Systematic Use of DDAVP to Prevent Serum Sodium Overcorrection in Severe Hyponatremia: a Multicenter Open-label Randomized Controlled Trial (DASSOH)

ICU patients with severe hyponatremia and a high risk of rapid SNa overcorrection.

Study Overview

• Status: Not yet recruiting
• Conditions: Hyponatremia
• Intervention / Treatment: Drug: DDAVP; Drug: Standard hyponatremia treatment

Detailed Description

Multicentre, prospective, open-label randomized controlled superiority trial with stratification on the presence of neurological symptoms at inclusion and on the presence/absence of risk factors for central pontine myelinolysis (chronic alcohol abuse, malnutrition, serum potassium < 3.0 mmol/L).

Patients in ICU with severe hyponatremia defined by SNa < 115 mmol/L or SNa < 120 mmol/L in the presence of neurological symptoms (convulsions, stupor defined by a Glasgow score <12 or signs of brain herniation) and a normal or decreased extracellular fluid volume will be included.

After written informed consent, they will be randomized (1:1), using a computer-generated randomization scheme of various-sized blocks, stratified by the presence of neurological symptoms at inclusion (seizures, stupor defined as Glasgow score <12 or signs of brain herniation) and on the presence/absence of risk factors for central pontine myelinolysis (chronic alcohol abuse [defined according to World Health Organization definition], malnutrition [BMI<20.5 or weight loss >5% in 3 months], serum potassium < 3.0 mmol/L), through a centralized 24-hour Internet service (CleanWEB™), to receive standard hyponatremic treatment alone or standard hyponatremic treatment and DDAVP 4 μg/ml IV, after randomisation and for a total duration of 48 hours. Since administration of DDAVP leads to an important decrease in urine output and increase in urine osmolarity which are clinically obvious very rapidly, a single or double blind trial is not appropriate. However, all investigators will be unaware of aggregate outcomes during the study and brain MRI imaging will be performed and analyzed blinded to the randomization group

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: GAUDRY Stéphane; Phone Number: 01.48.95.55.55; Email: stephane.gaudry@aphp.fr
• Study Contact Backup: Name: DECHANET Aline; Phone Number: 01 40 25 78 30; Email: aline.dechanet@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults ( ≥18 years)
• Current admission in ICU
• Severe hyponatremia defined by SNa <120 mmol/L in the presence of neurological symptoms (seizures, stupor defined as Glasgow score < 12, or signs of brain herniation) or by SNa <115 mmol/L
• Normal or decreased extracellular fluid volume

Exclusion Criteria:

• Obvious increase of extracellular fluid volume (cirrhosis with ascites, congestive heart failure, nephrotic syndrome);
• Previous DDAVP or hypertonic fluid administration for the current episode of severe hyponatremia
• SNa increased by 5 mmol or more between admission at hospital and randomisation (H0)

• Known contraindication to DDAVP

  • Allergy
  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
  • History of unstable angina and/or known or suspected heart failure.
  • Willebrand disease type 2b (due to risk of thrombocytopenia)
• Severe previous neurologic disability (Glasgow Outcome Scale < 3)
• Diabetes insipidus receiving DDAVP treatment
• Moribund state (patient likely to die within 24h)
• Need for invasive mechanic ventilation
• Limitation of life support (comfort care applied only) at the time of screening
• Enrolment to another interventional study on hyponatremia care/management
• Pregnancy or breastfeeding
• Subject deprived of freedom, subject under a legal protective measure
• No affiliation to any health insurance system
• Refusal to participate to the study (patient or legal representative or family member or close relative if present)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DDAVP; DDAVP 4µg/ml IV Additional doses may be administrated every 6h for a maximum of 48h - Standard hyponatremia treatment : Presence of neurological symptoms : sodium chloride 3% 150ml for 20 min Absence of neurological symptoms : Hyper or isotonic fluid but never hypotonic	Drug: DDAVP; Posology: 4µg in 2ml IV solution Route of administration: Intravenous Duration of treatment: 48h maximum (additional doses every 6h)
Active Comparator: Standard hyponatremia treatment; Standard hyponatremia treatment alone : Presence of neurological symptoms : sodium chloride 3% 150ml for 20 min Absence of neurological symptoms : Hyper or isotonic fluid but never hypotonic	Drug: Standard hyponatremia treatment; Standard hyponatremia treatment alone : Presence of neurological symptoms : sodium chloride 3% 150ml for 20 min Absence of neurological symptoms : Hyper or isotonic fluid but never hypotonic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
reduced occurrence of overcorrection of serum sodium concentration (SNa) in the first 48 hours after randomization	proportion of patients with SNa level overcorrection : any risk factor: SNa increase > 6 mmol/L in less than H24, or >12 mmol/L in less than H48. Without risk factor: SNa increase > 10 mmol/L in less than H24, or > 18 mmol/L in less than H48	48 hours after the randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the reversal of acute neurological symptoms in patients with neurological symptoms at inclusion	proportion of patients with neurological symptoms at inclusion and who subsequently have a normal Glasgow Coma Scale at H6	6 hours after the randomization
ICU and hospital length of stay	length of ICU and hospital stay	ICU or hospital discharge
survival	time to death after inclusion	death after randomization
the occurrence of central pontine myelinolysis diagnosed on clinical and MRI criteria	proportion of patients with the occurrence of central pontine myelinolysis diagnosed on clinical and MRI criteria at day 15 (or earlier if clinically justified)	15 days after randomization
the occurrence of any (pontine or extrapontine) osmotic demyelination as assessed by brain MRI	proportion of patients with any (pontine or extrapontine), symptomatic or not, osmotic demyelination as assessed by brain MRI at day 15 (or earlier if clinically justified)	15 days after randomization
on the percentage of patients with neurological symptoms at inclusion and reaching the initial goal of rapid partial pre-defined correction of SNa level	proportion of patients with neurological symptoms with an increase of 5.0 mmol/L or more of SNa from inclusion to H6	6 hours after the randomization
the urine output between H0 and H6	urine output between H0 and H6	6 hours after the randomization
the urine output between H6 and H12	urine output between H6 and H12	12 hours after the randomization
the urine output between H12 and H24	urine output between H12 and H24	24 hours after the randomization
the urine output between H24 and H48	urine output between H24 and H48	48 hours after the randomization
the urine osmolality between H0 and H6	urine osmolality between H0 and H6	6 hours after the randomization
the urine osmolality between H6 and H12	urine osmolality between H6 and H12	12 hours after the randomization
the urine osmolality between H12 and H24	urine osmolality between H12 and H24	24 hours after the randomization
the urine osmolality between H24 and H48	urine osmolality between H24 and H48	48 hours after the randomization
SNa level correction rate between H0 and H24	slope of the SNa increase between H0 and H24	24 hours after the randomization
SNa level correction rate between H0 and H48	slope of the SNa increase between H0 and H48	48 hours after the randomization
the maximal change of SNa level between H0 and H24	maximum change of SNa from baseline between H0 and H24	24 hours after the randomization
the maximal change of SNa level between H0 and H48	maximum change of SNa from baseline between H0 and H48	48 hours after the randomization
amount of hypotonic fluids administration	total amount of intravenous hypotonic fluids administered between H0 and H24	24 hours after the randomization
amount of hypotonic fluids administration	total amount of intravenous hypotonic fluids administered between H0 and H48	48 hours after the randomization
amount of sodium and potassium administered between H0 and H24	total amount of sodium and potassium administered between H0 and H24	24 hours after the randomization
amount of sodium and potassium administered between H0 and H48	total amount of sodium and potassium administered between H0 and H48	48 hours after the randomization
the occurrence of any new neurological sign in relation with hyponatremia in patients with a normal neurological exam at inclusion or on the reappearance of any neurological sign in relation with hyponatremia after inclusion	proportion of patients with seizures, stupor or sign of brain herniation appearing or reappearing after inclusion	28 days after randomization
the occurrence of excessive re-lowering of sodium	Occurrence of a reduction of SNa of 5.0 mmol/L or more from inclusion between H0 and H48	48 hours after the randomization

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: August 28, 2023
• First Submitted That Met QC Criteria: August 28, 2023
• First Posted (Actual): August 31, 2023

Study Record Updates

• Last Update Posted (Actual): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyponatremia
• Other Study ID Numbers: APHP220676

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No