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KetAmine and Recovery After Mechanical VentilAtion ( KARMA ) (KARMA)

13 maja 2026 zaktualizowane przez: Assistance Publique - Hôpitaux de Paris

Intensive Care Treatment With Adjuvant KetAmine and Recovery After Mechanical ventilAtion: a Multicenter Doubleblind Randomized Controlled Trial.

Invasive mechanical ventilation of critically ill patients in the intensive care unit (ICU) is associated with significant morbidity and mortality, as well as a severe prognosis in survivors, in terms of functional, psychological, and cognitive sequelae. During the initial phase, invasive mechanical ventilation aims to promote oxygenation and reduce respiratory effort, with most patients receiving continuous intravenous sedation comprising gamma-aminobutyric acid (GABA) agonists (propofol, midazolam), and opioids. This continuous intravenous sedation is associated with complications, particularly hemodynamic issues (e.g., hypotension, vasopressor dependency), and neurological concerns (e.g., coma, delayed awakening, withdrawal syndrome upon discontinuation of sedation) during the acute phase and is linked to prolonged mechanical ventilation and long-term neurocognitive sequelae.

The use of ketamine as an alternative sedative agent in ICU has garnered considerable attention in recent years. Ketamine has a rapid onset of action and a short duration of effect, potentially beneficial bronchodilatory effects, and minimal impact on hemodynamics or respiratory drive. It also provides effective analgesia. Due to its action on N-methyl-D-aspartate (NMDA) glutamatergic receptors, its mechanism of action differs from other commonly used agents such as propofol and benzodiazepines. Furthermore, emerging research suggests that ketamine may have anti-inflammatory/immunomodulatory and neuroprotective properties that could be advantageous in critically ill patients.

Recent observational studies utilizing low-dose ketamine have suggested an improvement in neurological complications in ICU (e.g., coma, delirium) while other authors have raised concerns about potential renal and hepatic toxicity associated with high doses of ketamine used for sedation. Despite its increasing use, there is currently a lack of high-quality data on the efficacy and safety of ketamine use for sedation in critically ill patients.

In this trial, we hypothesise that, critically ill patients requiring unplanned invasive mechanical ventilation, adjunctive treatment with low dose of ketamine will translate into better outcomes, with higher numbers of days alive outside of the hospital.

The study is a multicenter, randomised, double-blinded placebo-controlled superiority trial involving adult patients requiring unplanned mechanical ventilation, and sedation for more than 6 hours in the ICU. Patients will be randomised within 48 hours following initiation of mechanical ventilation adhering to a 1:1 allocation of ketamine or placebo.

Patients will be randomized to receive either intravenous ketamine or placebo as an adjunctive sedative agent during ICU stay for a maximum duration of 14 days.

Follow-up visits will be performed at day 3, day 14, ICU discharge, day 60, and day 90 after randomization.

The primary endpoint, "days alive and at home," will be assessed at day 60. The end of the research visit is the day 90 follow-up visit. If the patient has been discharged from the hospital, the day-90 visit will consist of telephone contact with the patient by a centralized research assistant and he also will complete the scales at D90.

Data collected by phone consist in Vital status, scales's results and Retrieval of Adverse Events if the patient has been discharged home or with the medical team of the healthcare structure if the patient has been discharged to another structure.

Przegląd badań

Status

Jeszcze nie rekrutacja

Warunki

Interwencja / Leczenie

Szczegółowy opis

Phase III study Prospective, multicenter, superiority, double-blind, randomized controlled study with two arms (1:1).

The study includes a screening/baseline visit (V0), followed by daily assessments during the intervention period (V1 to V4), and post-discharge (V5) follow-up visits at Day 60 (V6) and Day 90 (V7).

At screening and baseline (within 48 hours prior to Day 1), eligibility is confirmed, and informed consent is obtained when possible. In cases where prior consent cannot be obtained, deferred consent procedures are applied in accordance with French legislation. Baseline data include medical history, comorbidities, concomitant treatments, clinical examination, and pregnancy testing when applicable.

Randomization is performed at Day 1 (V1). From Day 1 to Day 14 (V4), patients will be receive either intravenous ketamine or placebo as an adjunctive sedative agent during ICU stay for a maximum duration of 14 days.

Until ICU discharge (V5), patients undergo daily assessments including clinical examination, vital status, organ dysfunction (Sequential Organ Failure Assessment [SOFA] score), At Day 14 (V4), opioid and sedative consumption during the treatment period will be quantified.

At Day 60 (V6), ventilator-free days and vasopressor-free days will be assessed.

Duration of delirium and coma are assessed using the RASS/CAM-ICU, at V 4, during the first 14 days following randomization.

Biological monitoring includes daily measurement of serum creatinine and liver function parameters (ASAT, ALAT, gamma-GT, and bilirubin) to evaluate potential renal and hepatic toxicity. Adverse events are collected throughout the ICU stay, and assessed at Day 60 (V6) At ICU discharge (V5), a clinical evaluation and morbidity/mortality assessment are performed if the patient is still hospitalized.

The primary endpoint-the number of days alive and at home-is assessed at Day 60. Secondary outcomes, including mortality (all-cause deaths), are assessed at both Day 60 (V6) and Day 90(V7).

Typ studiów

Interwencyjne

Zapisy (Szacowany)

640

Faza

  • Faza 3

Kontakty i lokalizacje

Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.

Kontakt w sprawie studiów

Kopia zapasowa kontaktu do badania

Lokalizacje studiów

  • Francja
      • Paris, Francja, 75018
        • Department of Intensive Care Medicine, APHP.Nord, hôpital Bichat Claude Bernard,
        • Kontakt:

Kryteria uczestnictwa

Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.

Kryteria kwalifikacji

Wiek uprawniający do nauki

  • Dorosły
  • Starszy dorosły

Akceptuje zdrowych ochotników

Nie

Opis

Inclusion Criteria :

  1. Patients over 18 years of age
  2. Signed informed consent or inclusion under the emergency provisions of the law (ArticleL1122 -1-3 of the PHC / modified by Order n°2016-800 of June 16 2016 - art. 2)
  3. Need for unplanned invasive mechanical ventilation
  4. Need for continuous intravenous sedative agents (propofol, midazolam or dexmedetomidine) for more than 6 hours.
  5. Affiliation to a social security system (excluding "Aide Médicale d'Etat" [AME])

Exclusion Criteria

  1. Refusal to participate in the study
  2. Acute brain injuries (i.e. acute stroke, traumatic brain injury, cardiac arrest, brain infections) or conditions (status epilepticus or coma with suspected/confirmed intracranial hypertension at admission requiring deep sedation)
  3. Psychosis
  4. Status asthmaticus
  5. Current liver failure with Model for End-Stage Liver Disease (MELD) > 30
  6. Initiation of mechanical ventilation > 48 hours
  7. Expected lifespan < 24 hours
  8. Patients already receiving a continuous infusion of ketamine
  9. Currently participating in another interventional clinical trial investigating sedation or protocols using Ketamine or another drug which may interact with Ketamine or which may have an impact on the evaluation of the trial's judgement criteria.
  10. Positive highly sensitive pregnancy test
  11. Persons deprived of liberty
  12. Persons on a protective judicial measure
  13. Breastfeeding
  14. Severe arterial hypertension (mean arterial pressure>130 mmHg) despite treatment
  15. Hypersensitivity to the active substances or any of the excipients
  16. Known contraindications to ketamine according to the SmPC (Severe heart failure, history of stroke, severe uncontrolled hypertension, severe aneurysmal disease, pheochromocytoma)

Plan studiów

Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.

Jak projektuje się badanie?

Szczegóły projektu

  • Główny cel: Leczenie
  • Przydział: Randomizowane
  • Model interwencyjny: Przydział równoległy
  • Maskowanie: Podwójnie

Broń i interwencje

Grupa uczestników / Arm
Interwencja / Leczenie
Aktywny komparator: Intervention group

Ketamine will be started at a dose of 0.2 mg/kg/hour for 4 hours and then adjusted as necessary (+/-0.1 mg/kg/hour every 4 hours) from 0 to 0.6 mg/kg/hour to maintain a targeted RASS of -1 to 0, in addition to standard per local sedation and pain protocols.

Duration of treatment: 14 days in maximum
Lek: Intervention Group
Ketamine ® is supplied in 250 mg/5 ml vials containing sterile solution for dilution in sodium chlorure 0.9% for infusions.
Komparator placebo: Control group

Intravenous placebo will be started at a dose of 0.2 mg/kg/hour for 4 hours and adjusted as necessary (+/-0.1 mg/kg/hour every 4 hours) from 0 to 0.6 mg/kg/hour to maintain a targeted RASS of -1 to 0, in addition to standard sedation per local protocol.

Duration of treatment : 14 days in maximum
Lek: Placebo
Placebo : NaCl 0.9% (vials)

Co mierzy badanie?

Podstawowe miary wyniku

Miara wyniku
Opis środka
Ramy czasowe
Number of days patients are alive and spent at home
Ramy czasowe: At 60 days after ketamine initiation
This endpoint will be collected by an independent research assistant, blinded to randomization groups, , and not involved in data monitoring onsite.
At 60 days after ketamine initiation

Miary wyników drugorzędnych

Miara wyniku
Opis środka
Ramy czasowe
Number of days alive free of encephalopathy
Ramy czasowe: During 14 days after randomization
Number of days spent alive without coma or delirium measured on the CAM-ICU
During 14 days after randomization
number of days spent alive without invasive mechanical ventilation
Ramy czasowe: At day 60
ventilation-free days
At day 60
Number of days spent alive without infusion norepinephrine infusion during ICU stay
Ramy czasowe: At day 60
Vasopressors-free days
At day 60
Mortality
Ramy czasowe: At Day 60 et Day 90
Defined by the prevalence of all-cause deaths
At Day 60 et Day 90
Renal toxicity,
Ramy czasowe: At Day 60
Defined by the proportion of patients with a KDIGO stage ≥2
At Day 60
Liver toxicity
Ramy czasowe: At Day 60
Defined by the highest bilirubin and phosphatase alkaline level
At Day 60
Quantification of opioid and sedative consumption
Ramy czasowe: Within the 14 days after randomization
During the treatment period, in each arms during the first 14 days
Within the 14 days after randomization
Mean daily pain (BPS)
Ramy czasowe: During the first 14 days after randomisation
Mean daily Behavioral Pain Scale (BPS) score assessed during the first 14 days.
During the first 14 days after randomisation
Cumulative incidence of hallucination events
Ramy czasowe: During 14 days after randomization
During 14 days after randomization
Mean daily sedation score (RASS)
Ramy czasowe: During the first 14 days after randomisation
Mean daily Richmond Agitation-Sedation Scale (RASS) score assessed during the first 14 days.
During the first 14 days after randomisation

Inne miary wyników

Miara wyniku
Opis środka
Ramy czasowe
Presence of anxiety and depression, defined by a score ≥11 on the anxiety and depression components of the Hospital Anxiety and Depression scale, respectively at 90 days;
Ramy czasowe: At Day 90

Defined by a score ≥11 on the anxiety and depression components of the Hospital Anxiety and Depression scale, respectively .

This outcome will be reported in an ancillary analysis separated from the main report of the trial.
At Day 90
Acute posttraumatic stressdisorder (PTSD)-related
Ramy czasowe: . At Day 90
Measured on the ICU memory tool. This outcomes will be reported in an ancillary analysis separated from the main report of the trial
. At Day 90

Współpracownicy i badacze

Tutaj znajdziesz osoby i organizacje zaangażowane w to badanie.

Sponsor

Assistance Publique - Hôpitaux de Paris

Śledczy

  • Główny śledczy: Romain Prof SONNEVILLE, MD-PHD, APHP

Publikacje i pomocne linki

Osoba odpowiedzialna za wprowadzenie informacji o badaniu dobrowolnie udostępnia te publikacje. Mogą one dotyczyć wszystkiego, co jest związane z badaniem.

Publikacje ogólne

Daty zapisu na studia

Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.

Główne daty studiów

Rozpoczęcie studiów (Szacowany)

19 października 2026

Zakończenie podstawowe (Szacowany)

19 grudnia 2029

Ukończenie studiów (Szacowany)

19 stycznia 2030

Daty rejestracji na studia

Pierwszy przesłany

5 maja 2026

Pierwszy przesłany, który spełnia kryteria kontroli jakości

13 maja 2026

Pierwszy wysłany (Rzeczywisty)

15 maja 2026

Aktualizacje rekordów badań

Ostatnia wysłana aktualizacja (Rzeczywisty)

15 maja 2026

Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości

13 maja 2026

Ostatnia weryfikacja

1 maja 2026

Więcej informacji

Terminy związane z tym badaniem

Słowa kluczowe

Dodatkowe istotne warunki MeSH

Inne numery identyfikacyjne badania

  • APHP240938

Informacje o lekach i urządzeniach, dokumenty badawcze

Bada produkt leczniczy regulowany przez amerykańską FDA

Nie

Bada produkt urządzenia regulowany przez amerykańską FDA

Nie

Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .

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