Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Ongoing, recruiting
Participants planned
260
Countries
1
Sites
27
Severe hyponatremia and a high risk of rapid SNa overcorrection
To determine whether the systematic DDAVP administration decreases the occurrence of serum sodium concentration (SNa) overcorrection during the first 48 hours after randomization in patients with severe hyponatremia (SNa < 115 mmol/L or < 120mmol/L in patients with neurological symptoms).
Key facts
- Sponsor
- Assistance Publique Hopitaux De Paris
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]
- Trial duration
- 17 Dec 2024 → ongoing
- Decision date (initial)
- 2024-05-16
- Transition trial
- No
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
- Funding sources
- Direction Générale de l’Offre des Soins du Ministère de la santé et de la prévention
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Prophylaxis, Efficacy, Therapy
To determine whether the systematic DDAVP administration decreases the occurrence of serum sodium concentration (SNa) overcorrection during the first 48 hours after randomization in patients with severe hyponatremia (SNa < 115 mmol/L or < 120mmol/L in patients with neurological symptoms).
Secondary objectives 14
- The reversal of acute neurological symptoms in patients with neurological symptoms at inclusion
- ICU and hospital length of stay
- Survival
- The occurrence of central pontine myelinolysis diagnosed on clinical and MRI criteria
- The occurrence of any (pontine or extrapontine) osmotic demyelination as assessed by brain MRI
- Percentage of patients with neurological symptoms at inclusion and reaching the initial goal of rapid partial pre-defined correction of SNa level
- The urine output between (i) H0 and H6, (ii) H6 and H12, (iii) H12 and H24, and (iv) H24 and H48
- The urine osmolality between (i) H0 and H6, (ii) H6 and H12, (iii) H12 and H24, and (iv) H24 and H48
- SNa level correction rate between (i) H0 and H24 and (ii) H0 and H48
- The maximal change of SNa level between (i) H0 and H24 and (ii) H0 and H48
- Amount of hypotonic fluids administration between (i) H0 and H24 and (ii) H24 and H48
- Amount of sodium and potassium administered between (i) H0 and H24 and (ii) H24 and H48
- 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
- The occurrence of excessive re-lowering of sodium
Conditions and MedDRA coding
Severe hyponatremia and a high risk of rapid SNa overcorrection
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 22.1 | LLT | 10054430 | Hyponatremia aggravated | 10027433 |
| 26.0 | LLT | 10070605 | Rapid correction of hyponatremia | 10042613 |
| 20.1 | LLT | 10021038 | Hyponatremia | 10027433 |
Study design 1 period
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | multicenter open-label randomized controlled trial This is a national, multicenter, 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).
This is a study with two comparative groups at a ratio of (1:1):
- Experimental arm: DDVAP + standard of care
- Control arm: standard of care alone
As already explained, due to the nature of the treatments received, investigator blinding to group assignment is not feasible. Indeed, the administration of DDAVP leads to an important decrease in urine output and increase in urine osmolarity which are clinically obvious very rapidly. 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 (see secondary outcomes section).
Biological analyses as well as statistical analyses will be performed blinded to treatment group.
|
Randomised Controlled | None | Experimental arm: DDAVP (IMP) + Standard of care (SOC) 1) IMP = DDAVP = MINIRIN© 2) SOC = standard hyponatremia treatment in accordance with international recommendations (without DDAVP administration*): * DDAVP can be used in rescue strategy: administration when the target SNa is exceeded and overcorrection has already occurred. - Presence of neurological symptoms: NaCl 3% 150 ml or 2mL/kg in case of weight < 50kg or > 120kg over 20 min - Absence of neurological symptoms isotonic fluid (NaCl 0.9%) but never hypotonic - Route of administration: intravenous - Duration of treatment: 48h maximum - In case of suspected overcorrection (= sudden significant diuresis or obviously overcorrection): Stop NaCl 3% infusion + glucose hypotonic fluid (D5 or D2.5): 10 ml/kg over 1h under strict monitoring. - In case of hypovolemia: saline solution (NaCL 0.9%) at a rate of 0.5 à 1 ml/kg/h - In case of hypervolemia: physicians are allowed to use furosemide - In case of hypokalaemia: potassium chloride (KCl), amount of KCl administration will depend on severity of hypokalemia. Physicians will be made aware that KCl administration may contribute to the rise of SNa.During potassium administration, the rate of 3% saline solution infusion should be slowed proportionally. Control arm: Standard of care (SOC) alone SOC = standard hyponatremia treatment in accordance with international recommendations (without DDAVP administration*): * DDAVP can be used in rescue strategy: administration when the target SNa is exceeded and overcorrection has already occurred. - Presence of neurological symptoms: NaCl 3% 150 ml or 2mL/kg in case of weight < 50kg or > 120kg over 20 min - Absence of neurological symptoms isotonic fluid (NaCl 0.9%) but never hypotonic - Route of administration: intravenous - Duration of treatment: 48h maximum - In case of suspected overcorrection (= sudden significant diuresis or obviously overcorrection): Stop NaCl 3% infusion + glucose hypotonic fluid (D5 or D2.5): 10 ml/kg over 1h under strict monitoring. - In case of hypovolemia: saline solution (NaCL 0.9%) at a rate of 0.5 à 1 ml/kg/h - In case of hypervolemia: physicians are allowed to use furosemide - In case of hypokalaemia: potassium chloride (KCl), amount of KCl administration will depend on severity of hypokalemia. Physicians will be made aware that KCl administration may contribute to the rise of SNa. During potassium administration, the rate of 3% saline solution infusion should be slowed proportionally. |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 4
- 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 GCS < 12, or signs of brain herniation) or by SNa < 115 mmol/L
- Normal or decreased extracellular fluid volume
Exclusion criteria 18
- Obvious increase of extracellular fluid volume (cirrhosis with ascites, congestive heart failure, nephrotic syndrome)
- Severe previous neurologic disability (Glasgow Outcome Scale: GOS < 3)
- Diabetes insipidus receiving DDAVP treatment
- Moribund state (patient likely to die within 24h)
- Need for invasive mechanic ventilation
- Hyponatremia caused by hyperglycaemia (> 30 mmol/L) or hypertriglyceridemia (10 g/L) or hyperproteinaemia (120 g/L)
- Severe acute kidney injury (KDIGO 3)
- Severe chronic kidney disease (eGFR <20 ml/min)
- Coronary patients well stabilized with trinitrine-based medicines
- Recent neurosurgery or traumatic brain injury
- 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 IIB
- Enrolment to another interventional study (clinical trial on medicinal product, medical device and interventional research involving human participants not concerning health product)
- 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)
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 2
- Proportion of patients with SNa level overcorrection at any time during the first 48h after randomization.
- SNa overcorrection is defined according to presence or absence of risk factors at the time of randomization (chronic alcohol abuse, malnutrition, thiazides or antidepressant medicines, serum potassium<3.0mmol/L, glycaemia>20mmol/L) for CPM: • Patients with any risk factor: SNa increase>6.0 mmol/L in less than 24h, or a SNa increase>12.0 mmol/L in less than 48h. • Patients without risk factor: SNa increase>10.0mmol/L in less than 24h, or a SNa increase>18.0 mmol/L in less than 48h.
Secondary endpoints 14
- Proportion of patients with neurological symptoms at inclusion and who subsequently have a normal Glasgow Coma Scale at H6
- Length of ICU and hospital stay
- Time to death after inclusion
- Proportion of patients with the occurrence of central pontine myelinolysis diagnosed on clinical and MRI criteria at day 15 (or earlier if clinically justified)
- 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)
- Proportion of patients with neurological symptoms with an increase of 5.0 mmol/L or more of SNa from inclusion to H6
- Urine output between (i) H0 and H6, (ii) H6 and H12, (iii) H12 and H24, and (iv) H24 and H48
- Urine osmolality between (i) H0 and H6, (ii) H6 and H12, (iii) H12 and H24, and (iv) H24 and H48
- Slope of the SNa increase between (i) H0 and H24 and (ii) H0 and H48
- Maximum change of SNa from baseline between (i) H0 and H24 and (ii) H0 and H48
- Total amount of intravenous hypotonic fluids administered between (i) H0 and H24 and (ii) H24 and H48
- Total amount of sodium and potassium administered between (i) H0 and H24 and (ii) H24 and H48
- Proportion of patients with seizures, stupor or sign of brain herniation appearing or reappearing after inclusion
- Occurrence of a reduction of SNa of 5.0 mmol/L or more from inclusion between H0 and H48
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 1
MINIRIN 4 microgrammes/ml, solution injectable
PRD454287 · Product
- Active substance
- Desmopressin Acetate Trihydrate
- Substance synonyms
- DESMOPRESSIN ACETATE HYDRATE
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 20 µg microgram(s)
- Max total dose
- 32 µg microgram(s)
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- H01BA02 — DESMOPRESSIN
- Marketing authorisation
- 34009 330 915 2 1
- MA holder
- FERRING S.A.S.
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Auxiliary 7
CHLORURE DE POTASSIUM B. BRAUN 10 % (0,10 g/ml), solution à diluer pour perfusion
PRD9993274 · Product
- Active substance
- Potassium Chloride
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 2.5 mmol/kg millimole(s)/kilogram
- Max total dose
- 2.5 mmol/kg millimole(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- B05AX01 — -
- Marketing authorisation
- 34009 560 240 7 0
- MA holder
- B.BRAUN MELSUNGEN AG
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
CHLORURE DE SODIUM HYPERTONIQUE 10 % LAVOISIER, solution à diluer injectable
PRD471169 · Product
- Active substance
- Sodium Chloride
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 45 ml millilitre(s)
- Max total dose
- 45 ml millilitre(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- B05XA03 — SODIUM CHLORIDE
- Marketing authorisation
- 34009 363 410 7 4
- MA holder
- LABORATOIRES CHAIX ET DU MARAIS
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- Extemporaneous dilution to prepare a 3% NaCl solution
GLUCOSE 2,5 % B. BRAUN, solution pour perfusion
PRD9984252 · Product
- Active substance
- Glucose Monohydrate
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 250 ml millilitre(s)
- Max total dose
- 500 ml millilitre(s)
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- B05BA03 — CARBOHYDRATES
- Marketing authorisation
- 34009 360 683 2 2
- MA holder
- B.BRAUN MELSUNGEN AG
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
CHLORURE DE SODIUM 0,9 % AGUETTANT, solution pour perfusion
PRD10486866 · Product
- Active substance
- Sodium Chloride
- Substance synonyms
- SODIUM CHLORID
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 250 ml millilitre(s)
- Max total dose
- 250 ml millilitre(s)
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- B05XA03 — SODIUM CHLORIDE
- Marketing authorisation
- 34009 353 591 9 3
- MA holder
- LABORATOIRE AGUETTANT
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP11412561 · ATC
- Active substance
- Meglumine Gadoterate
- Substance synonyms
- Gadoterate meglumine
- Route of administration
- INTRAVENOUS
- Max daily dose
- 0.2 millilitre(s)/kilogram
- Max total dose
- 0.2 millilitre(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- V08CA02 — GADOTERIC ACID
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
GLUCOSE 5 % VIAFLO, solution pour perfusion
PRD361621 · Product
- Active substance
- Glucose
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 250 ml millilitre(s)
- Max total dose
- 500 ml millilitre(s)
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- B05BA03 — CARBOHYDRATES
- Marketing authorisation
- 34009 359 575 5 9
- MA holder
- BAXTER SAS
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB15300MIG · Substance
- Active substance
- Sodium Lactate
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 3 l litre(s)
- Max total dose
- 6 l litre(s)
- Max treatment duration
- 2 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Assistance Publique Hopitaux De Paris
- Sponsor organisation
- Assistance Publique Hopitaux De Paris
- Address
- Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux
- City
- Paris Cedex 10
- Postcode
- 75475
- Country
- France
Scientific contact point
- Organisation
- Assistance Publique Hopitaux De Paris
- Contact name
- Coordinating investigator : Pr Stéphane GAUDRY
Public contact point
- Organisation
- Assistance Publique Hopitaux De Paris
- Contact name
- Coordinating investigator : Pr Stéphane GAUDRY
Locations
1 EU/EEA country · 27 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| France | Ongoing, recruiting | 260 | 27 |
| Rest of world | — | 0 | — |
Investigational sites
Centre Hospitalier Departemental Vendee
Imagerie Médicale, Boulevard Stephane Moreau, 85925, La Roche Sur Yon Cedex 9
Hospital Foch
Réanimation polyvalente, 40 Rue Worth, 92150, Suresnes
Centre Hospitalier General De St Denis
Médecine Intensive et Réanimation, 2 Rue Du Docteur Delafontaine, BP 279, St Denis Cedex
Assistance Publique Hopitaux De Paris
Neuroradiologie, 47 Boulevard De L Hopital, 75651, Paris Cedex 13
Centre Hospitalier Universitaire De Dijon
Médecine Intensive et Réanimation, 14 Rue Paul Gaffarel, 21000, Dijon
Assistance Publique Hopitaux De Paris
Réanimation, Avenue Du 14 Juillet, 93140, Bondy
Assistance Publique Hopitaux De Paris
Médecine Intensive et Réanimation, 125 Rue De Stalingrad, 93000, Bobigny
Assistance Publique Hopitaux De Paris
Neuroradiologie, 51 Av Du Mal De Lattre De Tassigny, 94000, Creteil
Centre Hospitalier Universitaire De Dijon
Neuroradiologie et imagerie des urgences, 14 Rue Paul Gaffarel, 21000, Dijon
Groupe Hospitalier Nord Essonne
Réanimation Médicale, ZAC De Corbeville, 1 Parvis De L Hopital, Orsay
Assistance Publique Hopitaux De Paris
Radiologie, 125 Rue De Stalingrad, 93000, Bobigny
Assistance Publique Hopitaux De Paris
Imagerie Médicale, Avenue Du 14 Juillet, 93140, Bondy
Centre Hospitalier General De St Denis
Radiologie, 2 Rue Du Docteur Delafontaine, BP 279, St Denis Cedex
Assistance Publique Hopitaux De Paris
Médecine Intensive et Réanimation, 178 Rue Des Renouillers, 92700, Colombes
Centre Hospital Region Metz Thionville
Imagerie médicale et radiodiagnostic, 1 Allee Du Chateau, Cs 45001 Ars Laquenexy, Metz Cedex 03
Centre Hospitalier Universitaire Amiens Picardie
Neuroradiologie et Radiologie - Imagerie Médicale, 1 Rond Point Du Pr Christian Cabrol, 80054, Amiens Cedex 1
Centre Hospitalier Universitaire Amiens Picardie
Médecine Intensive et Réanimation, 1 Rond Point Du Pr Christian Cabrol, 80054, Amiens Cedex 1
Assistance Publique Hopitaux De Paris
Médecine Intensive et Réanimation, 125 Rue De Stalingrad, 93000, Bobigny
Hospital Foch
Neuroradiologie, 40 Rue Worth, 92150, Suresnes
Assistance Publique Hopitaux De Paris
Radiologie, 178 Rue Des Renouillers, 92700, Colombes
Assistance Publique Hopitaux De Paris
Médecine Intensive et Réanimation, 51 Av Du Mal De Lattre De Tassigny, 94000, Creteil
Centre Hospital Region Metz Thionville
Réanimation Polyvalente, 1 Allee Du Chateau, Cs 45001 Ars Laquenexy, Metz Cedex 03
Centre Hospitalier Departemental Vendee
Réanimation polyvalente, Boulevard Stephane Moreau, 85925, La Roche Sur Yon Cedex 9
Centre Hospitalier Sud Francilien
Imagerie Médicale, 40 Avenue Serge Dassault, 91106, Corbeil Essonnes Cedex
Centre Hospitalier Sud Francilien
Réanimation Polyvalente et Surveillance continue, 40 Avenue Serge Dassault, 91106, Corbeil Essonnes Cedex
Assistance Publique Hopitaux De Paris
Médecine Intensive et Réanimation - R3S, 47 Boulevard De L Hopital, 75651, Paris Cedex 13
Groupe Hospitalier Nord Essonne
Imagerie Médicale, ZAC De Corbeville, 1 Parvis De L Hopital, Orsay
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| France | 2024-12-17 | 2024-12-17 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 14 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_CTCAE-scale-addendum5_2023-507254-32-00 | 5-0 |
| Protocol (for publication) | D1_Feuille-recueil_2023-507254-32-00 | 1-0 |
| Protocol (for publication) | D1_Pregnancy-notification-form-addendum3_2023-507254-32-00 | 2-0 |
| Protocol (for publication) | D1_Protocol_2023-507254-32-00_Public | 3-1 |
| Protocol (for publication) | D1_SAE-notification-form-addendum2_2023-507254-32-00 | 2-0 |
| Protocol (for publication) | D1_SAE-notification-form-annexe-addendum2_2023-507254-32-00 | 1-0 |
| Recruitment arrangements (for publication) | K1_Recruitment-arrangements | 1-0 |
| Subject information and informed consent form (for publication) | L1_SIS-ICF-patient | 2-0 |
| Subject information and informed consent form (for publication) | L1_SIS-ICF-patient-poursuite | 2-0 |
| Subject information and informed consent form (for publication) | L1_SIS-ICF-proche | 2-0 |
| Subject information and informed consent form (for publication) | L1_SIS-ICF-proche-poursuite | 2-0 |
| Subject information and informed consent form (for publication) | L1_SIS-ICF-utilisation-donnees | 1-0 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC MINIRIN | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol-synopsis-FR_2023-507254-32-00 | 3-0 |
Application history
3 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-01-30 | France | Acceptable 2024-05-15
|
2024-05-16 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2025-02-20 | France | Acceptable 2025-04-02
|
2025-04-04 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2025-08-21 | France | Acceptable 2025-10-23
|
2025-10-24 |