Evaluation of Early Administration of Levetiracetam in the Prevention and Treatment Encephalopathy in Septic Shock: Randomized, Double-blind, Placebo-controlled Trial (KiSS)

Evaluation de l'Administration précoce de lévétiracétam Dans la prévention et le Traitement de l'encéphalopathie au Cours du Choc Septique : Essai randomisé, en Double Aveugle, contrôlé Par Placebo

Sepsis-associated encephalopathy is associated with high mortality rates and long-term neuropsychiatric disorders. Currently, there is no specific treatment for sepsis-associated encephalopathy. Levetiracetam, a broad-spectrum antiepileptic widely used in intensive care units, has neuroprotective properties. We propose the KiSS study, a multicenter, prospective, randomized, double-blind trial with two arms, evaluating the effect of levetiracetam treatment for seven days during septic shock on the occurrence and duration of sepsis-associated encephalopathy.

Study Overview

• Status: Not yet recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Levetiracetam IV; Other: Placebo control

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jérôme Lambert, MD PhD; Phone Number: +33 0142499742; Email: jerome.lambert@u-paris.fr
• Study Contact Backup: Name: Shidasp Siami, MD; Phone Number: +33 160807940; Email: shidasp.siami@ch-sudessonne.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria :

• Aged 18 years or older
• Hospitalized in intensive care for less than 96 hours

• Presenting with septic shock evolving for less than 24 hours defined by:

  1. Clinically or microbiologically documented infection and
  2. SOFA score ≥ 2 or an increase in SOFA score ≥ 2 points if organ dysfunction was present before the infection and
  3. Need for vasopressor administration to maintain a mean arterial pressure ≥ 65mmHg and
  4. Lactate level > 2mmol/L (18mg/dL) despite adequate fluid resuscitation
• Patient's consent, their next of kin consent, or emergency inclusion

Non inclusion criteria :

• Chronic long-term antiepileptic treatment upon admission or patient with uncontrolled seizures
• Chronic or progressive central neurological pathologies of traumatic, inflammatory, vascular, infectious, neoplastic, or degenerative origin, defined by cognitive impairments preventing independent living or an IQCODE score > 4.5
• Patient with moderate to severe dementia
• Patient with psychiatric history and/or suicide attempts
• Severe head trauma within the past 3 months
• Patients with limitations on active therapies or for whom therapeutic commitment is not maximal
• Patient presenting a prolonged QTc interval on ECG and/or at risk of cardiovascular disease
• Concomitant treatment with Methotrexate during the administration of the investigational treatment
• Allergy to levetiracetam
• Minor patients
• Ongoing pregnancy (blood or urinary βHCG)
• Breastfeeding women
• Patients under guardianship or trusteeship
• Non-affiliation with social security or CMU
• Participation in another interventional trial with a drug that may interact with levetiracetam or may impact the evaluation of KiSS trial outcomes. In case of doubt, please contact the trial's coordinating investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo control	Other: Placebo control; NaCl 0.9% sodium chloride in the same route and method of administration as experimental treatment
Experimental: Early Levetiracetam administration	Drug: Levetiracetam IV; 1000 mg twice a day during 7 days maximum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of days alive without delirium or coma	14 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		At day 90
Mortality in intensive care		At day 28
Mortality in intensive care		At day 90
Mortality in hospital		At day 28
Mortality in hospital		At day 90
Duration of mechanical ventilation		At day 28
Length of stay in intensive care unit		Up to day 90
Length of stay in hospital		Up to day 90
Occurrence of epileptic seizures	From Day 1 to Day 14 (confirmed by EEG or tonic-clonic seizures) and/or occurrence of epileptic abnormalities (periodic epileptic discharges)	Up to day 14
Time between cessation of sedation and awakening	Defined by spontaneous eye opening, among patients not deceased under sedation	At day 90
Severity of cognitive impairment	Evaluated by a telephone survey using Telephone MoCA (Montreal Cognitive Assessment). The scores ranges from 0 to 30. A score of 26 or higher is typically considered normal. A score of 25 or lower may indicate cognitive impairment, such as mild cognitive impairment (MCI) or early-stage dementia.	At day 90
Severity of anxiety and depression	Assessed with HADS (Hospital Anxiety and Depression Scale) scale Score varies from 0 to 21 for each componant (Anxiety and depression) The higher the score, the more severe the anxiety or depression.	At day 90
Presence of post-traumatic stress (PTSD)	Assessed by IES-R (Impact of Event Scale Revisited) The total score can range from 0 to 88. Higher scores indicate greater trauma-related distress and a higher likelihood of experiencing PTSD symptoms.	At day 90
Quality of life scoring	Using EQ-5D-5L. It evaluates five dimensions : mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension has five levels : no problems, slight problems, moderate problems, severe problems and extreme problems. Answers are given on a 5-point scale by domain, the higher the score, the poorer the quality of life.	At day 90
Autonomy in daily life	Using Katz Index of Independence in Activities of Daily Living (ADL) The score varies from 0 to 6, the lower the score, the more dependent the person.	At day 90

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): March 15, 2025
• Primary Completion (Estimated): June 15, 2027
• Study Completion (Estimated): June 15, 2027

Study Registration Dates

• First Submitted: February 24, 2025
• First Submitted That Met QC Criteria: February 24, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 10, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic; Anticonvulsants; Nootropic Agents; Levetiracetam
• Other Study ID Numbers: APHP200068

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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