A randomized, placebo-controlled trial to assess the efficacy, tolerability, and pharmacokinetics of clemastine in children and adults with Pitt-Hopkins syndrome

INTERVENTION: Product Name: microcrystalline cellulose, Product Code:N/A, Pharmaceutical Form: N/A, Other descriptive name: N/A , Strength: , Pharmaceutical form of the placebo: N/A , Product Name: Tavegyl 1 mg, tabletten, Product Code:PRD8456812, Pharmaceutical Form: TABLET, Other descriptive name: , Strength: CONDITION: Pitt‐Hopkins syndrome ; MedDRA version: 28.0Level: PTClassification code: 10091320Term: Pitt‐Hopkins syndrome Class: 100000004850 Therapeutic area: Diseases [C] ‐ Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To assess the overall treatment effects of clemastine in PTHS, according to caretakers Primary end point(s): Caretaker Global Impression rating scale (CaGI) Secondary Objective: To assess the overall treatment effects of clemastine in PTHS, according to investigators, To assess the tolerability of clemastine in PTHS, To assess the effects of clemastine on behavior and wellbeing in PTHS, To assess the effects of clemastine on physical complaints in PTHS, To assess the effects of clemastine on motor function in PTHS, To assess the neurophysiological effects of clemastine in PTHS, To validate a translational pharmacokinetic/pharmacodynamic (PKPD)‐model of clemastine in patients with PTHS, To perform a health technology assessment (HTA) including trial‐ and model‐based cost‐effectiveness analyses (CEA), To assess the expectations of and experiences with clemastine of parents/caretakers of individuals with PTHS, To perform exploratory PK/PD analyses SECONDARY OUTCOME: Secondary end point(s):Aberrant Behavior Checklist; EuroQol‐5D‐Y‐5L; PROMIS Early Childhood Parent Report v1.0 – Child‐Caregiver Interactions; PROMIS Early Childhood Parent Report v1.0 – Anxiety; PROMIS Early Childhood Parent Report v1.0 – Depressive Symptoms Secondary end point(s):Clinical Global Impression rating scale (CGI) Secondary end point(s):Gross Motor Function Measure (GMFM‐88); Two minute walking test Secondary end point(s):IMTA Medical Consumption Questionnaire (iMCQ); IMTA Productivity Cost Questionnaire (iPCQ) Secondary end point(s):Pharmacokinetic parameters such as maximum concentration (Cmax), area under the concentration‐time curve (AUC), half‐life and predicted trough concentration (Ctrough) at steady state, using nonlinear mixed effects modelling (NONMEM). Secondary end point(s):PROMIS Custom Short Form – Fatigue; Numeric Rating Scale (NRS) – Fatigue Secondary end point(s):PROMIS Early Childhood Parent Report v1.0 ‐ Sleep disturbance; Numeric Rating Scale (NRS) – Sleep; Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms questionnaire, ‘stomach pain and hurt’, ‘heart burn and reflux’, ‘gas and bloating’, and ‘constipation’ scales; Rett‐syndrome Behavior Questionnaire, Breathing Problems (RSBQ‐BP), adapted for PTHS ;Number and type of epileptic seizures during past 30 days Secondary end point(s):Resting‐state electroencephalography (EEG) recording: power spectrum, long term temporal correlations and network level excitation‐inhibition dynamics Secondary end point(s):Semi‐structured, qualitative interviews Secondary end point(s):The relationship between clemastine PK and safety/efficacy‐related biomarkers INCLUSION CRITERIA: A molecularly confirmed diagnosis of PTHS according to the criteria described in the 2019 consensus statement.(Zollino et al. 2019), An age of at least 1.0 years old at the start of the trial., A bodyweight of at least 12.0 kilograms at the start of the trial., Ability of the parents or legally designated representative of the subject to understand the information about trial procedures and requirements., Ability and willingness of the parents or legally designated representative to provide written informed consent for trial participation.