A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children Aged 2-14 Years With Dup15q Syndrome

Study Overview
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Brief Summary
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This study consists of two parts. Part 1 will evaluate the safety, efficacy, and pharmacodynamics of 52-weeks of basmisanil treatment in children and adolescents (aged 2-14 years) with Dup15q syndrome. Part 1 will test the hypothesis that negative allosteric modulation of a GABAA receptor subtype can address excessive receptor function and positively impact core neurodevelopmental disease feature in individuals with Dup15q syndrome. Part 2 is an optional 2-year open-label extension to evaluate long-term safety, tolerability, and to provide supportive evidence of benefit of continued treatment with basmisanil in selected efficacy outcomes.

Official Title
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A Phase II, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety, Efficacy, and Pharmacodynamics of 52 Weeks of Treatment With Basmisanil in Participants Aged 2 to 14 Years Old With Dup15q Syndrome Followed by a 2-Year Optional Open-Label Extension

Conditions
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Dup15q Syndrome

Intervention / Treatment
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* Drug: Basmisanil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented maternal duplication (3 copies) or triplication (4 copies) of the chromosome 15q11.2-q13.1 region that includes the Prader Willi/Angelman critical region defined as [BP2-BP3] segment Dup15q syndrome Clinician Global Impression of Severity scale (Dup15q CGI-S) overall severity score ≥ 4 (at least moderately ill) Body weight equal to or above the third percentile for age Participant has a parent, caregiver, or legally authorized representative (hereinafter caregiver) of at least 18 years of age, who is fluent in the local language at the site, and capable and willing to provide written informed consent for the participant, according to International Council for Harmonisation and local regulations Participant's caregiver must be living with the participant and, in the opinion of the Investigator, able and willing to reliably assess the participant's ongoing condition, to accompany the participant to all clinic visits, and ensure compliance to study treatment throughout the study. The same caregiver is able and willing to complete the caregiver assessments and is available to the Investigational Site by telephone or email if needed Participant's caregiver is able and willing to use electronic devices to record information on the participant's condition and to complete assessments at home and agrees to home nursing visits, if local regulations allow for it and if home nursing service is available in the country/region Exclusion Criteria: Uncontrolled epilepsy at screening (as defined by the protocol) Lymphoma, leukemia, or any malignancy within the past 5 years, except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years Clinically significant ECG abnormalities at Screening Clinically significant abnormalities in laboratory test results at screening (including positive results for HIV, hepatitis B and/or hepatitis C) Allowed prior existing medication should be on a stable regimen (or frequency of intervention) for at least 6 weeks, and at least 8 weeks for anti-epileptic treatment, prior to Screening Non-pharmacological / behavioral therapies should not be stopped or newly started at least 6 weeks prior to Screening and are expected to remain stable for the entire study duration (excluding changes related to standard age and educational interventional programs and minor interruptions such as illness or vacation Concomitant use of prohibited medications Participation in an investigational drug study within one month or within 6 × the elimination half-life, whichever is longer, prior to dosing in the study Significant risk for suicidal behavior, as assessed through the suicidal behavior question adapted from the Columbia Classification Algorithm for Suicide Assessment (C-CASA) (participants ≥ 6 years of age only) Known sensitivity to any of the study treatments or components thereof or drug or other allergy that, in the opinion of the Investigator, contraindicates the participation in the study, including severe lactose intolerance (e.g., unable to tolerate 250 mL [8 oz. or 1 cup] of milk, ice cream, or yogurt) Concomitant clinically relevant disease or condition or any clinically significant finding at screening that could interfere with, or for which, the treatment might interfere with, the conduct of the study or that would pose an unacceptable risk to the participants in this study Known active or uncontrolled bacterial, viral, or other infection (excluding fungal infections of nail beds) or any major clinically significant episode of infection or hospitalization (relating to the completion of the course of antibiotics) within 6 weeks prior to the start of drug administration

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Basmisanil<br>Participants will receive oral basmisanil twice daily (BID) on the first day of treatment, then three times per day (TID) until the end of Part 1 of the trial (Day 365) or the end of Part 2 (Day 1095) | Drug: Basmisanil<br>* Participants will receive oral basmisanil at age-appropriate dosages<br>|
| Placebo Comparator: Placebo<br>Participants will receive oral placebo BID on the first day of treatment, then TID until the end of Part 1 of the trial (Day 365). | Drug: Placebo<br>* Participants will receive oral placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vineland-3 adaptive behavior composite scores |  | Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vineland-3 gross and fine motor subdomains scores |  | Up to 52 weeks | 
| Mullen Scales of Early Learning (MSEL) gross and fine motor domains |  | Up to 52 weeks | 
| MSEL visual reception domain scores |  | Up to 52 weeks | 
| Vineland 3 expressive and receptive communication subdomains |  | Up to 52 weeks | 
| MSEL expressive and receptive language subdomains |  | Up to 52 weeks | 
| Vineland-3 play and leisure time and interpersonal relationships subdomains |  | Up to 52 weeks | 
| Dup15q syndrome Clinician Global Impression of Severity (CGI-S) scale scores |  | Up to 52 weeks | 
| Dup15q syndrome Clinician Global Impression of Change scale (CGI-C) scores |  | Up to 52 weeks | 
| Aberrant Behavior Checklist - Second Edition - Community Version (ABC-2-C) domain scores |  | Up to 52 weeks | 
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Up to 52 weeks | 
| Incidence of treatment discontinuations due to AEs |  | Up to 52 weeks | 
| Incidence of laboratory abnormalities based on hematology, clinical chemistry, and urinalysis test results |  | Up to 52 weeks | 
| ECG QTc interval changes from baseline |  | Up to 52 weeks | 
| Incidence of abnormal electrocardiogram (ECG) assessments |  | Up to 52 weeks | 
| Change from baseline in seizure frequency, duration, and type |  | Up to 52 weeks | 
| Abnormal changes in EEG recordings compared to baseline with a focus on treatment-emergent epileptiform abnormalities |  | Up to 52 weeks | 
| Systolic and diastolic blood pressure measurements |  | Up to 52 weeks | 
| Heart rate measurements |  | Up to 52 weeks | 
| Suicidality as assessed through questions from selected items adapted from the Columbia Classification Algorithm for Suicide (C-CASA) in participants aged 6 years and above |  | Up to 52 weeks | 
| Height in meters (m) |  | Up to 52 weeks | 
| Weight in kilograms (kg) |  | Up to 52 weeks | 
| Head circumference in centimeters (cm) |  | Up to 52 weeks | 
| Tanner staging over time in participants aged 9 years and above |  | Up to 52 weeks | 
| Plasma concentration of basmisanil |  | Up to 52 weeks | 
| Plasma concentration of the basmisanil metabolite M1 |  | Up to 52 weeks | 
| Area under the concentration-time curve during one dosing interval at steady state (AUCtau,ss) of basmisanil |  | Up to 52 weeks | 
| Maximum concentration at steady state (Cmax,ss) of basmisanil |  | Up to 52 weeks | 
| Trough plasma concentration at steady state (Ctrough, ss) of basmisanil |  | Up to 52 weeks | 
| Apparent clearance (CL/F) of basmisanil |  | Up to 52 weeks | 
| Apparent volume of distribution (Vd/F) of basmisanil |  | Up to 52 weeks | 
| Plasma concentration ratio of M1 to basmisanil at trough |  | Up to 52 weeks | 
| Cmax,ss of M1 |  | Up to 52 weeks | 
| Ctrough, ss of M1 |  | Up to 52 weeks | 
| Quantitative EEG (qEEG) beta-band power |  | Up to 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dup15q, dup15q syndrome, 15q, duplication 15q, 15q duplication, chromosome 15q duplication, 15q duplication syndrome, duplication 15, triplication 15