Urea for Chronic Hyponatremia

NCT ID: NCT04588207

Last Updated: 2024-05-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-28
• Study Completion Date: 2022-09-29

Brief 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. 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.

Conditions

Hyponatremia; Inappropriate ADH Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Urea

Intervention Type: 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-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.

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)

Group Type: EXPERIMENTAL

Urea

Intervention Type: 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-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.

Interventions

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-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.

Intervention Type: DRUG

Other Intervention Names

Ure-Na

Eligibility Criteria

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:

1. Hyponatremia with a PNa between 125 mmol/L and 132 mmol/L

2. Plasma osmolality < 275 mOsm/kg

3. Clinical euvolemia

4. Urine osmolality > 100 mosm/kg

5. Urine Na ≥ 20 mmol/L

6. Intact adrenal function (i.e., morning plasma cortisol value ≥15 μg/dL, or negative corticotropin stimulation test)

7. Normal thyroid stimulating hormone (TSH) level (i.e., TSH between 0.3 to 5 μIU/mL)

8. eGFR >= 45 ml/min/1.73 m2)

Exclusion Criteria

• Cirrhosis and/or end-stage liver disease
• Heart failure on diuretics and/or with recorded left ventricular ejection fraction <40 percent
• Chronic kidney disease with most recent estimated glomerular filtration rate <45 ml/min/1.73m2
• Adrenal insufficiency
• Untreated hypothyroidism
• Urinary tract obstruction within the prior 2 months
• Uncontrolled hyperglycemia (most recent random plasma glucose ≥ 200 mg/dL)
• Ongoing drug treatment for hyponatremia with vaptans or combination of loop diuretics and salt tablets.
• Active malignancy
• Active infection
• Neurological disorders with impairment of ambulation or cognition
• End-stage lung disease with marked impairment in ambulatory capacity
• Chronic pain with impairment of ambulation or cognition
• Chronic nausea
• Hypersensitivity to urea
• Women who are pregnant, breast feeding, or of childbearing potential who are not using contraception
• Patient is unable to consent for himself/herself

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Helbert Rondon Berrios, MD, MS

OTHER

Sponsor Role: lead

Responsible Party

Helbert Rondon Berrios, MD, MS

Associate Professor of Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Helbert Rondon Berrios, MD. MS

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Countries

United States

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-limits-duration-and-usage-samsca-tolvaptan-due-possible-liver

FDA Drug Safety Communication: FDA limits duration and usage of Samsca (tolvaptan) due to possible liver injury leading to organ transplant or death

Other Identifiers

R21DK122023

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY20050035

Identifier Type: -

Identifier Source: org_study_id