Stratifying Psychoses for Personalized REpetitive TMS in Persistent NEgative Symptoms Alleviation

NCT ID: NCT06184165

Last Updated: 2023-12-28

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

NA

Total Enrollment

160 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-03-01

Study Completion Date

2028-11-01

Brief Summary

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In its 2012's release guideline on therapy for schizophrenia, the EMA joined the FDA to acknowledge primary and persistent negative symptoms (PNS) as an unmet need in the treatment of schizophrenia. Functional brain imaging studies showed a correlation between NS and reduced perfusion in the left dorsolateral prefrontal cortex (L-DLPFC). Pre-frontal activation (PFA) using repetitive transcranial magnetic stimulation (rTMS) significantly improve PNS (meta-analyses: effect size SMD = 0.55, ΔPANSS-N = -2.5). Yet schizophrenia is likely to gather many different natural entities of distinct pathophysiological mechanisms. Pursuing a one-size-fits-all approach will not adapt to this diversity and might account for inconsistencies in the results.

Progressive periodic catatonia (PPC) is a rare psychotic phenotype (0.1 - 0.5 ‰) which has been shown to be longitudinally stable (30-years follow-up) and consistent within families (about 1 third of first-degree relatives are affected). The core of this phenotype is a disintegration of psychomotor processes which progresses with each relapse, resulting in a "deficit state", i.e., PNS, responsible for most social and occupational disabilities. The investigators and others reported PPC to come with hyper-perfusions in premotor cortices compared to controls or non-PPC chronic psychoses (nPPC). These hyper-perfusions discriminate PPC from nPPC or depressive patients (Sensitivity = 82%; Specificity = 95%). Last, in independent proof-of-principle studies the investigators and others have shown that premotor inhibition (PMI) using rTMS significantly improved PNS in PPC and that the most dramatic improvements followed personalized accelerated rTMS protocols (5 days of rTMS; CGI-improvement = 2 which is equivalent to ΔPANSS-N = -10; lasting \> 1 month - vs virtually no change for PFA). The efficacy index was very good (no side effects).

the investigators hypothesize that: (1) in PPC, add-on personalized premotor inhibition (PMI) is more effective in reducing PNS than L-DLPFC activation (PFA); (2) patient stratification is relevant as personalized PMI will not be as effective in the nPPC group (even expected to be less effective than PFA).

Detailed Description

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Conditions

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Schizophrenia Persistent Negative Symptoms Progressive Periodic Catatonia Aviation Apathy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors
Informants (caregivers)

Study Groups

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N°1: PMI in PPC

Progressive periodic catatonia (SSD phenotype) Premotor inhibition using personalized rTMS (40 sec continuous theta-burst on each of the 5 targets corresponding to hyper-perfused regions, i.e. functional biomarker, 120%).

N = 40.

Group Type EXPERIMENTAL

Personalized rTMS

Intervention Type PROCEDURE

5 "personalized" targets accessible to TMS (at less than 3.5 cm distance from the scalp or the coil's hot spot) are placed in the hyper-perfused premotor regions.

The patient is installed on the robotic device. The technician puts a neuro-navigation tracker on the subject's forehead and proceeds to the co-registration. The motor threshold is defined, and stimulator output's intensity is adjusted accordingly (120%) The robotic system ensures that the actual stimulation is performed according to the personalized protocol. This adequacy will be evaluated secondarily based on the recordings of the coil positions during each

N°2: PFA in PPC

Progressive periodic catatonia (SSD phenotype) Classical left-prefrontal activation using intermittent theta-burst rTMS (72 trains, 120%).

N = 40.

Group Type ACTIVE_COMPARATOR

Personalized rTMS

Intervention Type PROCEDURE

5 "personalized" targets accessible to TMS (at less than 3.5 cm distance from the scalp or the coil's hot spot) are placed in the hyper-perfused premotor regions.

The patient is installed on the robotic device. The technician puts a neuro-navigation tracker on the subject's forehead and proceeds to the co-registration. The motor threshold is defined, and stimulator output's intensity is adjusted accordingly (120%) The robotic system ensures that the actual stimulation is performed according to the personalized protocol. This adequacy will be evaluated secondarily based on the recordings of the coil positions during each

N°3: PMI in nPPC

Other phenotype of SSD than PPC (nPPC) Premotor inhibition using personalized rTMS (40 sec continuous theta-burst on each of the 5 targets corresponding to most perfused premotor regions).

N = 40.

Group Type ACTIVE_COMPARATOR

Personalized rTMS

Intervention Type PROCEDURE

5 "personalized" targets accessible to TMS (at less than 3.5 cm distance from the scalp or the coil's hot spot) are placed in the hyper-perfused premotor regions.

The patient is installed on the robotic device. The technician puts a neuro-navigation tracker on the subject's forehead and proceeds to the co-registration. The motor threshold is defined, and stimulator output's intensity is adjusted accordingly (120%) The robotic system ensures that the actual stimulation is performed according to the personalized protocol. This adequacy will be evaluated secondarily based on the recordings of the coil positions during each

N°4: PFA in nPPC

Non-progressive periodic catatonia SSD phenotype Classical left-prefrontal activation (PFA) using intermittent theta-burst rTMS (72 trains, 120%).

N = 40.

Group Type EXPERIMENTAL

Personalized rTMS

Intervention Type PROCEDURE

5 "personalized" targets accessible to TMS (at less than 3.5 cm distance from the scalp or the coil's hot spot) are placed in the hyper-perfused premotor regions.

The patient is installed on the robotic device. The technician puts a neuro-navigation tracker on the subject's forehead and proceeds to the co-registration. The motor threshold is defined, and stimulator output's intensity is adjusted accordingly (120%) The robotic system ensures that the actual stimulation is performed according to the personalized protocol. This adequacy will be evaluated secondarily based on the recordings of the coil positions during each

Interventions

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Personalized rTMS

5 "personalized" targets accessible to TMS (at less than 3.5 cm distance from the scalp or the coil's hot spot) are placed in the hyper-perfused premotor regions.

The patient is installed on the robotic device. The technician puts a neuro-navigation tracker on the subject's forehead and proceeds to the co-registration. The motor threshold is defined, and stimulator output's intensity is adjusted accordingly (120%) The robotic system ensures that the actual stimulation is performed according to the personalized protocol. This adequacy will be evaluated secondarily based on the recordings of the coil positions during each

Intervention Type PROCEDURE

Eligibility Criteria

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Inclusion Criteria

* 18-70 years of age; affiliated to health insurance; superior or equal to B2 level of linguistic competency in French.
* Suffering from schizophrenia spectrum disorder (SSD) in residual state with persistent negative symptoms (PNS): (1) SSD: ICD-11 codes beginning with 6A2 + primary catatonia (codes beginning with 6A4) + simple schizophrenia as defined in ICD-10 (F20.6); (2) PNS: persistence (≥6 months - based on patient ± informant's interview) of ≥2 negative symptoms (PANSS-N1, N2, N3, N4, N6 ≥4) with functional impact.
* Half of subjects having PPC, the other half suffering from another phenotype or nPPC (neuropsychiatric procedure or probabilistic, i.e. Bayes-PPC).
* Under a stable medication regimen for \>6 weeks,
* Subjects who have received the protocol information and signed informed consent.

Exclusion Criteria

* \- Contraindications for MRI or rTMS.
* Motor deficit at neurological examination.
* Secondary negative symptoms: (1) withdrawal secondary to severe anxiety (especially due to positive symptoms), (2) depression, (3) maintenance on high dose antipsychotics, (4) extra-pyramidal or (5) sedation side-effects, (6) treatment non-compliance, (7) current substance abuse (except nicotine and caffeine), (8) unsubstituted past opioid addiction, (9) poor health or social condition.
* Under antiepileptic drugs (except lamotrigine and long-term use of benzodiazepines).
* Pregnancy; severe medical condition; care under constraint.
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University Hospital, Strasbourg, France

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Central Contacts

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Jack Foucher, MD

Role: CONTACT

Phone: 03.88.11.69.21

Email: [email protected]

Other Identifiers

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8371

Identifier Type: -

Identifier Source: org_study_id