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

• ClinicalTrials.gov Identifier: NCT05307679
• Recruitment Status: Terminated
• First Posted: April 1, 2022
• Last Update Posted: May 15, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Dup15q Syndrome	Drug: Basmisanil; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 16, 2022
• Actual Primary Completion Date: March 4, 2024
• Actual Study Completion Date: March 4, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Basmisanil; 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; Participants will receive oral basmisanil at age-appropriate dosages
Placebo Comparator: Placebo; 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; Participants will receive oral placebo

Outcome Measures

Primary Outcome Measures :

1. Vineland-3 adaptive behavior composite scores [ Time Frame: Up to 52 weeks ]

Secondary Outcome Measures :

1. Vineland-3 gross and fine motor subdomains scores [ Time Frame: Up to 52 weeks ]
2. Mullen Scales of Early Learning (MSEL) gross and fine motor domains [ Time Frame: Up to 52 weeks ]
3. MSEL visual reception domain scores [ Time Frame: Up to 52 weeks ]
4. Vineland 3 expressive and receptive communication subdomains [ Time Frame: Up to 52 weeks ]
5. MSEL expressive and receptive language subdomains [ Time Frame: Up to 52 weeks ]
6. Vineland-3 play and leisure time and interpersonal relationships subdomains [ Time Frame: Up to 52 weeks ]
7. Dup15q syndrome Clinician Global Impression of Severity (CGI-S) scale scores [ Time Frame: Up to 52 weeks ]
8. Dup15q syndrome Clinician Global Impression of Change scale (CGI-C) scores [ Time Frame: Up to 52 weeks ]
9. Aberrant Behavior Checklist - Second Edition - Community Version (ABC-2-C) domain scores [ Time Frame: Up to 52 weeks ]
10. Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 52 weeks ]
11. Incidence of treatment discontinuations due to AEs [ Time Frame: Up to 52 weeks ]
12. Incidence of laboratory abnormalities based on hematology, clinical chemistry, and urinalysis test results [ Time Frame: Up to 52 weeks ]
13. ECG QTc interval changes from baseline [ Time Frame: Up to 52 weeks ]
14. Incidence of abnormal electrocardiogram (ECG) assessments [ Time Frame: Up to 52 weeks ]
15. Change from baseline in seizure frequency, duration, and type [ Time Frame: Up to 52 weeks ]
16. Abnormal changes in EEG recordings compared to baseline with a focus on treatment-emergent epileptiform abnormalities [ Time Frame: Up to 52 weeks ]
17. Systolic and diastolic blood pressure measurements [ Time Frame: Up to 52 weeks ]
18. Heart rate measurements [ Time Frame: Up to 52 weeks ]
19. 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 [ Time Frame: Up to 52 weeks ]
20. Height in meters (m) [ Time Frame: Up to 52 weeks ]
21. Weight in kilograms (kg) [ Time Frame: Up to 52 weeks ]
22. Head circumference in centimeters (cm) [ Time Frame: Up to 52 weeks ]
23. Tanner staging over time in participants aged 9 years and above [ Time Frame: Up to 52 weeks ]
24. Plasma concentration of basmisanil [ Time Frame: Up to 52 weeks ]
25. Plasma concentration of the basmisanil metabolite M1 [ Time Frame: Up to 52 weeks ]
26. Area under the concentration-time curve during one dosing interval at steady state (AUCtau,ss) of basmisanil [ Time Frame: Up to 52 weeks ]
27. Maximum concentration at steady state (Cmax,ss) of basmisanil [ Time Frame: Up to 52 weeks ]
28. Trough plasma concentration at steady state (Ctrough, ss) of basmisanil [ Time Frame: Up to 52 weeks ]
29. Apparent clearance (CL/F) of basmisanil [ Time Frame: Up to 52 weeks ]
30. Apparent volume of distribution (Vd/F) of basmisanil [ Time Frame: Up to 52 weeks ]
31. Plasma concentration ratio of M1 to basmisanil at trough [ Time Frame: Up to 52 weeks ]
32. Cmax,ss of M1 [ Time Frame: Up to 52 weeks ]
33. Ctrough, ss of M1 [ Time Frame: Up to 52 weeks ]
34. Quantitative EEG (qEEG) beta-band power [ Time Frame: Up to 52 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 14 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90010

Rady Children's Hospital - San Diego

San Diego, California, United States, 92123

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612-3244

United States, North Carolina

University of North Carolina At Chapel Hill

Chapel Hill, North Carolina, United States, 27514

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37212

Poland

Uniwersytecki Szpital Kliniczny w Poznaniu; Od. Kliniczny Neurologii Dzieci i M?odziezy

Pozna?, Poland, 60-355

Portugal

CHULC, E.P.E. - Hospital Dona Estefania; Servico de Neuropediatria

Lisboa, Portugal, 1169-045

Spain

Hospital Sant Joan De Deu

Esplugues De Llobregas, Barcelona, Spain, 08950

Hospital Universitario La Paz; Servicio de Neurologia

Madrid, Spain, 28046

Hospital Universitario Virgen del Rocío

Sevilla, Spain, 41013

United Kingdom

Evelina London Children's Hospital

London, United Kingdom, SE1 7EH

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

Additional Information:

https://forpatients.roche.com/ 

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT05307679
• Other Study ID Numbers: BP42992
• First Posted: April 1, 2022
• Last Update Posted: May 15, 2024
• Last Verified: May 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hoffmann-La Roche:

dup15q; dup15q syndrome; 15q; duplication 15q; 15q duplication; chromosome 15q duplication; 15q duplication syndrome; duplication 15; triplication 15

Additional relevant MeSH terms:

Syndrome; Disease; Pathologic Processes