Continuous Hyperosomolar Therapy for Traumatic Brain-injured Patients (COBI)

Continuous Hyperosomolar Therapy for Traumatic Brain-injured Patients Study Protocol for a Multicenter Randomized Open-label Trial With Blinded Adjudication of Primary Outcome

Traumatic brain injury (TBI) is a major cause of death and severe prolonged disability. Intracranial hypertension (ICH) is a critical risk factor of bad outcomes after TBI. Continuous infusion of hyperosmolar therapy has been proposed for the prevention or the treatment of ICH. Whether an early administration of continuous hyperosmolar therapy improves long term outcomes is uncertain. The aim of the current study is to assess the efficiency and the safety of continuous hyperosmolar therapy in TBI patients.

The COBI trial is the first randomized controlled trial powered to investigate whether continuous hyperosmolar therapy in TBI patients improve long term recovery.

Hypothesis

Patients treated with early continuous hyperosmolar therapy have reduced morbidity and mortality rates compared to those receiving standard care alone after traumatic brain injury.

Research Questions

1. Does early continuous hyperosmolar therapy reduce morbidity and mortality rates at 3 and 6 months after TBI assessed by the GOSE questionnaire?
2. Does early continuous hyperosmolar therapy prevent intracranial hypertension?

Study Overview

• Status: Completed
• Conditions: Moderate to Severe Traumatic Brain Injury
• Intervention / Treatment: Drug: NaCl20% (Continuous hyperosmolar therapy)

Detailed Description

Background Traumatic brain injury (TBI) is a major cause of death and severe prolonged disability. Intracranial hypertension (ICH) is a critical risk factor of bad outcomes after TBI.

Continuous infusion of hyperosmolar therapy has been proposed for the prevention or the treatment of ICH. Whether an early administration of continuous hyperosmolar therapy improves long term outcomes is uncertain. The aim of the current study is to assess the efficiency and the safety of continuous hyperosmolar therapy in TBI patients.

Methods The COBI (Continuous hyperosmolar therapy in traumatic brain-injured patients) trial is a multicenter, randomized, controlled, open-label, two-arms study with blinded adjudication of primary outcome. Three hundred and seventy patients hospitalized in Intensive Care Unit with a traumatic brain injury (Glasgow Coma Scale ≤ 12 and abnormal brain CT-scan) are randomized in the first 24 hours following trauma to standard care or continuous hyperosmolar therapy (NaCl 20%) plus standard care. Continuous hyperosmolar therapy is maintained for at least 48 hours in the treatment group and continued for as long as is necessary to prevent intracranial hypertension. The primary outcome is the score on the Extended Glasgow Outcome Scale (GOS-E) at 6 months. The treatment effect is estimated with ordinal logistic regression adjusted for pre-specified prognostic factors and expressed as a common odds ratio.

Discussion The COBI trial is the first randomized controlled trial powered to investigate whether continuous hyperosmolar therapy in TBI patients improve long term recovery.

• Study Type: Interventional
• Enrollment (Actual): 370
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France
    • CHU Angers
  • Brest, France, 29600
    • CHU Brest Hopital la Cavale Blanche
  • Clichy, France, 92118
    • AP-HP Beaujon
  • Montpellier, France
    • CHU Montpellier
  • Nantes, France, 44093
    • CHU de Nantes
  • Paris, France, 75014
    • Centre Hospitalier Sainte-Anne
  • Poitiers, France, 86000
    • CHU Poitiers
  • Rennes, France
    • CHU Rennes-Hôpital Pontchaillou
  • Toulouse, France, 31059
    • CHU Toulouse Hôpital Pierre-Paul Riquet
  • Tours, France, 37044
    • CHU Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18-80 years old
• Moderate to severe traumatic brain injury defined as the association of a Coma Glasgow Scale ≤ 12 together with a traumatic abnormal brain CT-scan
• Time to inclusion inferior to 24 hours
• Informed consent (or emergency procedure)

Exclusion Criteria:

• dependence for daily activity
• Coma Glasgow Scale of 3 and fixed dilated pupils
• associated cervical spine injury
• imminent death and do-not-resuscitate orders
• pregnancy.
• Major not legally responsible
• Oedemato-ascitic decompensation of hepatic cirrhosis
• State of hydro-sodium retention secondary to heart failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Continuous hyperosmolar therapy; Standard cares plus continuous hyperosmolar therapy (NaCl20%)	Drug: NaCl20% (Continuous hyperosmolar therapy); Early intravenous administration (<24 hours after traumatic brain injury) of NaCl20% for a minimal duration of 48 hours (continued for as long as is necessary to prevent intracranial hypertension) 1-hour bolus (15 g if Na+ < 145 mmol/L; 7.5 g if 145 < Na+ < 150 mmol/L; or no bolus) followed by 1 g/hour as long as Na+< 150 mmol/L, reduced to 0.5 g/L if 150 < Na+ < 155 mmol/L, Discontinuation when 155 mmol/L
No Intervention: Control; Standard cares alone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Score on the Extended Glasgow Outcome Scale (GOS-E) at 6 months	The GOS-E is a scale measuring the neurological recovery after traumatic brain injuries	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate in ICU		3 months
Mortality rate in ICU		6 months
GOS-E	The GOS-E is a scale measuring the neurological recovery after traumatic brain injuries	3 months
functional independence measure : ADL (Activities of Daily Living) of Katz	Scale measuring the autonomy of patient	3 months
functional independence measure : ADL (Activities of Daily Living) of Katz	Scale measuring the autonomy of patient	6 months
Short Form 36	Scale measuring the quality of life	3 months
Short Form 36	Scale measuring the quality of life	6 months
Rate of patients with anterograde amnesia		3 months
Rate of patients with anterograde amnesia		6 months
Intracranial pressure control		7 Days
Blood level of sodium		7 Days
blood osmolality		7 Days
Rate of thrombo-embolic events		28 days
Rate of acute kidney injury	KDIGO 3	28 days
Rate of centropontine myelinolysis	Diagnosis on MRI realized in case of clinical suspicion	28 days
Blood level of chlore		7 Days
Blood level of potassium		5 Days
Blood level of pH (Hydrogen Potention)		5 Days
brain oxygenation (PtiO2)		5 Days
blood level of creatinine		5 Days
Diuresis		5 Days
weight		5 Days
Ancillary study: questionnaire HADS (Hospital Anxiety and Depression Scale) in patient's relative	Scale measuring the quality of life	6 months

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Investigators: Principal Investigator: Olivier Huet, PU-PH, CHU de Brest; Principal Investigator: Lasocki Sigismond, PU-PH, University Hospital, Angers; Principal Investigator: Thomas Geerraerts, PU-PH, University Hospital, Toulouse; Principal Investigator: Francis Remerand, PU-PH, CHU de Tours; Principal Investigator: Philippe Seguin, PU-PH, Rennes University Hospital; Principal Investigator: Claire Dahyot, PU-PH, CHU Poitiers; Principal Investigator: Pierre François Perrigault, PU-PH, University Hospital, Montpellier; Principal Investigator: Jean Denis Moyer, PU-PH, AP-HP Beaujon; Principal Investigator: Tarek SHARSHAR, PU-PH, AP-HP Saint-Anne

Publications and helpful links

General Publications

• Roquilly A, Moyer JD, Huet O, Lasocki S, Cohen B, Dahyot-Fizelier C, Chalard K, Seguin P, Jeantrelle C, Vermeersch V, Gaillard T, Cinotti R, Demeure Dit Latte D, Mahe PJ, Vourc'h M, Martin FP, Chopin A, Lerebourg C, Flet L, Chiffoleau A, Feuillet F, Asehnoune K; Atlanrea Study Group and the Societe Francaise d'Anesthesie Reanimation (SFAR) Research Network. Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial. JAMA. 2021 May 25;325(20):2056-2066. doi: 10.1001/jama.2021.5561.
• Roquilly A, Lasocki S, Moyer JD, Huet O, Perrigault PF, Dahyot-Fizelier C, Seguin P, Sharshar T, Geeraerts T, Remerand F, Feuillet F, Asehnoune K; COBI group. COBI (COntinuous hyperosmolar therapy for traumatic Brain-Injured patients) trial protocol: a multicentre randomised open-label trial with blinded adjudication of primary outcome. BMJ Open. 2017 Sep 24;7(9):e018035. doi: 10.1136/bmjopen-2017-018035.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2017
• Primary Completion (Actual): March 5, 2020
• Study Completion (Actual): March 5, 2020

Study Registration Dates

• First Submitted: April 28, 2017
• First Submitted That Met QC Criteria: May 4, 2017
• First Posted (Actual): May 8, 2017

Study Record Updates

• Last Update Posted (Actual): December 8, 2020
• Last Update Submitted That Met QC Criteria: December 4, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic
• Other Study ID Numbers: RC16_0474

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