Perampanel for White-Sutton syndrome (POGZ-related disorder)

Inclusion criteria

• {"criterion_text":"- 1.\tAge: both pediatric and young adult population are eligible. A minimum age of 4 is required; the maximum age limit is 25 years.\n- 2.\tGender: 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\n- 3.\tType 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.\n- 4.\tInformed 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

• {"criterion_text":"- 1.\tMedical Conditions: other, concomitant diagnosis of a genetic neurodevelopmental disorder.\n- 10.\tOther Exclusions: breastfeeding, or intending to conceive during the course of the study.\n- 11.\tAny condition that in the investigator’s opinion would present an unreasonable risk to the participant.\n- 12.\tAny participant considered by the investigator unsuitable to receive Perampanel or unable or unlikely to comply with the dosing schedule or the study evaluations.\n- 2.\tSevere ID.\n- 3.\tEpilepsy\n- 4.\tPregnancy\n- 5.\tPrior adverse effect to non-competitive AMPA receptor agonist/Perampanel\n- 6.\tContraindication to non-competitive AMPA receptor agonist/Perampanel.\n- 7.\tBeing already in therapy with non-competitive AMPA receptor agonist/Perampanel.\n- 8.\tTherapy 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\n- 9.\tHistory of attempted suicide or suicidal ideation, or current suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)."}

Primary endpoints

• {"endpoint_text":"- Evaluation of differences in total CBCL scores, administered before (at baseline) and at month 6, during Perampanel intake at minimum dosage","definition_or_measurement_approach":"Difference in total CBCL scores between baseline and month 6 during Perampanel intake at minimum dosage. Improvement on CBCL is defined in the protocol as 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’)."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Differences in scores of neuropsychological scales between baseline and month 12 or 18 during Perampanel intake. Recording of the listed clinical and assessment data as part of outcome measurement."}

Other endpoints

• {"endpoint_text":"- 3.2.1\tTo evaluate the improvement on the CBCL scores between before and 12 or 18 months after treatment\n- 3.2.2\tTo evaluate the improvement on the VABS scores between before and 12 or 18 months after treatment\n- 3.2.3\tTo 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)\n- 3.2.4\tTo 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.\n- 3.2.5\tTo investigate the association between the genotype and the therapeutic outcome.\n- 3.2.6\tTo study epigenetic signature before and during Perampanel treatment.\n- 3.2.7\tTo 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.","definition_or_measurement_approach":"Various exploratory and secondary analyses as described: long-term CBCL and VABS changes at 12/18 months; collection and analysis of neuropsychological test scores, safety analysis using CTCAE v5.0 (grade frequency), genotype-phenotype association studies, and epigenetic signature analysis; data collection via eCRF as listed."}

Italy

Earliest CTIS Part Ii Submission Date

13-01-2025

Latest Decision Or Authorization Date

03-11-2025

Processing Time Days

294

Number Of Sites

2

Number Of Participants

41

Primary sponsor

Full Name

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

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy