Clinical trial NCT05210062: Impact of Closely Grouped, Iterative Exposures to Suxamethonium During ECT on the Sensitization to NMBA and the Development of Protective Antibodies
Official title: Impact of Closely Grouped, Iterative Exposures to Suxamethonium During Electroconvulsive Therapy (ECT) on the Sensitization to Neuro-Muscular Blocking Agents (NMBA) and the Development of Protective Antibodies
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Depression
Mania
Hallucinations
Keywords: Electroconvulsive therapy
Depressive disorders
Sensitization
Protective antibodies
Neuro-Muscular Blocking Agents (NMBA)
Suxamethonium
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2022-01-27
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients requiring ECT for psychiatric pathologies that are resistant to medical treatments (particularly depression, mania, hallucinations).

* Phase P (pilot): 10 patients to be included in 1 month with a unique dose. The analysis will be done the following month. The objective is to ennsure the number of patients to include in phase E.
* Phase E (study): 60 patients to be included in 12 months (follow-up care until 6 months) with 5 biological samples: before the first exposure to ECT (S0), after 2 weeks (S2), at 4 weeks (S4), between 6 - 14 weeks (S10) and at 6 months (M6). Only patients having exposed to ECT in the past 10 years will be included in this trial. Grouped analysis shall be done at the end of the study.

Brief summary: Acute per-anesthetic hypersensitivity reaction (HSA-PA) is a rapidly occurring systemic reaction following injection of a drug during anesthesia (mortality between 3 and 9%). The substances responsible for these reactions in France are Neuro-Muscular Blocking Agents (NMBA) in 60% of cases. The main mechanism mentioned is an immediate systemic hypersensitivity immune reaction (anaphylaxis). The mechanism of immunization to NMBA is not yet understood.

Electroconvulsive therapy (ECT) is a long-standing therapeutic approach still widely used today, for its high efficiency, particularly in depressive syndromes resistant to antidepressants. It has an efficacy comparable (or even superior) to pharmacological treatments and improves the mortality associated with this disease. Treatment with iterative ECT sessions includes an attack phase with an average of 12 sessions over 4 weeks, with secondary spacing of sessions before switching to antidepressant treatment. These sessions are carried out in the operating room under general anesthesia, thanks to a hypnotic and a NMBA, suxamethonium, as recently recommended by the French Anesthesiology Society in 2020.

ECT therefore represent an interesting model of iterative exposure of a relatively homogeneous population to a single highly sensitizing substance, which could make it possible to study the evolution of sensitization as a function of various factors, in particular cumulative exposure, for which no data is currently available.

Detailed description: Acute per-anesthetic hypersensitivity reaction (HSA-PA) is a rapidly occurring systemic reaction following injection of a drug during anesthesia (mortality between 3 and 9%). The substances responsible for these reactions are different types of Neuro-Muscular Blocking Agents (NMBA) in 60% of cases. The main mechanism mentioned is an immediate systemic hypersensitivity immune reaction (anaphylaxis). Anaphylactic reactions are classically described as IgE-dependent, triggered by the allergen which, by bridging specific IgE antibodies on the surface of mast cells and basophils, induces a massive release, in particular of histamine, which is responsible for the symptoms. Other immunological mechanisms, in particular by specific IgGs, have been described. The mechanism of immunization to Neuro-Muscular Blocking Agents (NMBA) is not yet understood. The quaternary ammonium group (AQ) is the common epitope of NMBA recognized by IgE. Due to the absence of previous exposure to NMBA reported in 50% of patients with HSA-PA to NMBA, other substances carrying substituted AQ ions are suspected of inducing cross-sensitization, such as household cleaners, cosmetics or drug (pholcodine). However, the sensitizing role of NMBA themselves is not established, and no study has analyzed iterative exposure to Neuro-Muscular Blocking Agents (NMBA) as a sensitizing factor.

Electroconvulsive therapy (ECT) is a long-standing therapeutic approach still widely used today, for its high efficiency, particularly in depressive syndromes resistant to antidepressants. It has an efficacy comparable (or even superior) to pharmacological treatments and improves the mortality associated with this disease. Treatment with iterative ECT sessions includes an attack phase with an average of 12 sessions over 4 weeks, with secondary spacing of sessions before switching to antidepressant treatment. These sessions are carried out in the operating room under general anesthesia, thanks to a hypnotic and a NMBA, suxamethonium, as recently recommended by the French Anesthesiology Society in 2020.

ECT therefore represent an interesting model of iterative exposure of a relatively homogeneous population to a single highly sensitizing substance, which could make it possible to study the evolution of sensitization as a function of various factors, in particular cumulative exposure, for which no data is currently available.

A single patient group is planned in this study, consisting of patients with a medical indication for ECT for psychiatric pathologies resistant to medical treatment (depression, mania, hallucinatory episode in particular). The study will take place in two parts: a preliminary phase "phase P" in 10 patients (with previous exposure to ECT) and a "phase E" study phase in 60 patients. For phase E, only patients with first-time access to ECT or without ECT in the previous ten years will be eligible.

Eligibility criteria: Inclusion Criteria:

* Patient requiring iterative exposure to ECT as part of their psychiatric pathology in one of the investigator center
* Patient who has not had ECT in the last 10 years for the phase E group, regardless of their previous ECT exposure for the phase P group
* Patient who has been informed and has signed the consent form

Exclusion Criteria:

* Absence of written informed consent
* Allergies identified specifically to Neuro-Muscular Blocking Agents (NMBA)
* Patient under tutelage, curatorship or judicial protection
* Patient without social security
* Contraindication to ECT : intracranial hypertension, intracranial lesions without intracranial hypertension, recent episode of cerebral hemorrhage, recent myocardial infarction or embologenic disease, presence of aneurysms or vascular malformations at risk of hemorrhage, retinal detachment, pheochromocytoma, history of ineffective treatment with ECT having had serious side effects, taking anticoagulant treatments

Primary outcomes:
measure: Evaluate the development of specific antibodies against suxamethonium (type IgG4 anti-suxamethonium) after iterative exposure to ECT at 10 weeks.
timeFrame: 10 weeks
measure: Incidence of protective antibodies against suxamethonium assessed by the presence of specific anti-suxamethonium IgG4 antibodies (via ImmunoCAP method) following iterative exposure to ECT after 10 weeks.
timeFrame: 10 weeks
Secondary outcomes:
measure: Evaluate the development of specific IgE antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 2 weeks.
timeFrame: 2 weeks
measure: Evaluate the development of specific IgE antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 4 weeks.
timeFrame: 4 weeks
measure: Evaluate the development of specific IgE antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 10 weeks.
timeFrame: 10 weeks
measure: Evaluate the development of specific IgG antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 2 weeks.
timeFrame: 2 weeks
measure: Evaluate the development of specific IgG antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 4 weeks.
timeFrame: 4 weeks
measure: Evaluate the development of specific IgG antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 10 weeks.
timeFrame: 10 weeks
measure: Evaluate the development of specific IgG4 antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 2 weeks.
timeFrame: 2 weeks
measure: Evaluate the development of specific IgG4 antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 4 weeks.
timeFrame: 4 weeks
measure: Evaluate the development of specific IgG4 antibodies against quaternary ammoniums and suxamethonium after iterative exposure to ECT at 10 weeks.
timeFrame: 10 weeks
measure: Evaluate the evolution of anti-suxamethonium IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 2 weeks.
timeFrame: 2 weeks
measure: Evaluate the evolution of anti-suxamethonium IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 4 weeks.
timeFrame: 4 weeks
measure: Evaluate the evolution of anti-suxamethonium IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 10 weeks.
timeFrame: 10 weeks
measure: Evaluate the evolution of anti-quaternary ammoniums IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 2 weeks.
timeFrame: 2 weeks
measure: Evaluate the evolution of anti-quaternary ammoniums IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 4 weeks.
timeFrame: 4 weeks
measure: Evaluate the evolution of anti-quaternary ammoniums IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 10 weeks.
timeFrame: 10 weeks
measure: Evaluate the evolution of anti-rocuronium IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 2 weeks.
timeFrame: 2 weeks
measure: Evaluate the evolution of anti-rocuronium IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 4 weeks.
timeFrame: 4 weeks
measure: Evaluate the evolution of anti-rocuronium IgE/IgG4 ratio, described as an evaluation factor during desensitization procedures before exposure to ECT at 10 weeks.
timeFrame: 10 weeks
measure: Evaluate the evolution of polarization of memory T cells before and after iterative exposure to ECT at 10 weeks via flow cytometry after re-stimulation with NMBA.
timeFrame: 10 weeks
measure: Evaluate circulating concentrations of tolerogenic factors (IL-10, IL-4, TGF-beta) before the first exposure to ECT.
timeFrame: Week 0
measure: Evaluate circulating concentrations of tolerogenic factors (IL-10, IL-4, TGF-beta) at 10 weeks.
timeFrame: 10 weeks
measure: Evaluate whether iterative exposure induces cross-reactivity against rocuronium by quantitative analysis of anti-rocuronium IgE.
timeFrame: 18 months
measure: Evaluate whether iterative exposure induces cross-reactivity against rocuronium by quantitative analysis of anti-rocuronium IgG.
timeFrame: 18 months
measure: Evaluate the persistence of antibodies (IgE and IgG4 against quaternary ammoniums and suxamethonium) detected at 10 weeks since the last exposure to ECT.
timeFrame: 10 weeks
measure: Evaluate the persistence of antibodies (IgE and IgG4 against quaternary ammoniums and suxamethonium) detected at 6 months since the last exposure to ECT.
timeFrame: 6 months
measure: Describe the antibody profile before exposure to NMBA, and the potential link with previous drug exposures in the previous year of antidepressant, mood stabilizers and anxiolytics.
timeFrame: 18 months
measure: Evaluate the influence of hormonal changes induced by ECT on immunization.
timeFrame: 18 months
measure: Incidence of specific IgE antibodies against quaternary ammonium, suxamethonium and rocuronium at 2 weeks.
timeFrame: 2 weeks
measure: Incidence of specific IgE antibodies against quaternary ammonium, suxamethonium and rocuronium at 4 weeks.
timeFrame: 4 weeks
measure: Incidence of specific IgE antibodies against quaternary ammonium, suxamethonium and rocuronium at 10 weeks.
timeFrame: 10 weeks
measure: Incidence of specific IgE antibodies against quaternary ammonium, suxamethonium and rocuronium at 6 months.
timeFrame: 6 months
measure: Incidence of specific IgG against quaternary ammonium, suxamethonium and rocuronium at 2 weeks.
timeFrame: 2 weeks
measure: Incidence of specific IgG against quaternary ammonium, suxamethonium and rocuronium at 4 weeks.
timeFrame: 4 weeks
measure: Incidence of specific IgG against quaternary ammonium, suxamethonium and rocuronium at 10 weeks.
timeFrame: 10 weeks
measure: Incidence of specific IgG against quaternary ammonium, suxamethonium and rocuronium 6 months.
timeFrame: 6 months
measure: Incidence of specific IgG4 against quaternary ammonium, suxamethonium and rocuronium at 2 weeks.
timeFrame: 2 weeks
measure: Incidence of specific IgG4 against quaternary ammonium, suxamethonium and rocuronium at 4 weeks.
timeFrame: 4 weeks
measure: Incidence of specific IgG4 against quaternary ammonium, suxamethonium and rocuronium at 10 weeks.
timeFrame: 10 weeks
measure: Incidence of specific IgG4 against quaternary ammonium, suxamethonium and rocuronium at 6 months.
timeFrame: 6 months
measure: Levels of specific IgE antibodies against quaternary ammonium, suxamethonium and rocuronium before the ECT session.
timeFrame: 18 months
measure: Levels of specific IgG antibodies against quaternary ammonium, suxamethonium and rocuronium before the ECT session.
timeFrame: 18 months
measure: Levels of specific IgG4 antibodies against quaternary ammonium, suxamethonium and rocuronium before the ECT session.
timeFrame: 18 months
measure: Cytokine profile, particularly pro-tolerogenic, and development of Tregs lymphocytes.
timeFrame: 18 months
measure: Risk factors: number of ECT sessions, exposure to pholcodine before or during the study, occupational exposure to quaternary ammoniums (hairdressers, cleaning agents, beauticians).
timeFrame: 18 months
measure: Exposures of the previous year to antidepressant, mood stabilizers and anxiolytics.
timeFrame: 18 months
measure: Assay of ACTH, cortisol at week 0.
timeFrame: Week 0
measure: Assay of ACTH, cortisol at week 10.
timeFrame: Week 10
Other outcomes:
Locations:
city: Paris
country: France
facility: Saint-Antoine Hospital
Study officials:
affiliation: APHP
name: Aurélie Gouel
role: PRINCIPAL_INVESTIGATOR
References: