A Multicentric, Drug-Repositioning, Self Controlled Case Series (SCCS) Clinical Trial to Evaluate the Efficacy and Safety of Perampanel in Improving Behavioral Symptoms and Increasing the Quality of Life in Patients with White-Sutton syndrome (POGZ-Related Disorder)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Istituto Di Ricovero E Cura A Carattere Scientifico Materno Infantile Burlo Garofolo

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Genetic Phenomena [G05]

Decision date (initial)

2025-02-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2025-520611-14-00

EudraCT number

2021-001839-77

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary study outcome will be the improvement on the Child Behavior Checklist (CBCL) scores and/or on the Vineland Adaptive Behavior Scales (VABS) scores between before and 6 months after treatment (Figure 1).
The improvement on CBCL is defined as the shifting from ‘Clinical’ to ‘Borderline clinical’ or from ‘Borderline clinical’ to ‘Normal’ in at least one of the CBCL subscales (‘Internalization’, ‘Exteriorization’, ‘Other problems’ and ‘Total’). The improvement on VABS is defined as the shifting from ‘Low’ to ‘Moderately low’ or from ‘Moderately low’ to ‘Normal’) in ate least one of the VABS subscales (among ‘Communication’, ‘Daily living skills’, ‘Socialization’, ‘Motor skills’, or ‘Total’).
Subjects with improvement will continue with the same dosage of Perampanel until month 12, while those with no positive effects will receive a double dosage until month 18

Secondary objectives 7

1. 3.2.1 To evaluate the improvement on the CBCL scores between before and 12 or 18 months after treatment
2. 3.2.2 To evaluate the improvement on the VABS scores between before and 12 or 18 months after treatment
3. 3.2.3 To evaluate the improvement between before and 12 or 18 months after treatment on scores of neuropsychological tests -selected to evaluate cognitive, motor, speech and language, emotion/reciprocal social interaction areas, attention and executive function- as well as on scores from questionnaires for aggressive behavior, quality of life and psychopathology (see ‘Neuropsychological Assessment’, paragraph 10.1.5)
4. 3.2.4 To evaluate the frequency and grade of adverse events (SAFETY ANALYSIS). Patients who will display unacceptable drug-related adverse effects during this first period will interrupt treatment and will be reevaluated at the end of the study (see ‘Discontinuation of Study Treatment’, paragraph n. 8). Adverse events will be classified by CTCAE v5.0 and we will consider to be unacceptable those graded as III or higher.
5. 3.2.5 To investigate the association between the genotype and the therapeutic outcome.
6. 3.2.6 To study epigenetic signature before and during Perampanel treatment.
7. 3.2.7 To collect and analyze molecular and clinical data of POGZ-affected subjects in order to expand the knowledge about this syndromic ID as well as to further investigate the partially detected genotype-phenotype associations. The following data will be collected by means of an eCRF (electronic Case Report Form): personal history: prenatal, neonatal and perinatal life; general medical history; pharmacological history; neurologic, cardiologic, gastroenterological history; other relevant clinical manifestations; dysmorphology features: photos.

Conditions and MedDRA coding

White-Sutton syndrome (POGZ-Related Disorder)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 1. Age: both pediatric and young adult population are eligible. A minimum age of 4 is required; the maximum age limit is 25 years.
2. 2. Gender: male and/or female. All females must have a negative serum beta-human chorionic gonadotropin test result or a negative urine pregnancy test result at baseline. For the evidence reported in pre-clinical results from animal models (http://www.ema.europa.eu) as well as in clinical studies16 (see for details the paragraph n. 10.3.1 about ‘Pregnancy’), following the Clinical Trials Facilitation and Coordination Group (CTFG) 21/09/2020 guidance, Perampanel is supposed to fit the ‘Unlike human teratogenicity/fetotoxicity’ risk category. In this category, women of childbearing potential (WOCBP) included in the clinical trial have to agree to use a medically acceptable method of contraception (eg, abstinence, an intrauterine device, a double barrier method such as condom plus spermicide or condom plus diaphragm with spermicide, a contraceptive implant, an oral contraceptive or have a vasectomized partner) throughout the entire study period and for 30 days after study drug discontinuation. The only female subjects who may be exempted from this requirement are those who have been sterilized surgically or who are otherwise proven sterile (ie, bilateral tubal ligation with surgery at least 6 months prior to dosing, hysterectomy, or bilateral oophorectomy with surgery at least 2 months prior to dosing). All women who are of reproductive potential and who are using hormonal contraceptives will be required to be on a stable dose of the same hormonal contraceptive product for at least 12 weeks prior to the first pregnancy testing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. As the maximum dose of Perampanel for patients enrolled in the study will be 8 mg per day –ie the upper end of the maintenance dose range recommended for the treatment of epilepsy (see paragraph n. 7.1, ‘Study Treatment Administered’) –additional non-hormonal forms of contraception will not be recommended to women on progesterone-containing hormonal contraceptives. Instead, no contraception measures are needed for male subjects included in the clinical trial with pregnant or non-pregnant WOCBP partner
3. 3. Type of Patient and Disease Characteristics: a diagnosis of WHSUS (POGZ-related disorder), defined as a molecular identification of a mutation in POGZ and a clinical diagnosis consistent with a neurodevelopmental disorder. Patients diagnosed with either de novo or familial POGZ mutation are eligible for enrollment.
4. 4. Informed Consent: written consent will be given by the patients if capable or by parent(s)/legal representative if minors or incapable of giving informed consent.

Exclusion criteria 12

1. 1. Medical Conditions: other, concomitant diagnosis of a genetic neurodevelopmental disorder.
2. 2. Severe ID.
3. 3. Epilepsy
4. 4. Pregnancy
5. 5. Prior adverse effect to non-competitive AMPA receptor agonist/Perampanel
6. 6. Contraindication to non-competitive AMPA receptor agonist/Perampanel.
7. 7. Being already in therapy with non-competitive AMPA receptor agonist/Perampanel.
8. 8. Therapy with CYP3A inhibitors (clarithromycin, stiripentol, valproate)/inductors (oral steroids, PHT, CBZ, PB, Primidone), unless there is a proper wash out period before stating treatment with Perampanel
9. 9. History of attempted suicide or suicidal ideation, or current suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS).
10. 10. Other Exclusions: breastfeeding, or intending to conceive during the course of the study.
11. 11. Any condition that in the investigator’s opinion would present an unreasonable risk to the participant.
12. 12. Any participant considered by the investigator unsuitable to receive Perampanel or unable or unlikely to comply with the dosing schedule or the study evaluations.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Evaluation of differences in total CBCL scores, administered before (at baseline) and at month 6, during Perampanel intake at minimum dosage

Secondary endpoints 1

1. Evaluation of differences in scores of all neuropsychological scales administered before (at baseline) and during (at month 12 or 18) Perampanel intake. Recording of: - Medical history; - Clinical features; - Pharmacological history; - Physical examination; - Instrumental evaluation; - Neuropsychological assessment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Istituto Di Ricovero E Cura A Carattere Scientifico Materno Infantile Burlo Garofolo

Sponsor organisation

Istituto Di Ricovero E Cura A Carattere Scientifico Materno Infantile Burlo Garofolo

Address

Via Dell' Istria 65/1

City

Trieste

Postcode

34137

Country

Italy

Scientific contact point

Organisation

Istituto Di Ricovero E Cura A Carattere Scientifico Materno Infantile Burlo Garofolo

Contact name

Paolo Gasparini

Public contact point

Organisation

Istituto Di Ricovero E Cura A Carattere Scientifico Materno Infantile Burlo Garofolo

Contact name

Paolo Gasparini

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications