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Effect of Protein Supplementation on Plasma Sodium Levels and Urinary Urea Excretion in Patients With SIAD (TREASURE)

Primary Purpose

Syndrome of Inappropriate Antidiuresis (SIAD)

Status

Completed

Phase

Not Applicable

Locations

Switzerland

Study Type

Interventional

Intervention

Protein supplementation

Oral urea

About this trial

This is an interventional treatment trial for Syndrome of Inappropriate Antidiuresis (SIAD) focused on measuring protein supplementation, plasma sodium level, hyponatremia, urea

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

previous documented diagnosis of chronic SIAD
confirmed diagnosis of SIAD at screening visit defined as:
- plasma sodium concentration <135 mmol/L, measured in lithium heparin plasma
- Plasma osmolality <300 mOsm/kg
- Urine osmolality >100 mOsm/kg
- Urine sodium concentration >30mmol/l
- Clinical euvolemia, defined as an absence of signs of hypovolemia (orthostasis, tachycardia, decreased skin turgor, dry mucous membranes) or hypervolemia (edema, ascites)

Exclusion Criteria:

lactose intolerance, celiac disease, milk protein allergy, soja allergy, nuts allergy or known hypersensitivity or allergy to one of the components of the protein supplementation (Whey Protein®, foodspring GmbH, Germany or Clear Whey Isolate®, MyProtein THG Company, United Kingdom)
inborn metabolic disorders implying carbohydrate, lipid or protein metabolism - severe symptomatic hyponatremia in need of treatment with 3% NaCl-solution or in need of intensive/intermediate care treatment at time of inclusion
Risk factors for osmotic demyelination syndrome: hypokalaemia (K <3,4 mmol/L), malnutrition, advanced liver disease, alcoholism.
contraindication for lowering blood pressure
type 1 diabetes mellitus
uncontrolled type 2 diabetes mellitus (defined as HbA1c >8.0%)
uncontrolled hypothyroidism
uncontrolled adrenal insufficiency
reduction of eGFR <60 mL/min/1,73 m2 (KDIGO G3, G4 and G5) or end stage renal disease (dialysis)
severe hepatic impairment (ALAT/ASAT >3x upper limit) or advanced symptomatic liver disease defined as past or current hepatic encephalopathy, liver cirrhosis Child C or decompensated (bleeding, jaundice, hepatorenal syndrome).
treatment with a diuretic, a SGLT2 inhibitor or a corresponding combined preparation, lithium chloride, urea, vaptans, demeclocycline in the two weeks before screening.
severe immunosuppression defined as leucocytes <2G
pregnancy, wish to become pregnant during study period or breastfeeding
end of life care
Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc.
Current participation in another intervention study
lack of capacity or other reason preventing from giving informed consent or following study procedures.

Sites / Locations

University Hospital Basel, Department of Endocrinology

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

single arm: Phase 1: protein supplementation, Phase 2: Urea

Arm Description

Outcomes

Primary Outcome Measures

Change in plasma sodium concentration, (mmol/l)

The change of blood sodium during protein supplementation regimen will be visualized by means of line plots and boxplots for patients with chronic SIAD.

Secondary Outcome Measures

Change in estimated glomerular filtration rate (eGFR), (ml/min/1,73m2)

Change in estimated glomerular filtration rate (eGFR)

Change in blood and urine osmolality, (mOsm/kg)

Change in blood and urine osmolality

Change in blood and urine potassium, (mmol/L)

Change in blood and urine potassium

Change in blood and urine creatinine, (umol/L)

Change in blood and urine creatinine

Change in blood and urine urea, (mmol/L)

Change in blood and urine urea,

Change in blood and urine uric acid, (umol/L)

Change in blood and urine uric acid

Change in blood and urine glucose, (mmol/L)

Change in blood and urine glucose

Change in copeptin, (pmol/l)

Change in copeptin

Change in aldosterone, (pmol/l)

Change in aldosterone

Change in renin, (mIU/L)

Change in renin

Change in MR-proANP, (pmol/l)

Change in MR-proANP

Change in NT-proBNP, (pmol/L)

Change in NT-proBNP

Change in oral daily fluid intake, (ml)

Change in oral daily fluid intake assessed by a self-completed drinking protocol

Change in body weight, (kg)

Change in body weight (kg)

Change in both systolic and diastolic blood pressure, (mmHg)

Change in both systolic and diastolic blood pressure (mmHg)

Change in heart rate, (beats/minute)

Change in heart rate (beats/minute)

Change in general well-being measured by visual analogue scale (VAS, 0-10)

Change in general well-being measured by visual analogue scale (VAS, 0-10), with a range from 0 "worst well-being" to 10 "excellent well-being".

Number of signs of hyponatremia (vertigo, headache, nausea, attention deficit, mental slowness, forgetfulness, gait instability) assessed by a questionnaire (yes/no)

number of signs of hyponatremia (vertigo, headache, nausea, attention deficit, mental slowness, forgetfulness, gait instability) assessed by a questionnaire (yes/no)

Short-term change in plasma sodium level (mmol/L)

Short-term change in plasma sodium levels in patients with a plasma sodium concentration <125 mmol/L at baseline.

Full Information

NCT ID

NCT04987385

First Posted

July 21, 2021

Last Updated

February 20, 2023

Sponsor

University Hospital, Basel, Switzerland

1. Study Identification

Unique Protocol Identification Number

NCT04987385

Brief Title

Effect of Protein Supplementation on Plasma Sodium Levels and Urinary Urea Excretion in Patients With SIAD

Acronym

TREASURE

Official Title

Effect of Protein Supplementation on Plasma Sodium Levels and Urinary Urea Excretion in Patients With SIAD - a Monocentric Open- Label Proof-of-concept Study -The TREASURE Study

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Completed

Study Start Date

October 8, 2021 (Actual)

Primary Completion Date

February 20, 2023 (Actual)

Study Completion Date

February 20, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Basel, Switzerland

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This study aims to investigate whether a 7-day dietary high protein supplementation of 90 grams per day increases plasma sodium levels in hyponatremic patients with chronic SIAD. Enrolled patients will receive first dietary high protein supplementation for one week. After a wash-out phase of at least one week, the patients will receive oral urea for another week.

Detailed Description

Hyponatremia (blood sodium <135 mmol/l) is the most frequent electrolyte and fluid disturbance with a prevalence up to 30% in hospitalized patients. The most common etiology of euvolemic hyponatremia is the syndrome of inappropriate antidiuresis (SIAD) which is also the main etiology of hyponatremia overall. Urea osmotic diuresis has been reported to cause hypernatremia in critically ill patients in intensive care unit (ICU), showing that urea can influence sodium levels. Increasing solute intake with oral urea represents a valid treatment approach to increase urine volume and solute free water clearance through osmotic diuresis and reduction of urinary sodium excretion in SIAD. In Switzerland, urea is a medical food prepared as a compounding agent by pharmacies. Endogenous proteins and dietary protein are metabolized into nitrogen which is metabolized to soluble excretable urea by the liver. Protein intake could represent an osmotic relevant source of urea. The Jone's factor of 6,25 is commonly used to convert nitrogen to protein equivalent, assuming an average nitrogen content of 16% in protein (100g protein / 6,5 = 16g nitrogen). Urea (CH₄N₂O) contains 46,6% nitrogen (atomic weight of nitrogen = 14 g/mol, atomic weight of urea = 60,1 g/mol). Using these ratios, 30g urea would correspond to 14g nitrogen and 87,5g protein. In this study, a 90g protein supplementation will be used, which corresponds roughly to 30g urea, in form of a daily intake of protein powder (Whey Protein®, foodspring GmbH, Germany or Clear Whey Isolate®, MyProtein THG Company, United Kingdom), which is freely marketed as food in Switzerland. Both interventional products are not considered as drugs. Patients with a plasma sodium concentration <125 mmol/L are at increased risk for overcorrection, i.e., an increase in plasma sodium levels >10 mmol/L in the first 24 hours of treatment. An additional visit will be planned on the second day of treatment in order to recognize rise over this limit and initiate relowering counteractions, which will include the skip of the second powder intake and oral fluid intake. This study is to analyze whether protein supplementation can increase plasma sodium levels in patients with SIAD by increasing urinary urea excretion.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Syndrome of Inappropriate Antidiuresis (SIAD)

Keywords

protein supplementation, plasma sodium level, hyponatremia, urea

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Model Description

proof-of-concept study, no control group needed since patients serve as their own control in the second treatment phase

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

single arm: Phase 1: protein supplementation, Phase 2: Urea

Arm Type

Other

Intervention Type

Dietary Supplement

Intervention Name(s)

Protein supplementation

Intervention Description

Patients will receive a box with 7 sealable of 90-gram protein containers that will be dissolved in maximal 1L liquid (i.e., water or milk) that should be integrated in the usual daily hydration volume documented at baseline and taken daily for the following 7 days, while keeping their usual meal composition and usual fluid intake. A wash-out period of minimum 7 days between Protein supplementation and Oral urea will be performed.

Intervention Type

Dietary Supplement

Intervention Name(s)

Oral urea

Intervention Description

Patients will receive a box with 7 30-grams urea sealable containers. The total daily oral urea dosage of 30 grams that will be dissolved in maximal 1L of a liquid of choice (water, milk, juice, …) that should be integrated in the usual daily hydration volume documented at baseline and taken daily for the following 7 days, while keeping their usual meal composition and usual fluid intake.

Primary Outcome Measure Information:

Title

Change in plasma sodium concentration, (mmol/l)

Description

The change of blood sodium during protein supplementation regimen will be visualized by means of line plots and boxplots for patients with chronic SIAD.

Time Frame

from baseline to 7 days after protein supplementation (7 days)

Secondary Outcome Measure Information:

Title

Change in estimated glomerular filtration rate (eGFR), (ml/min/1,73m2)

Description

Change in estimated glomerular filtration rate (eGFR)

Time Frame