiang R, Yang J. Efficacy and Safety of Vasopressin Receptor Antagonists for Euvolemic or Hypervolemic Hyponatremia: A Meta-Analysis. Medicine (Baltimore). 2016 Apr;95(15):e3310. doi: 10.1097/MD.0000000000003310. |
| 23121377 | Background | Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. doi: 10.1056/NEJMoa1205511. Epub 2012 Nov 3. |
| 24569496 | Background | Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant. 2014 Apr;29 Suppl 2:i1-i39. doi: 10.1093/ndt/gfu040. Epub 2014 Feb 25. |
| 20946646 | Background | Decaux G, Andres C, Gankam Kengne F, Soupart A. Treatment of euvolemic hyponatremia in the intensive care unit by urea. Crit Care. 2010;14(5):R184. doi: 10.1186/cc9292. Epub 2010 Oct 14. |
| 30614552 | Background | Lockett J, Berkman KE, Dimeski G, Russell AW, Inder WJ. Urea treatment in fluid restriction-refractory hyponatraemia. Clin Endocrinol (Oxf). 2019 Apr;90(4):630-636. doi: 10.1111/cen.13930. Epub 2019 Jan 25. |
| 30868608 | Background | Nervo A, D'Angelo V, Rosso D, Castellana E, Cattel F, Arvat E, Grossi E. Urea in cancer patients with chronic SIAD-induced hyponatremia: Old drug, new evidence. Clin Endocrinol (Oxf). 2019 Jun;90(6):842-848. doi: 10.1111/cen.13966. Epub 2019 Mar 29. |
| 22403276 | Background | Soupart A, Coffernils M, Couturier B, Gankam-Kengne F, Decaux G. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol. 2012 May;7(5):742-7. doi: 10.2215/CJN.06990711. Epub 2012 Mar 8. |
| 25905459 | Background | Corona G, Giuliani C, Verbalis JG, Forti G, Maggi M, Peri A. Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS One. 2015 Apr 23;10(4):e0124105. doi: 10.1371/journal.pone.0124105. eCollection 2015. |
| 26835607 | Background | Vandergheynst F, Gombeir Y, Bellante F, Perrotta G, Remiche G, Melot C, Mavroudakis N, Decaux G. Impact of hyponatremia on nerve conduction and muscle strength. Eur J Clin Invest. 2016 Apr;46(4):328-33. doi: 10.1111/eci.12597. Epub 2016 Feb 23. |
| 30153330 | Background | Refardt J, Kling B, Krausert K, Fassnacht M, von Felten S, Christ-Crain M, Fenske W. Impact of chronic hyponatremia on neurocognitive and neuromuscular function. Eur J Clin Invest. 2018 Nov;48(11):e13022. doi: 10.1111/eci.13022. Epub 2018 Sep 19. |
| 26584969 | Background | Verbalis JG, Greenberg A, Burst V, Haymann JP, Johannsson G, Peri A, Poch E, Chiodo JA 3rd, Dave J. Diagnosing and Treating the Syndrome of Inappropriate Antidiuretic Hormone Secretion. Am J Med. 2016 May;129(5):537.e9-537.e23. doi: 10.1016/j.amjmed.2015.11.005. Epub 2015 Nov 14. |
| 30670116 | Background | Connaboy C, Johnson CD, LaGoy AD, Pepping GJ, Simpson RJ, Deng Z, Ma L, Bower JL, Eagle SR, Flanagan SD, Alfano CA. Intersession Reliability and Within-Session Stability of a Novel Perception-Action Coupling Task. Aerosp Med Hum Perform. 2019 Feb 1;90(2):77-83. doi: 10.3357/AMHP.5190.2019. |
| 21705283 | Background | Erickson GB, Citek K, Cove M, Wilczek J, Linster C, Bjarnason B, Langemo N. Reliability of a computer-based system for measuring visual performance skills. Optometry. 2011 Sep;82(9):528-42. doi: 10.1016/j.optm.2011.01.012. Epub 2011 Jun 25. |
| 25747573 | Background | Wang L, Krasich K, Bel-Bahar T, Hughes L, Mitroff SR, Appelbaum LG. Mapping the structure of perceptual and visual-motor abilities in healthy young adults. Acta Psychol (Amst). 2015 May;157:74-84. doi: 10.1016/j.actpsy.2015.02.005. Epub 2015 Mar 5. |
| 20670457 | Background | Borg FG, Laxaback G. Entropy of balance--some recent results. J Neuroeng Rehabil. 2010 Jul 30;7:38. doi: 10.1186/1743-0003-7-38. |
| 19679739 | Background | Kang HG, Costa MD, Priplata AA, Starobinets OV, Goldberger AL, Peng CK, Kiely DK, Cupples LA, Lipsitz LA. Frailty and the degradation of complex balance dynamics during a dual-task protocol. J Gerontol A Biol Sci Med Sci. 2009 Dec;64(12):1304-11. doi: 10.1093/gerona/glp113. Epub 2009 Aug 13. |
| 18236239 | Background | Vereeck L, Wuyts F, Truijen S, Van de Heyning P. Clinical assessment of balance: normative data, and gender and age effects. Int J Audiol. 2008 Feb;47(2):67-75. doi: 10.1080/14992020701689688. |
| 11524452 | Background | Wallmann HW. Comparison of elderly nonfallers and fallers on performance measures of functional reach, sensory organization, and limits of stability. J Gerontol A Biol Sci Med Sci. 2001 Sep;56(9):M580-3. doi: 10.1093/gerona/56.9.m580. |
| 25635717 | Background | Sterns RH, Silver SM, Hix JK. Urea for hyponatremia? Kidney Int. 2015 Feb;87(2):268-70. doi: 10.1038/ki.2014.320. |
| NOT COMPLETED |
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| NOT COMPLETED |
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| BG001 | Off Urea, Then On Urea | 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) Urea: 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-Naâ„¢), 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Plasma sodium concentration | Mean | Standard Deviation | mmol/L |
|
| Accuracy action boundary selection | Accuracy of affordance perception. Scores goes from 0% to 100% with higher score representing increased accuracy | Mean | Standard Deviation | percentage of accuracy |
|
| Score of sensorimotor ability battery | The Senaptecâ„¢ Sensory test battery was included to, in part, act as an azimuth check (i.e NFQ, CS, Visual Acuity, Depth Perception), for any changes in vision status cross the testing period, as this can influence balance control and potential fall risk. Additionally, some of the assessments provide insight into underlying sensorimotor process common to our active engagement with our surrounding environment (Reaction Time, MOT, Perception Span). Score goes from 0 to1500 with higher scores representing better sensorimotor ability | Mean | Standard Deviation | units on a scale |
|
| 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 | Mean | Standard Deviation | percentage |
|
| Percentage angular deviation of vestibular control system using dynamic representation of upright st | The SOT consists of 6 conditions, each comprised of 3 trials lasting 20 sec each. Scores range between -100% to +200%. Lower percentage indicate poorer balance control | Mean | Standard Deviation | percentage |
|
| Percentage angular deviation of somatosensory control system using dynamic representation of upright | The SOT consists of 6 conditions, each comprised of 3 trials lasting 20 sec each. Scores range between -100% to +200%. Lower percentage indicate poorer balance control | Mean | Standard Deviation | percentage |
|
| Percentage angular deviation of visual control system using dynamic representation of upright stance | The SOT consists of 6 conditions, each comprised of 3 trials lasting 20 sec each. Scores range between -100% to +200%. Lower percentage indicate poorer balance control | Mean | Standard Deviation | percentage |
|
| Percentage weight symmetry using dynamic representation of upright stance | 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. | Mean | Standard Deviation | percentage |
|
| Movement latency of posture control and stability using dynamic representation of upright stance | 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. | Mean | Standard Deviation | msec |
|
| Amplitude scaling of posture control and stability using dynamic representation of upright stance | The participant's ability to generate a response that is in proportion to the perturbation. It is scored in units of angular momentum and normalized to body height and weight. Scores range from 0 to 50 with values beyond a range of 0-15 are consider outside optimal | Mean | Standard Deviation | units on a scale |
|
| SF-12 (Health Survey) Mental Component Summary (MCS) | Scores range from 0 to 100, with higher scores indicating better mental health functioning | Mean | Standard Deviation | units on a scale |
|
| SF-12 (Health Survey) Physical Component Summary (PCS) | Scores range from 0 to 100, with higher scores indicating better physical health functioning | Mean | Standard Deviation | units on a scale |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Primary | 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. | Posted | Count of Participants | Participants | 9 months |
|
|
|
| Primary | Monthly Enrollment Rate | Number of participants enrolled in the study every month. To be assessed by analysis of enrollment data | Posted | Mean | Standard Deviation | participants per month | 9 months |
|
|
|
| Primary | 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. | The measure is only applicable when on urea | Posted | Mean | Full Range | 15-g urea packets | Baseline to day 42 while taking urea |
|
|
|
| Primary | 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 | The measure is only applicable when on urea | Posted | Count of Participants | Participants | Baseline to day 42 while taking urea |
|
|
|
| Primary | 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. | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Mean | Full Range | mmol/L | Baseline to day 42 |
|
|
|
| Primary | 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 | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Mean | Full Range | percentage accuracy | Baseline to day 42 |
|
|
|
| Primary | 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 Stationâ„¢ 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 | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Mean | Full Range | score on a scale | Baseline to day 42 |
|
|
|
| Primary | 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 | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Mean | Full Range | percentage change from baseline | Baseline to day 42 |
|
|
|
| Primary | 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 NeuroComâ„¢ 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. | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Mean | Full Range | percentage | Baseline to day 42 |
|
|
|
| Primary | 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 NeuroComâ„¢ 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. | Posted | Mean | Full Range | percentage change from baseline | Baseline to day 42 |
|
|
|
| Primary | 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 NeuroComâ„¢ 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. | Posted | Mean | Full Range | percentage change from baseline | Baseline to 42 days |
|
|
|
| Primary | 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. | Posted | Mean | Full Range | percentage change from baseline | Baseline to day 42 |
|
|
|
| Primary | 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. | Posted | Mean | Full Range | milliseconds | Baseline to day 42 |
|
|
|
| Primary | 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. | Posted | Mean | Full Range | units on a scale | Baseline to day 42 |
|
|
|
| Primary | 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. | This measure is only relevant when on urea | Posted | Count of Participants | Participants | Baseline to day 42 while taking urea |
|
|
|
| Primary | 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. | The measure is only applicable when on urea | Posted | Count of Participants | Participants | Baseline to day 42 while taking urea |
|
|
|
| Secondary | Number of Patients Screened | Number of patients screened. To be assessed by analysis of screening data. | Posted | Count of Participants | Participants | 9 months |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | 9 months |
|
|
|
| Secondary | 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. | All participants who received at least one dose of each intervention and completed all study visits were included. The measure is only applicable when on urea. | Posted | Count of Participants | Participants | Baseline to day 42 while taking urea |
|
|
|
| Secondary | 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. | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Count of Participants | Participants | Baseline to day 42 while taking urea |
|
|
|
| Secondary | 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 | The measure is only applicable when on urea | Posted | Mean | Full Range | units on a 5-point Likert scale | Baseline to day 42 while taking urea |
|
|
|
| Secondary | 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. | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Mean | Full Range | score on SF-12 scale | Baseline to day 42 |
|
|
|
| Secondary | 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. | All participants who received at least one dose of each intervention and completed all study visits were included | Posted | Mean | Full Range | score on a SF-12 scale | Baseline to day 42 |
|
|
|
| 2 |
| 0 |
| 2 |
| 2 |
| 2 |
| EG001 | No Urea | Participants assigned to this group will be off urea for 42 days | 0 | 2 | 0 | 2 | 1 | 2 |
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Headaches | Nervous system disorders | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Hypercalcemia | Metabolism and nutrition disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D007027 | Hypothalamic Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D004700 | Endocrine System Diseases |
| Title | Measurements |
|---|
|
| Medication tastes poorly |
|
| Medications makes me feel sick |
|
| Severe |
|
| Vomiting |
|
| Diarrhea |
|
| Headaches |
|