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
Phase: PHASE2
Conditions: Dup15q Syndrome
Sponsor: Hoffmann-La Roche

 
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 
NCT Number: 
NCT05307679 
Document Date: 
Protocol Version 3: 25-July-2023 
 
 

CONFIDENTIAL 
 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore, is provided to you in confidence as 
an Investigator, potential Investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Basmisanil (RO5186582)—F. Hoffmann-La Roche Ltd 
Protocol BP42992, Version 3 
PROTOCOL 
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 
PROTOCOL NUMBER: 
BP42992 
VERSION: 
3 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  
 
EudraCT Number:  2021-003791-13 
EU Trial Number:  2022-502165-20-00  
Clinical Investigation Identification 
Number (CIV ID):  Not applicable 
TEST PRODUCT: 
Basmisanil (RO5186582) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  29 July 2021 
DATE AMENDED: 
Version 2:  25 January 2022 
Version 3:  See electronic signature and date 
stamp on the final page of this document 

Basmisanil (RO5186582)—F. Hoffmann-La Roche Ltd 
2/Protocol BP42992, Version 3 
PROTOCOL ACCEPTANCE FORM 
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 
PROTOCOL NUMBER: 
BP42992 
VERSION NUMBER: 
3 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  
 
EudraCT Number:  2021-003791-13 
EU Trial Number:  2022-502165-20-00  
Clinical Investigation Identification 
Number (CIV ID):  Not applicable 
TEST PRODUCT: 
Basmisanil (RO5186582) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please keep the signed original form in your study files, and return a copy to your local 
Site Monitor. 
 

RO5186582 (Basmisanil)—F. Hoffmann-La Roche Ltd 
3/Protocol BP42992, Version 3 
PROTOCOL AMENDMENT, BP42992 VERSION 3 
RATIONALE 
Trial readiness in the Dup15q syndrome patients and clinical communities is at an early 
stage. 
 
 
 
 
 
 
 
 
 
. A shift in the clinical development plan 
for basmisanil in Dup15q syndrome, and consequently in the age range of the study 
population in BP42992, is required to generate data for the assessment of basmisanil 
across ages within a reasonable time frame.  
The substantial changes described below thus aim to reduce patient and site burden, 
ease study execution and provide an opportunity for participants to receive active 
treatment in an open label extension (OLE). 
 
 
The following substantial changes have been implemented accordingly in Version 3:  
1. 
Addition of an optional open-label extension (OLE) of 2 years (study Part 2). 
The OLE maximizes the long-term safety and tolerability data collected for 
basmisanil in this rare disorder by collecting data from all participants including 
those treated with placebo. As previously committed to by the Sponsor in the 
protocol (Section 6.7), the OLE provides an opportunity for participants who have 
completed the 52 weeks of blinded study treatment in Part 1 to receive active 
treatment with basmisanil with a direct prospect of benefit. This is considered a 
critical factor to raise interest in study participation in a placebo-controlled study and 
is anticipated to positively impact recruitment.  
Changes related to the addition of the optional OLE have been implemented in 
the following sections: 
Sections 1.2 Schematic of Study Design, 1.3 Schedule of activities (changes to 
Table 1 and Table 2; new Table 3 and Table 4), 2.1 Study Rationale, 2.3.2 Prospect 
of Direct Clinical Benefit for Pediatric Participants, 3 Objectives and Endpoints (new 
Table 6), 4.1 Overall Design, 4.1.1 Length of the Study, 4.2.2 Rationale for Study 
Duration, 4.3 Justification for Dose, 5 Study Population, 5.3 Lifestyle 

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Considerations, 6.1 Table 9 (new), Summary of Treatment Administered, 6.3.1 
Method of Treatment Assignment, 6.5 Concomitant Therapy, 6.5.1 Permitted 
Therapy, 6.7 Treatment at the End of Part 1 of the Study, 8 Study Assessments and 
Procedures, 8.1.3.2 Devices, 8.1.4 Data Collection Methods for Clinical Outcome 
Assessments, 
 
 
8.10 Timing of Study Assessments, 8.10.4 Follow-Up Assessments, 9.4 Statistical 
Analyses of Part 2, and 9.5 Interim Analyses. 
2. 
Modification of upper age limit to 14 years, inclusive 
 
 of conducting a dedicated study in an adolescent population, the 
BP42992 study population has been extended to young adolescents aged 12 to 
14 years, inclusive. Taking into account the significant delay in development 
associated with Dup15q syndrome, and the inclusion criterion of at least “moderate” 
disease severity as measured by CGI-S, inclusion of young adolescents aged 12 to 
14 years is considered a reasonable extension of the pediatric study population. A 
positive impact to recruitment is anticipated to manifest rapidly, as the study will be 
open to a broader age range as of Stage 1 of the study, which is currently open to 
recruitment.  
The integrity of the safety data, primary efficacy data (Vineland Adaptive Behavior 
Scales–Third Edition [Vineland-3, Adaptive Behavior Composite]) and quantitative 
EEG (qEEG) biomarker data is not impacted, and the statistical analysis plan 
remains unchanged. The expansion of the upper age limit was made taking into 
account the added baseline variability of neurodevelopmental outcomes in this age 
range (see Section 4.2.1 Rationale for Study Population) and the suitability of the 
different endpoints for individuals aged 12 to 14 years. The adequacy of the Mullen 
Scales of Early Learning (MSEL; secondary efficacy outcome measure) is not 
known in this older age group as few data are available. It is conceivable that a 
proportion of study participants, although at least moderately ill at screening 
(Dup15q syndrome Clinician Global Impression of Severity scale [CGI-S] inclusion 
criterion in Section 5.1), function at a developmental level exceeding those captured 
by the MSEL on one or more of the five domain scores (Section 3, Table 5 
Objectives and Endpoints for Part 1). The data generated in BP42992 will support 
the characterization of the psychometric properties of the MSEL across ages and 
clinical severities for use in Dup15q syndrome clinical trials. 
Additionally, the extension of the age range will provide open-label data for 
participants up to the age of 17 years (at the end of Part 2) and thus provide 
valuable bridging information to support future clinical development of basmisanil in 
adolescent and young adult populations. 

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5/Protocol BP42992, Version 3 
Changes related to the modification of the upper age range of the study 
population have been implemented in the following sections: 
Sections 2.1 Study Rationale, 2.2.2 Current Therapies and Unmet Medical Need, 
2.3.1.3 Risk Evaluation of Measures Implemented in the Study, 3 Objectives and 
Endpoints, 4.1 Overall Design, 4.2.1 Rationale for Study Population, 4.3 Justification 
for Dose, 5 Study Population, 5.1 Inclusion Criteria, 6.1 (Table 8, Summary of 
Treatment Administered in Part 1), 6.3.1 Method of Treatment Assignment, and 
Section 1.3 of Appendix 1. 
3. 
Modification of staggered recruitment (see Section 4.1 including Figure 2) 
  
 
The inclusion criteria for Stage 2 have been partially relaxed to allow inclusion 
of all participants meeting study eligibility criteria irrespective of their age or 
epilepsy diagnosis. Staggered recruitment thus occurs in two stages, instead of 
3 previously. 
 
The interim analysis will be performed when approximately 24 participants 
recruited in Stages 1 and 2 reach 4 weeks of treatment, with a minimum of 
9 participants aged 2-5 years. 
 
The staggered approach by age and by presence or absence of epilepsy remains 
(see Section 4.1). The change, however, allows recruitment of both younger 
patients and patients without epilepsy simultaneously in Stage 2, rather than 
consecutively. There is no evidence for differences in epilepsy severity or 
presentation, nor a mechanistic rationale suggesting a different pro-epileptic risk 
with basmisanil treatment between age groups. The theoretical risk of worsening of 
seizures is related to the mechanism of action of basmisanil and should thus occur 
at a high frequency (Type A event). As such, the safety profile of basmisanil can be 
adequately assessed based on data from 9 participants aged 6 to 14 years 
presenting with epilepsy to safely ungate enrollment in Stage 2. Similarly, the interim 
analysis performed on approximately 24 participants recruited in Stages 1 and 2, 
with a minimum of 9 participants aged 2 to 5 years, will allow adequate evaluation of 
the overall safety profile of basmisanil in individuals representative of the study 
population. These changes therefore do not affect individual participants’ safety and 
monitoring is in place at all times throughout the study. 
The impact of the changes on staggered recruitment is anticipated to be significant. 
In fact, patients without epilepsy represent about 40% of the Dup15q population 
(see Section 2.2.1) and their inclusion opens earlier participation to a larger pool of 
patients. This is expected to accelerate decision-making in Study BP42992. A timely 
confirmation of age-dependent doses based on the safety and PK data by the 
Internal Monitoring Committee (IMC) + Scientific Oversight Committee (SOC) (see 
Section 4.1.2.2) is essential to maximize the number of participants who receive 
study treatment doses that reach the targeted exposures as early as possible in this 

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6/Protocol BP42992, Version 3 
study: the target exposures are anticipated to offer the greatest likelihood of 
prospective benefit. 
Changes related to the study stages have been implemented in the following 
sections: 
Sections 1.2 Schematic of Study Design, 4.1 Overall Design, 4.1.2.2 Review 
Objectives and Procedures (IMC and SOC), 4.2.1 Rationale for Study Population, 
4.2.3.1 Electroencephalography, 5.1 Inclusion Criteria, 6.1 (Table 8, Summary of 
Treatment Administered in Part 1), and 9.5 Interim Analyses. 
 
4. 
Alleviation of the study burden for participants and sites at the Day 1 visit: 
Taking into consideration the learnings gained from study execution and feedback 
from Investigators, the following changes have been implemented: 
EEG and PK assessments 
 
The duration of the EEG recording on Day 1 has been reduced from 10 hours 
to 6.5 hours in total. The shorter recording duration decreases the number of 
pharmacodynamic (PD) timepoints collected (see Section 1.3) and will only 
marginally impede exploratory PK/PD analyses, without affecting study 
integrity, including the PD qEEG objectives of the planned interim analysis (see 
Section 4.1.2.2.). The change does not impact safety monitoring as the duration 
of the EEG recording required for safety review purposes is not reduced. 
Table 2 and Section 8.2.9 Seizures (EEG Monitoring) have been updated 
accordingly. 
 
To further reduce Day 1 visit burden, the timing of the last two PK samples has 
been amended to decrease the overall study visit duration by approximately 
1 hour (see Table 2).  
Change in EEG safety review process 
 
Section 8.2.9 Seizures (EEG Monitoring) and footnote "f" in Table 2 (Schedule 
of Activities for Part 1 – Detailed Table) have been amended to replace the 
requirement for a local review of the EEG by the site personnel with a central 
review process at the Day 1 visit. The sites will be provided with an EEG safety 
report based on review of the recording by a central reader (qualified 
neurologist independent of the site personnel). The report will be available to 
sites within 22 hours of receipt of the EEG recordings by the central reading 
vendor, and thus available before the end of the clinic visit the next day (Day 2 
visit).
 
 The central review process will additionally 
ensure consistency of the EEG safety review within a defined time-window. In 
addition, footnote “f” in Table 2 is applicable only at the Day 1 visit (addressed 
in Protocol Clarification Letter number 3 from 14 October 2022).  
 

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7/Protocol BP42992, Version 3 
Additional clarifications have been added to improve the clarity and consistency 
of the protocol and ease study execution: 
• 
To clarify genetic information required and genetic tests implemented in the 
study as per Protocol Clarification Letter number 2 from 14 October 2022 
Per protocol Section 8, “A previously established genetic diagnosis of Dup15q 
syndrome (medical history obtained before signing of the ICF) which contains 
the required information to determine eligibility may be utilized for screening.” 
Table 1 in Section 1.3, Section 8.2.1 Medical History and Demographic Data, 
and Section 8.6.1 Genetic and Genomic Analyses have been amended to 
specify that the genetic tests in the study are not mandatory and that 
Investigators decide on a case-by-case basis which genetic test(s) are required 
to be performed to obtain the full genetic information per study requirements. 
• 
Section 1.3 Schedule of Activities 
o Table 1 has been amended to: 
– 
Add caregiver expectation guidance assessment at screening to 
ensure caregivers have the opportunity to discuss the requirements 
with the site personnel before the Baseline visit (footnote “u”). 
Section 8.1.2 Caregiver Expectations Guidance has been updated 
accordingly. 
– 
Add an Informed Consent Form (ICF) at the Day 365 visit for 
participants who continue study participation in Part 2 (footnote “t”).  
o Footnotes for SoA Table 1 have been updated as follows: 
– 
“a” has been amended to correct conflicting information in the protocol 
on the duration of the screening period, which lasts up to 5 weeks. 
Section 4.1.1 Length of the Study has been updated accordingly. This 
change has been addressed in Protocol Clarification Letter number 4 
from 9 February 2023. It also indicated that all screening assessments 
required for eligibility must be completed with result available before 
the Baseline visit. 
– 
“g” has been updated to specify that the applicable age for the Tanner 
staging assessment is determined based on the participant’s age at 
the time of signing the ICF and to indicate that once Stage 5 on a scale 
is reached for a participant, the scale is not used anymore. Section 
8.2.3 Tanner Staging has been updated accordingly. 
– 
“l” and Section 8.1.4.1 Clinician-Reported Outcome Assessments and 
Section 8.1.5.2 Vineland Adaptive Behavior Scales –Third Edition have 
been updated to specify that the Vineland-3 interview is performed by 
central raters independent of the site personnel and a time window of 
5 days before the scheduled clinic visit has been specified for a remote 
assessment. 
– 
“o” has been amended to specify that the applicable age for the 
suicidality assessment is determined based on the participant’s age at 

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8/Protocol BP42992, Version 3 
the time of signing the ICF. Section 8.2.8 Clinical Assessment of 
Suicidality has been updated accordingly. 
– 
“p” and Section 8.1.5.12 (Wearable Device) have been updated to 
provide updated information on the technical and scheduling 
requirements for the wearable device in the study. 
– 
“s” has been added to provide clarity that the caregiver exit interview 
should be performed within 4 weeks after the Day 365 visit and that 
the independent interviewers unrelated to the site personnel should 
perform this. Section 8.1.5.14 (Caregiver Exit Interview) has been 
updated accordingly. The optional caregiver exit interview has also 
been listed as an exploratory endpoint in Table 5 Objectives and 
Endpoints in Part 1. 
o Table 2 has been amended to provide more clarity on the timing of 
assessments at the visits with EEG/qEEG, PK, and safety assessments.  
o Footnotes for SoA Table 2 have been updated as follows: 
– 
“a” has been updated to provide information that the assessments 
should start in the morning, consistently across all study visits 
(addressed in Protocol Clarification Letter number 4 from 
9 February 2023).  
– 
“g” and “h” have been removed and replaced as per below:  
▪ 
“g” and Section 6.4 Treatment Compliance have been 
amended to clarify that all doses administrated at site should 
be supervised and given within 30 minutes after the start of the 
meal. 
▪ 
“h” has been added to inform that the assigned assessments at 
the Day 365 visit will be performed only for participants who do 
not continue study participation in the optional OLE.  
– 
“i” to “m” have been added to provide instructions on the order of the 
assessments and blood draws. 
 
Section 3 Objectives and Endpoints, Table 5, Exploratory Objectives has been 
amended to list the optional Caregiver Exit Interview as per Table 1 Schedule of 
Activities for Part 1 and Section 8.1.5.14.  
 
Section 4.1.2.1 Administrative Structure paragraph “Scientific Oversight 
Committee (SOC)” has been amended to clarify the periods of SOC 
involvement in the study. 
 
Section 5.2, Exclusion Criterion 1 has been amended to clarify that the 
restrictions related to the use of rescue medication are limited to treatment of 
one seizure episode or seizure cluster per month on average in the past 
6 months and that the concomitant use of more than 4 anti-epileptic 
medications is exclusionary in case of chronic use. 

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9/Protocol BP42992, Version 3 
 
Section 5.3 has been amended to clarify that a ketogenic diet needs to be on a 
stable regimen for 6 weeks prior to screening as initially stated in Section 6.5. 
As ketogenic diet is not a concomitant medication. 
 
Section 6 Treatments has been updated and a new Appendix 6 Investigational 
Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) 
Designations has been added to implement the requirements of the EU Clinical 
Trials Regulation (CTR) on the designations of the IMPs and auxiliary medicinal 
products (AxMPs)/NIMPs. 
 
Section 6.2 Preparation/Handling/Storage/Accountability has been updated to 
add that only unused stick-packs need to be returned by the caregiver at clinic 
visit or IMP shipment. The empty stick-packs will not be returned. This is to limit 
caregiver and site burden. 
 
Section 6.5.3 Therapy to be Used with Caution has been amended to allow for 
reschedule of a study visit with a 2-day window (even if it falls out of the 
protocol-defined visit window) in case an emergency occurs requiring treatment 
with benzodiazepines/benzodiazepine-related drugs. 
 
Section 8.1.4.2 Caregiver-Reported Assessments has been updated to provide 
more information about caregiver-reported data and requirements for reporting 
remotely. 
 
Section 8.1.5.3 Mullen Scales of Early Learning has been amended to further 
describe the MSEL. 
 
Section 8.1.5.10 Children’s Sleep Habit Questionnaire (CSHQ) has been 
amended to further describe the CSHQ. 
 
Section 8.2.4 Seizure Status and Appendix 7 (new) have been updated with a 
list of seizure types to facilitate seizure diary entries. 
 
Section 8.3.7 Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious adverse events has been amended to 
clarify when seizure activity should be reported as an AE/SAE. 
 
 
 
 
Section 8.10 Timing of Study Assessments has been amended to provide 
further guidance on the order of assessments and to clarify that efficacy 
assessments related to primary and secondary objectives should be prioritized 
over exploratory assessments.  
 
Section 9.3.2 Efficacy Analyses has been updated to include the formal 
statistical hypotheses testing for Part 1 of the study as per FDA request.  
 
Appendix 1 Regulatory, Ethical, and Study Oversight Considerations has been 
updated to align with Clinical Trials Regulation (CTR) requirements. 
 
Section 5.2 Special Situations of Appendix 2 has been updated to clarify that 
special situations, regardless of whether they result in an AE, should be 
reported on the Special Situations eCRF.  

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10/Protocol BP42992, Version 3 
 
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment 
represents cumulative changes to the original protocol. 

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11/Protocol BP42992, Version 3 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 2 
PROTOCOL AMENDMENT, BP42992 VERSION 3 RATIONALE ....................... 3 
1. 
PROTOCOL SUMMARY ............................................................... 20 
1.1 
Synopsis .................................................................................. 20 
1.2 
Schematic of Study Design ...................................................... 32 
1.3 
Schedule of Activities ............................................................... 32 
2. 
INTRODUCTION ........................................................................... 45 
2.1 
Study Rationale ....................................................................... 45 
2.2 
Background.............................................................................. 46 
2.2.1 
Background on Disease ........................................................... 46 
2.2.2 
Current Therapies and Unmet Medical Need .......................... 47 
2.2.3 
Background on Basmisanil ...................................................... 48 
2.2.3.1 
Non-Clinical Studies ................................................................ 48 
2.2.3.2 
Clinical Studies ........................................................................ 49 
2.3 
Benefit/Risk Assessment ......................................................... 51 
2.3.1 
Risk Evaluation ........................................................................ 51 
2.3.1.1 
Identified Risks for Basmisanil ................................................. 51 
2.3.1.2 
Potential Risks for Basmisanil .................................................. 51 
2.3.1.3 
Risk Evaluation of Measures Implemented in the Study .......... 53 
2.3.2 
Prospect of Direct Clinical Benefit for Pediatric Participants .... 54 
2.3.3 
Overall Benefit/Risk Assessment ............................................. 56 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 56 
4. 
STUDY DESIGN ........................................................................... 62 
4.1 
Overall Design ......................................................................... 62 
4.1.1 
Length of the Study .................................................................. 65 
4.1.2 
Internal Monitoring Committee and Scientific Oversight 
Committee ............................................................................... 65 
4.1.2.1 
Administrative Structure ........................................................... 65 
4.1.2.2 
Review Objectives and Procedures ......................................... 66 
4.1.3 
Stopping Rules Criteria ............................................................ 67 
4.2 
Scientific Rationale for Study Design ....................................... 68 

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4.2.1 
Rationale for Study Population ................................................ 68 
4.2.2 
Rationale for Study Duration .................................................... 70 
4.2.3 
Rationale for Assessments ...................................................... 71 
4.2.3.1 
Electroencephalography .......................................................... 71 
4.2.3.2 
Gait Assessment ...................................................................... 71 
4.2.4 
Rationale for Control Group ..................................................... 72 
4.3 
Justification for Dose ............................................................... 72 
4.4 
End of Study Definition ............................................................ 74 
5. 
STUDY POPULATION .................................................................. 74 
5.1 
Inclusion Criteria ...................................................................... 74 
5.2 
Exclusion Criteria ..................................................................... 76 
5.3 
Lifestyle Considerations ........................................................... 77 
5.4 
Screen Failures ........................................................................ 77 
5.5 
Recruitment Procedures .......................................................... 78 
6. 
TREATMENTS .............................................................................. 78 
6.1 
Treatments Administered ......................................................... 78 
6.2 
Preparation/Handling/Storage/Accountability........................... 80 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....... 82 
6.3.1 
Method of Treatment Assignment ............................................ 82 
6.3.2 
Blinding .................................................................................... 82 
6.4 
Treatment Compliance ............................................................ 83 
6.5 
Concomitant Therapy .............................................................. 83 
6.5.1 
Permitted Therapy ................................................................... 84 
6.5.2 
Prohibited Therapy .................................................................. 85 
6.5.3 
Therapy to be Used with Caution ............................................. 86 
6.6 
Dose Modification, Temporary Interruption and 
Rechallenge ............................................................................. 87 
6.6.1 
Temporary Interruption ............................................................ 87 
6.7 
Treatment after the End of Part 1 of the Study ........................ 87 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ................... 88 
7.1 
Discontinuation of Study Treatment ......................................... 88 
7.2 
Participant Discontinuation/Withdrawal from the Study ........... 89 

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7.3 
Lost to Follow-Up ..................................................................... 90 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 90 
8.1 
Efficacy Assessments .............................................................. 91 
8.1.1 
Requirements and Instructions for Caregivers ......................... 91 
8.1.2 
Caregiver Expectations Guidance ........................................... 91 
8.1.3 
Equipment for Home Measurements ....................................... 91 
8.1.3.1 
Dedicated Website (TrialMax) ................................................. 91 
8.1.3.2 
Devices .................................................................................... 92 
8.1.4 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 92 
8.1.4.1 
Clinician-Reported Outcome Assessments ............................. 94 
8.1.4.2 
Caregiver-Reported Assessments ........................................... 95 
8.1.5 
Clinical Outcome Assessments ............................................... 95 
8.1.5.1 
Dup15q Syndrome Clinician Global Impression of Severity 
and Clinician Global Impression of Change ............................. 95 
8.1.5.2 
Vineland Adaptive Behavior Scales–Third Edition ................... 96 
8.1.5.3 
Mullen Scales of Early Learning .............................................. 96 
8.1.5.4 
Autism Diagnostic Observational Schedule, Second 
Edition ...................................................................................... 96 
8.1.5.5 
Aberrant Behavior Checklist-Community – Second Edition ..... 97 
8.1.5.6 
Pediatric Quality of Life InventoryFamily Impact Module ...... 97 
8.1.5.7 
Observer-Reported Communication Ability .............................. 97 
8.1.5.8 
Repetitive Behavior Scale–Revised ......................................... 97 
8.1.5.9 
Assessment of Hypotonia ........................................................ 98 
8.1.5.10 
Children’s Sleep Habit Questionnaire ...................................... 98 
8.1.5.11 
Dup15q Syndrome Caregiver Global Impression of 
Severity and Caregiver Global Impression of Change ............. 98 
8.1.5.12 
Wearable device ...................................................................... 98 
8.1.5.13 
Palatability questionnaire ......................................................... 99 
8.1.5.14 
Caregiver Exit Interview ........................................................... 99 
8.2 
Safety Assessments ................................................................ 99 
8.2.1 
Medical History and Demographic Data ................................ 100 
8.2.2 
Physical Examinations ........................................................... 100 
8.2.3 
Tanner Staging ...................................................................... 101 

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8.2.4 
Seizure Status ....................................................................... 101 
8.2.5 
Vital Signs .............................................................................. 102 
8.2.6 
Electrocardiograms ................................................................ 102 
8.2.7 
Clinical Safety Laboratory Assessments ................................ 103 
8.2.8 
Clinical Assessment of Suicidality .......................................... 104 
8.2.9 
Seizures (EEG Monitoring) .................................................... 104 
8.3 
Adverse Events and Serious Adverse Events ....................... 105 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information ................................ 105 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events .................................................................................... 106 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .. 106 
8.3.3.1 
Investigator Follow-Up ........................................................... 106 
8.3.3.2 
Sponsor Follow Up ................................................................ 106 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events .................................................................................... 106 
8.3.4.1 
Emergency Medical Contacts ................................................ 107 
8.3.5 
Pregnancy.............................................................................. 107 
8.3.6 
Adverse Events of Special Interest ........................................ 107 
8.3.7 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as Adverse Events or Serious 
Adverse Events ...................................................................... 108 
8.3.8 
Management of Specific Adverse Events .............................. 108 
8.4 
Treatment of Overdose .......................................................... 110 
8.5 
Pharmacokinetics .................................................................. 111 
8.6 
Pharmacodynamics and Biomarkers Analyses ...................... 112 
8.6.1 
Genetic and Genomic Analyses ............................................. 112 
8.6.2 
Effect of Basmisanil on the EEG (qEEG) Assessments ......... 112 
8.7 
Pharmacodynamics and Biomarker Samples ........................ 113 
8.8 
Samples for Research Biosample Repository........................ 113 
8.8.1 
Overview of the Research Biosample Repository .................. 113 
8.8.2 
Sample Collection .................................................................. 113 
8.9 
Health Economics .................................................................. 115 
8.10 
Timing of Study Assessments ................................................ 115 

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Table 13 
Analysis Sets ............................................................................ 117 
 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ........................................................... 32 
Figure 2 
Staggered Enrollment in Part 1 .................................................. 63 
 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ......... 128 
Appendix 2 
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting ........................................................... 138 
Appendix 3 
Procedures for Recording Adverse Events ............................... 146 
Appendix 4 
Clinical Laboratory Tests .......................................................... 151 
Appendix 5 
Contraceptive and Barrier Guidance ......................................... 154 
Appendix 6 
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations .............................................. 159 
Appendix 7 
International League against Epilepsy 2017 Classification of 
Seizure Types ............................................................................ 160 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABC-2-C 
Aberrant Behavior Checklist - Second Edition – Community 
Version 
ADOS-2 
Autism Diagnostic Observational Schedule, second edition 
AE 
adverse event 
AESI 
adverse event of special interest 
ASD 
autism spectrum disorder 
AUC0-inf 
area under the concentration–time curve from time 0 to infinity 
AUC0-12h 
area under the concentration-time curve from time 0 to 12 hours 
AUCtau,ss 
area under the concentration–time curve during one dosing 
interval at steady state 
BID 
twice a day 
CA 
competent authority 
CBD 
cannabidiol 
C-CASA 
Columbia Classification Algorithm for Suicide 
CFB 
change from baseline 
CIAS 
cognitive impairment associated with schizophrenia 
ClinRO 
clinician-reported outcome 
CMA 
chromosomal microarray 
Cmax 
maximum concentration  
Cmax,ss 
maximum concentration at steady state 
COA 
clinical outcome assessment 
CRF 
case report form 
CSHQ 
Children’s Sleep Habit Questionnaire 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events 
Ctrough,ss 
trough plasma concentration at steady state 
DDI 
drug-drug interaction 
DOAC 
direct-acting oral anticoagulant 
Dup15q CaGI-C 
Dup15q syndrome Caregiver Global Impression of Change 
scale 
Dup15q CaGI-S 
Dup15q syndrome Caregiver Global Impression of Severity 
scale 
Dup15q CGI-C 
Dup15q syndrome Clinician Global Impression of Change scale 
Dup15q CGI-S 
Dup15q syndrome Clinician Global Impression of Severity scale 
EC 
Ethics Committee 
eCOA 
electronic clinical outcome assessment 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEA 
European Economic Area 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 

 
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GABA 
gamma-aminobutyric acid 
GABAA 
GABA A receptor  
GABAAR 
GABAA receptor protein 
GABAA α5R 
α5 subunit-containing GABA A receptor subtype 
GABR 
GABAA receptor subunit genes 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
idic(15) 
isodicentric 15 
IEC 
Independent Ethics Committee 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
int(15) 
interstitial 15 
IQ 
intellectual quotient 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IxRS 
interactive (voice/web) response system 
LPLO 
last participant, last observation 
MMRM 
mixed effects model for repeated measures 
MN 
mobile nurse 
MSEL 
Mullen Scales of Early Learning 
MS-MLPA 
methylation specific-multiplex ligation-dependent probe 
amplification 
NAM 
negative allosteric modulator 
NCI 
National Cancer Institute 
NDD 
neurodevelopmental disorder 
OLE 
open-label extension 
ORCA 
Observer-Reported Communication Ability 
OTC 
over-the-counter 
PBPK 
physiologically-based pharmacokinetic 
PD 
pharmacodynamic 
PedsQL-FIM 
Pediatric Quality of Life Inventory Family Impact Module 
PET 
positron emission tomography 
P-gp 
p-glycoprotein 
PI 
prediction interval 
PK 
pharmacokinetic 
PR 
PR interval 
PRO 
patient-reported outcome (also refers to participants) 
PTZ 
pentylenetetrazole 
qEEG 
quantitative EEG 
QRS 
QRS complex 

 
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QT 
QT interval 
QTc 
QT corrected for heart rate 
QTcB 
QT corrected for heart rate using Bazett’s formula 
QTcF 
QT corrected for heart rate using the Fridericia’s correction 
factor 
RBR 
Research Biosample Repository 
RBS-R 
Repetitive Behavior Scale–Revised 
RO 
receptor occupancy 
SAE 
serious adverse event 
SMT 
Study Management Team 
SoA 
schedule of activities 
SOC 
Scientific Oversight Committee 
TID 
three times a day 
ULN 
upper limit of normal 
Vineland-3 
Vineland Adaptive Behavior Scales–Third Edition 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 

 
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 
Double-blind 52-week treatment period (Day 1 to Day 365) 
 
Optional OLE period of approximately 2 years/104 weeks (Day 366 to Day 1095/Year 3)  
 
Follow-up period of approximately 4 weeks (Part 1: Days 365 to 395 or Part 2: Days 1095 
to 1125) 
 
The screening period will start once the first actual screening assessment is performed (not with 
signing the Informed Consent Form). All screening assessments required to confirm 
participant’s eligibility for study participation need to be completed before the Baseline visit. 
The Baseline visit can be done anytime between Day -7 and Day-1.  
 
END OF STUDY 
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last scheduled procedure per the schedule of activities or withdrawal of 
consent.  
The end of the study is defined as the date when the last participant’s last observation occurs.  
 
IMC AND SOC 
A Sponsor IMC will be responsible for regular reviews of accumulating safety, tolerability, and 
PK data to assess the adequacy of the selected doses in terms of tolerability and exposure. It 
will also oversee up to two interim analyses. 
During Part 1 of the study, an SOC will help monitor safety and tolerability data until all 
participants have completed or were prematurely withdrawn from Part 1. Specifically, the 
SOC will help interpret any changes in seizure status and/or EEG findings in this patient 
population, to ensure that the study in its current form does not pose unacceptable safety risks 
to participants.  
 
PARTICIPANT POPULATION 
The participants in this study will be female and male children and adolescents aged 2 to 
14 years at the time of signing the ICF for Part 1 with genetically confirmed maternal 
duplications (3 copies) or triplications (4 copies) of chromosome 15q11.2‐q13.1 (Dup15q 
syndrome), who fulfill all of the given inclusion criteria and do not meet any exclusion criteria. 
 
INCLUSION CRITERIA (PART 1) 
Informed Consent/Age 
1. Participants aged 2 to 14 years inclusive at the time the caregiver signs the informed 
consent. 
 
Type of Participants and Disease Characteristics 
2. In the investigator’s opinion, able to participate and deemed appropriate for participation in 
the study. 
3. 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. 
4. Dup15q syndrome Clinician Global Impression of Severity scale (Dup15q CGI-S) overall 
severity score  4 (at least moderately ill). 
5. Stage 1 specific inclusion criterion: Participants aged 6 to 14 years with epilepsy. 
 
Weight 
6. Body weight equal to or above the third percentile for age. 
 
Sex and Contraception/Barrier Requirements 
7. Male and female participants 

 
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Some of the provisions that follow may have limited applicability based on the age range of 
study participants (i.e., up to the age of 14) and the nature of the disease under study. 
These provisions are nonetheless included for purposes of completeness to make clear that 
individuals who are pregnant or are engaging in actions that may cause them to become 
pregnant, should not participate in this study. Consent must be provided by the legal 
representative for all participants. 
a) Female Participants 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies: 
 Female participants of non-childbearing potential. 
 Female participants of childbearing potential who agree to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods during the treatment 
period and for at least 28 days after the final dose of study treatment. The following are 
acceptable contraceptive methods: bilateral tubal occlusion/ ligation, male sexual partner 
who is sterilized, established proper use of hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices and copper intrauterine devices, male 
or female condom with or without spermicide; and cap, diaphragm, or sponge with 
spermicide. 
b) Male Participants 
Male contraception is not required in this study because of the minimal seminal dose 
transmitted through sexual intercourse.  
 
Caregiver Requirements 
8. The 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. 
9. The 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. 
10. The 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 (PART 1) 
Medical Conditions 
1. 
Uncontrolled epilepsy at screening as indicated by: 
a) 
Use of rescue medication(s) to treat more than one seizure episode or seizure cluster 
per month, on average in the past 6 months, 
OR 
b) 
Concomitant chronic use of more than four anti-epileptic medications, 
OR 
c) 
Status epilepticus within the past 6 months requiring hospitalization for treatment of the 
status epilepticus, 
OR 
d) 
Any implanted devices to treat drug-resistant epilepsy 

 
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2. 
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. 
3. 
Clinically significant ECG abnormalities at screening, including an average triplicate 
QTcF  450 ms for participants  10 years or QTcB  450 ms for children up to and 
including age 10 years (because Bazett’s correction is more appropriate in young children). 
4. 
Clinically significant abnormalities in laboratory test results at screening (including positive 
results for HIV, hepatitis B and/or hepatitis C). ALT values  1.5  the upper limit of normal 
(ULN; re-testing is allowed to confirm). GFR < 90 mL/min per 1.73 m2 (Grade 1 CKD) as 
estimated using Schwarz formula. 
 
Prior/Concomitant Therapy 
5. 
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.  
6. 
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). 
7. 
Concomitant use of prohibited medications. 
 
Prior/Concurrent Clinical Study Experience 
8. 
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. 
 
Other Exclusions 
9. 
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). 
10. 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).  
11. 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.  
12. 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. 
 
NUMBER OF PARTICIPANTS 
Approximately 90 participants with Dup15q syndrome are planned to be randomized 2:1 to 
basmisanil or placebo. Assuming approximately 10% of randomized participants may not be 
evaluable for efficacy, there will be approximately 81 evaluable participants. The sample size 
may be increased in case of higher-than-expected rates of early study withdrawals or number of 
participants requiring dose adjustments due to exposures substantially deviating from target 
trough plasma concentrations. 
 

 
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CONCOMITANT THERAPY 
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter (OTC) 
drugs, vaccines (including COVID-19 vaccines) approved dietary and herbal supplements, 
nutritional supplements, and dietary restrictions used by a participant from 6 weeks prior to 
screening until the follow-up visit.  
Anti-epileptic medication must be on a stable regimen 8 weeks prior to screening and for at 
least the first 4 weeks of treatment in Part 1. After the Day 28 visit, dose adjustments within the 
therapeutic range and changes within the same class of anti-epileptic medication may be 
allowed as part of routine clinical care, upon consultation with the Medical Monitor. In Part 2, 
for the first 28 days (until Day 395) dose changes are not allowed. Changes in the number or 
the class of anti-epileptic medications are not allowed until the Part 1 follow-up visit for 
participants who do not continue study participation in the optional OLE or until the Day 
548 visit for participants who roll over to Part 2 of the study. 
Non-pharmacological (e.g., physiotherapy) / behavioral therapies should not be stopped or 
newly started at least 6 weeks prior to screening and are expected to remain stable until the 
Part 1 follow-up visit or until the Day 548 visit for Part 2 participants (excluding changes 
related to standard age and educational interventional programs or minor interruptions such as 
illness or vacation).  
 
Permitted Therapy 
Permitted therapy includes all medication used by a participant to manage symptoms 
associated with Dup15q syndrome that is not specified as prohibited therapy, taken from 
6 weeks prior to screening until the Part 1 Follow-up visit or until the Day 548 visit for 
participants in Part 2. 
Participants who use oral contraceptives with a failure rate of < 1% per year, 
hormone-replacement therapy, or other maintenance therapy should continue their use. 
 
Prohibited Therapy 
The below listed therapies are prohibited and should not be administered within 2 weeks (or 
within 5-times the elimination half-life, whichever is longer) prior to dosing and until the 
Follow-up visit, unless otherwise specified. Methods of administration which do not produce 
appreciable systemic drug exposure (e.g., topical administration for skin conditions) are 
permitted: 
Modulators of CYP3A4 Activity: Basmisanil is predominantly cleared by metabolism via 
CYP3A4 and concomitant medications that significantly alter CYP3A4 activity will affect the 
pharmacokinetics of basmisanil.  
Strong inhibitors of CYP3A4 (e.g., itraconazole, erythromycin, fluconazole, nefazodone, 
ritonavir, verapamil, grapefruit or grapefruit juice) taken within 2 weeks (or within 5-times the 
elimination half-life, whichever is longer) prior to dosing is prohibited. Moderate CYP3A4 
inhibitors may be used after discussion with the Medical Monitor and eventual use of inhibitors 
of CYP3A should be accompanied by dedicated safety monitoring, in particular the QT interval 
(QT). 
Inducers of CYP3A4 (e.g., rifampicin, carbamazepine, pioglitazone, rifampin, modafinil, 
systemic glucocorticoids, oxycarbazepine, carbamazepine, phenobarbital, phenytoin, St John’s 
Wort) taken within 4 weeks prior to dosing (or within 5 × the elimination half-life, whichever is 
longer) are not permitted.  
Dofetilide use is not permitted because of the potential for interaction between basmisanil and 
renally cleared cationic drugs, as well as the very narrow therapeutic window of dofetilide. 
Benzodiazepines (chronic use): Based on the potential for interactions to occur between 
basmisanil and other medications whose effects are mediated via GABAA receptors, chronic 
use of benzodiazepines, including as treatment for epilepsy (e.g., clobazam) is not allowed. 
Restrictions for acute use of benzodiazepines are described in the protocol. 

 
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Direct-acting oral anticoagulants (DOACs): In vitro assays of the DOACs dabigatran-
etexilate, edoxaban, apixaban, and rivaroxaban in combination with basmisanil indicate the 
potential for in vivo drug-drug interaction at both gastrointestinal and systemic concentrations.  
OTC Cannabidiol (CBD): Use of artisanal CBDs (products, derivatives, cannabis 
plants/extracts) is prohibited. Epidiolex/Epidyolex is not prohibited. 
 
Therapy to be Used With Caution 
P-glycoprotein (P-gp) substrates (with exception of DOACs which are prohibited): Basmisanil 
has been shown in in vitro assays to inhibit the activity of P-gp. Therefore, caution is advised 
when using basmisanil treatment with medications known to be P-gp substrates, especially 
those with a narrow therapeutic window (e.g., digoxin, colchicine, loperamide). Therapeutic drug 
monitoring of digoxin concentrations should be performed regularly but in particular when 
initiating and stopping basmisanil treatment. 
Concomitant medications with an effect on QT: Drugs known to prolong the QT corrected for 
heart rate (QTc) interval will be allowed if stable at screening provided the screening QTc does 
not meet exclusion QTc criterion. Use of currently approved prokinetics (e.g., domperidone, 
metoclopramide) is not prohibited, but requires closer monitoring of QTc interval on ECG due to 
risk of arrhythmias. 
Benzodiazepines / GABAergic medications: Benzodiazepines and benzodiazepine-related 
drugs may be exceptionally used with the following restrictions: 
 
For the treatment of intermittent medical conditions (e.g., for insomnia and anxiety / 
agitation, analgosedation) 
o 
Medications with a short half-life (e.g., lorazepam, alprazolam, or oxazepam) are 
preferred  
o 
Short-term use only (no more than 4 days per month) 
o 
Should not be taken within 2 days before a scheduled visit. 
 
For the treatment of emergency situations (e.g., for the acute management of a seizure) 
o 
If benzodiazepines/benzodiazepine-related drugs are required in an emergency 
situation, the visit can be rescheduled to allow for a 2-day window between emergency 
medication and visit date (even if it falls out of the protocol defined visit window). 
o 
If benzodiazepines, in particular diazepam, midazolam, or clonazepam are used, the 
Investigator should be aware that a higher-than-normal dose of the medication may be 
required to achieve clinical response.  
o 
Similarly, in case of acute use of anesthetics that are GABAA positive allosteric 
modulators (e.g., volatile anesthetics or hypnotics) in a participant treated with 
basmisanil, a higher dose of the anesthetics may be required to achieve the desired 
effect.  
 
As described above, these recommendations are based on the potential for competition (PD 
interaction) at the GABAA receptor level. 
 

 
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1.2 
SCHEMATIC OF STUDY DESIGN 
An overview of the study design is provided in Figure 1. 
Figure 1 Overview of Study Design 
A. PART 1 – 52-week double-blind placebo controlled (main study)  
 
D= Day; IMC = Internal Monitoring Committee; N = number of participants; PK = 
pharmacokinetics; qEEG = quantitative EEG; SOC = Scientific Oversight Committee. 
* The follow-up period will not be completed for participants entering Part 2. 
 
 
B. PART 2 – optional open-label extension (OLE) of 2 years 
 
 
1.3 
SCHEDULE OF ACTIVITIES 
The schedule of activities (SoA) for Part 1 is provided in Table 1 (overview of Part 1) 
and Table 2 (Part 1 detailed table). The SoA for Part 2 is provided in Table 3 (Part 2 – 
optional open-label extension [OLE]) and Table 4 (Part 2 – optional OLE – detailed 
table). 

 
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Table 1 
Schedule of Activities for Part 1 – Overview 
 

 
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Table 1 
Schedule of Activities for Part 1 – Overview (cont.) 
 

 
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Table 1 
Schedule of Activities for Part 1 – Overview (cont.) 
ABC-2-C = Aberrant Behavior Checklist - Second Edition – Community Version; ADOS = Autism Diagnostic Observational Schedule, second 
edition; BID = twice a day; CMA = chromosomal microarray; CSHQ = Children’s Sleep Habit Questionnaire; Dup15q CaGI-C = Dup15q syndrome 
Caregiver Global Impression of Change scale; Dup15q CaGI-S = Dup15q syndrome Caregiver Global Impression of Severity scale; Dup15q 
CGI-C = Dup15q syndrome Clinician Global Impression of Change scale; Dup15q CGI-S = Dup15q syndrome Clinician Global Impression of 
Severity scale; FISH = fluorescence in situ hybridization; MSEL = Mullen Scales of Early Learning; MS-MLPA = methylation specific-multiplex 
ligation-dependent probe amplification; ORCA = Observer-Reported Communication Ability; PedsQL-FIM = Pediatric Quality of Life Inventory 
Family Impact Module; PK = pharmacokinetics; qEEG = quantitative EEG; RBR = Research biosample repository; RBS-R = Repetitive Behavior 
Scale–Revised; TID = three times a day; Vineland-3 = Vineland Adaptive Behavior Scales–Third Edition. 
 
a Screening period starts once first screening assessment is performed; informed consent can be signed earlier. All screening assessments 
required to confirm participant’s eligibility for study participation need to be completed with results available before the Baseline visit. The 
Baseline visit can be done anytime between Day -7 and Day -1. 
b Visit can be split over two consecutive days if needed. 
c Visit can be done remotely if local regulations allow for it and if home nursing service is available in the country/region. 
d Telephone call only. 
e Height and head circumference do not need to be recorded at Baseline.  
f Urine pregnancy test for female participants of childbearing potential. If the urine pregnancy test is positive, it must be confirmed by a blood 
pregnancy test. 
g For participants aged 9 years and above at the time of signing the Informed Consent Form. Once a participant reaches Stage 5, Tanner staging 
no longer needs to be performed. 
h Performed by the clinician either at the clinic visit or via telephone/video call at the remote/telephone call visits.  
i See the detailed schedule in Table 2 for length of EEG and timing of qEEG timepoints. 
j Study treatment administration is BID on Day 1 and TID from Day 2 onward. 
k See detailed schedule in Table 2 for exact PK timings. 
l Vineland-3 interview will be performed by central raters, independent of the site personnel. Caregivers may choose to complete the Vineland-
3 interview at the clinic visit or remotely within 5 days before the scheduled clinic visit. The preferred method should be determined at Baseline 
and kept consistent throughout the study. 
m Assessment will be video recorded.  
n Caregiver-reported questionnaires can be completed either during the clinic visit or at home with support from the site within 5 days before the 
scheduled clinic visit using a dedicated website (TrialMax). The preferred method should be determined at Baseline and kept consistent 
throughout the study. 

 
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Table 1 
Schedule of Activities for Part 1 – Overview (cont.) 
o Assessed in participants aged 6 years and above at the time of signing the Informed Consent Form. 
p 
 
 
 
 
 
 
 
 
 
 
 
 
q Only for participants who have either early terminated Part 1, or completed Part 1 but do not consent to enter the optional OLE. 
r Genetic tests and associated samples are not mandatory assessments and do not need to be performed within the study in cases where the 
required genetic information is available in the patient’s medical history. 
s Optional exit interview, which should be performed within 4 weeks after the Day 365 visit (during the follow-up period if the participant does 
not enter Part 2 or during the first 4 weeks of Part 2), as applicable, will be performed by a trained interviewer independent of the site 
personnel. The exit interview can be performed whether or not the participant enters Part 2.  
t Only for participants who enter Part 2 of the study. Should be signed before initiation of any activities at the Day 365 visit.  
u The assessment should be done preferably before any other caregiver-reported assessments. 
 

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Table 3 
Schedule of Activities for Part 2 (Optional Open-Label Extension) – Overview 
 

 
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Table 3 
Schedule of Activities for Part 2 (Optional Open-Label Extension) – Overview (cont.) 
 

 
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Table 3 
Schedule of Activities for Part 2 (Optional Open-Label Extension) – Overview (cont.) 
ABC-2-C = Aberrant Behavior Checklist - Second Edition – Community Version; AE = adverse event; Dup15q CaGI-C = Dup15q syndrome 
Caregiver Global Impression of Change scale; Dup15q CaGI-S = Dup15q syndrome Caregiver Global Impression of Severity scale; Dup15q 
CGI-C = Dup15q syndrome Clinician Global Impression of Change scale; Dup15q CGI-S = Dup15q syndrome Clinician Global Impression of 
Severity scale; ECG = electrocardiogram; EEG = electroencephalogram; MSEL = Mullen Scales of Early Learning; OLE = open -label extension; 
PedsQL-FIM = Pediatric Quality of Life Inventory Family Impact Module; PK = pharmacokinetic; qEEG = quantitative EEG; TID = three 
times a day; Vineland-3 = Vineland Adaptive Behavior Scales–Third Edition. 
 
a Visit can be split over two consecutive days if needed. 
b Telephone call only. 
c The assessment should be done preferably before any other caregiver-reported assessments. 
d Urine pregnancy test for female participants of childbearing potential. If the urine pregnancy test is positive, it must be confirmed by a blood 
pregnancy test. 
e For participants aged 9 years and above at the time of the assessment. Once a participant reaches Stage 5, Tanner staging no longer needs to 
be performed. 
f Performed by the clinician either at the clinic visit or via telephone/video call at the telephone call visits.  
g See the detailed schedule in Table 4 for length of EEG and timing of qEEG recordings. 
h Study treatment administration is TID throughout Part 2.  
i See detailed schedule in Table 4 for exact timings for PK sampling. 
j Vineland-3 will be performed by central raters, independent of the site personnel. Caregivers may choose to complete the Vineland-3 
interview at the clinic visit or remotely within 5 days before the scheduled clinic visit. The preferred method determined at Baseline visit in 
Part 1 of the study should be kept consistent throughout Part 2 of the study. 
k Assessment will be video recorded. 
l Caregiver-reported questionnaires can be completed either during the clinic visit or at home with support from the site 5  days before the 
scheduled clinic visit using a dedicated website (TrialMax). The preferred method determined at Baseline visit in Part 1 of the study should be 
kept consistent throughout Part 2 of the study. 
m Assessed in participants aged 6 years and above at the time of the assessment.  
n Information on AEs, concomitant treatments, and suicidality assessment should be collected at minimum every 3 months via phone call.  

 
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2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Dup15q syndrome is a rare and severe neurodevelopmental disorder (NDD) with a high 
unmet medical need (Section 2.2.3). It is caused by maternal duplication or triplication of 
the q11.2-q13.1 region of chromosome 15, which contains several genes and noncoding 
regions. The disease pathophysiology cannot be causally ascribed to any single gene 
(Finucane et al 2016). Genotype-phenotype associations in Dup15q syndrome suggest 
that the maternally expressed UBE3A gene is an important determinant of the clinical 
severity of the syndrome (Section 2.2.1). 
A careful analysis of genotype-phenotype associations shows that core distinctive 
clinical features of the syndrome can manifest without the expression of UBE3A 
(paternal interstitial triplications, Castronovo et al 2015), and do not appear fully 
recapitulated in maternal duplications restricted to UBE3A only (Noor et al 2015). This 
points to an important contribution of other, non-imprinted genes in the 15q11.2-q13.1 
region to the pathophysiology of Dup15q syndrome. Of particular relevance, the cluster 
of 3 GABAA receptor subunit genes (GABRA5, GABRB3, and GABRG3) are critical for 
normal neuronal development and function. Indeed, mutations in the GABRB3 and 
GABRA5 genes, including gain-of-function mutations have been causally linked to 
epilepsy, developmental delay, and hypotonia phenotypes (Menzikov et al 2021, Butler 
et al 2018, Hernandez et al 2019, Boonsimma et al 2020, Absalom et al 2020) 
reminiscent of Dup15q symptomatology.  
The GABRA gene cluster encodes the α5, β3, and γ3 GABAA R subunits, which can 
co-assemble to form a GABAA α5-containing receptor subtype (GABAA α5R, Sur et al 
1998). This receptor plays a central role in the control of neuronal excitability and 
inhibitory circuit formation early in CNS development (Jacob 2019). Emerging evidence 
from human postmortem studies and neuronal cellular models suggests increased 
GABAAR expression in people with Dup15q (Urraca et al 2018, Germain et al 2014). 
This is proposed to translate into increased GABAAR-mediated inhibitory function as 
revealed by the characteristic EEG signature observed in patients with Dup15q 
syndrome (Urraca et al 2013, Frohlich et al 2019), which closely resembles the effects of 
GABAAR enhancing drugs (e.g., benzodiazepines; see the Basmisanil Investigator’s 
Brochure for details).  
Negative allosteric modulation of GABAA α5R with basmisanil is therefore proposed as 
the first therapeutic approach for the treatment of Dup15q syndrome. Intervention in 
early childhood, a critical period characterized by rapid maturation of the human brain 
(Kolb and Gibb 2011), may offer the opportunity to affect the trajectory of the disease 
and to maximize learning and socialization opportunities during key neurodevelopmental 
stages (Vivanti et al 2018), with a greater prospect of benefit than intervention later in life 
(see Section 4.2.1). 

 
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This study consists of two parts. Part 1 is a multi-center, randomized, double-blind, 
placebo-controlled, parallel group study to evaluate the safety, efficacy, and 
pharmacodynamics of 52 weeks of basmisanil treatment in children and adolescents with 
Dup15q syndrome aged 2 to 14 years. Part 1 of the study will test the hypothesis that 
negative allosteric modulation of GABAA α5R can address excessive GABAAR function 
driven by the additional GABR copy numbers, as indexed by EEG, and positively impact 
core neurodevelopmental disease features in individuals with Dup15q syndrome. Part 2 
of the study is an optional 2-year open-label extension (OLE) to evaluate long-term 
safety and tolerability and provide supportive evidence of continued treatment benefit 
in selected efficacy outcomes. The OLE presents an opportunity for all enrolled 
participants who have completed 52 weeks of treatment in the placebo-controlled part of 
the study (Part 1) to receive active treatment (see Section 6.7). 
The rationale for the study design is provided in Section 4.2. 
2.2 
BACKGROUND 
2.2.1 
Background on Disease 
Dup15q syndrome is a rare genetic NDD, caused by copy number gains of the 
q11.2-q13.1 region on chromosome 15 that contains both UBE3A and GABR genes. 
The evidence on Dup15q syndrome incidence and prevalence is limited (Kirov et al 
2014, Schinzel and Niedrist 2001); the birth incidence is estimated between 1 in 11,000 
to 1 in 20,000. The majority (60%80%) and most affected individuals present with an 
isodicentric [idic(15)] supernumerary chromosome of maternal origin, resulting in 
triplication of the chromosomal segment (4 copies). The remaining 20%40% of the 
population have interstitial tandem rearrangements [int(15)], resulting in duplication 
(3 copies) or very rarely in triplication (4 copies) of the 15q11.2-q13.1 region (Finucane 
et al 2016, Lusk et al 2021). Clinically, the syndrome is characterized by a distinctive but 
heterogeneous neurodevelopmental phenotype. Hypotonia in infancy, motor 
impairments, global developmental delay, language and speech impairments are the 
most frequent features (Finucane et al 2016, Kalsner et al 2015). Autism spectrum 
disorder (ASD), epilepsy, behavioral difficulties are also common in Dup15q syndrome 
(Finucane et al 2016, Kalsner et al 2015). People with Dup15q syndrome have low 
adaptive skills, impeding their independent day-to-day functioning. 
Cognitive delays may manifest as intellectual disability ranging from mild (intellectual 
quotient [IQ] 50 to 70) to severe (IQ  35), with most patients functioning in the moderate 
to severe range. Language is affected and speech difficulties include echolalia, pronoun 
reversal, and stereotyped utterances. While some may completely lack functional 
speech, a small subset of individuals can be highly verbal. Individuals with Dup15q 
syndrome typically also exhibit challenging behaviors. These include hyperactivity and 
non-compliance, irritability, anxiety, stereotyped behavior or emotional lability (Battaglia 
et al 1997, DiStefano et al 2020) and are particularly disruptive in early childhood.  

 
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Moderate to severe hypotonia in newborns and infants with Dup15q syndrome is 
associated with impaired sucking, feeding difficulties, and gross motor delays (delays in 
sitting and inability to walk independently at age 2 to 3 years). These aggregate with a 
typical wide-based or ataxic gait, slow pace and poor postural control. Persistent 
impairments in both fine and gross motor skills distinguish children with Dup15q 
syndrome from those with idiopathic ASD (Wilson et al 2020).  
Approximately 60% of patients with Dup15q syndrome present with seizures (Kalsner 
and Chamberlain 2015) and most have EEG abnormalities. Epilepsy typically develops 
early in infancy or in later childhood, around 9 years of age (Battaglia 2008), according 
to an expert advisory panel consulted by the Sponsor. In some individuals, seizures can 
be well controlled; however, two-thirds of those with idic(15) have seizures into 
adulthood (Kalsner and Chamberlain 2015). Up to 8% of idic(15) cases with epilepsy 
may succumb to status epilepticus or sudden unexpected death in epilepsy (Conant et al 
2014). 
Other associated medical conditions include gastrointestinal problems, feeding 
difficulties and poor weight gain, and minor facial dysmorphisms (Shaaya et al 2015). 
The clinical severity of Dup15q syndrome depends on multiple factors including the 
number of copies of the 15q11.2-13.1 region and the presence or absence of epilepsy. 
Idic(15) are typically more severely impaired than patients with int(15) (Cook et al 1997) 
across domains (DiStefano et al 2016, DiStefano et al 2020) and present more 
frequently with epilepsy (up to 80% vs. up to 25% for Idic(15) vs int(15), respectively) 
(Conant et al 2014, Beghi et al 2020, Battaglia et al 2016).  
The recent approach to more systematic genetic testing of children with global 
developmental delay has facilitated the identification and earlier diagnosis of rare genetic 
syndromes. The median age of diagnosis of Dup15q syndrome is reported to be around 
2 years of age (Wheeler et al 2022). Dup15q syndrome patients with a severe clinical 
presentation (e.g., early onset epilepsy, severe infantile hypotonia, often idic[15] 
Dup15q) are more likely to be diagnosed in infancy. 
2.2.2 
Current Therapies and Unmet Medical Need 
There is a high unmet medical need for people living with Dup15q syndrome, with no 
approved treatment and none in development other than basmisanil. Life-long 
supportive care may include occupational and physical therapy, alternative and 
augmentative communication, behavioral therapy, psychotropic medications for 
behavioral manifestations, and standard management for seizures. The overall clinical 
severity, including intellectual disability, functional motor impairments, behavioral 
difficulties, and for many, associated seizures, precludes most individuals with Dup15q 
syndrome from functioning independently. Children, adolescents and adults with Dup15q 
syndrome with impaired adaptive abilities require full time support and care to manage 

 
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daily living tasks. Dup15q syndrome carries a high and life-long burden for the affected 
individuals, their families and caregivers, ultimately impacting society. 
2.2.3 
Background on Basmisanil 
Basmisanil is a clinically characterized, brain penetrant, and highly selective negative 
allosteric modulator (NAM) of the GABAA 5R. Basmisanil has been developed for its 
high selectivity and specificity for the 5-containing receptors versus the 1-, 2-, and 
3-containing receptors, and is devoid of the anxiogenic and pro-convulsant liabilities of 
non-selective GABAA NAMs and antagonists, as described below. 
Previous clinical studies have demonstrated that basmisanil engages with GABAA 5 
receptors in the brain (positron emission tomography [PET] study) and induces a 
characteristic change of the EEG signature (Hipp et al 2021 and Basmisanil 
Investigator’s Brochure), which opposes the EEG signature of GABAAR–enhancing 
drugs (e.g., benzodiazepines, Greenblatt et al 1989). 
Basmisanil was safe and well tolerated in all completed Phase I and Phase II clinical 
studies in other CNS disorders to date, including also a pediatric population 
aged  6 years (see Sections 2.2.3.1 and 2.2.3.2). 
A summary of non-clinical and clinical studies is provided in Section 2.2.3.1 and 
Section 2.2.3.2. Detailed information on non-clinical pharmacology studies including 
pro-cognitive effects; non-clinical pharmacokinetics and metabolism, toxicology, and 
safety studies; as well as clinical studies, is provided in the Basmisanil Investigator’s 
Brochure. 
2.2.3.1 
Non-Clinical Studies 
Non-clinical studies were performed in vitro and in vivo to investigate the specificity, 
selectivity, and activity of basmisanil. In vitro studies examined binding and functional 
activities at different GABAAR subtypes from rat and human, as well as non-specific 
interaction with other binding sites. The in vivo studies investigated the efficacy of 
basmisanil in several animal models (rat and monkey for cognition, Ts65Dn mouse 
model for Down syndrome, and rat and mouse for potential for anxiogenic and pro-
convulsant effects).  
Rat and dog were chosen for in vivo safety studies due to the similarity to humans with 
regard to their drug metabolism patterns, and suitable kinetic data including moderate 
oral bioavailability and comparable pharmacology. All in vivo studies were conducted 
using once daily oral administration unless otherwise specified. 
Repeat-dose toxicity studies in Wistar rats of up to 26-week and in beagle dogs of up to 
39-week duration have been completed. The potential effects of basmisanil on 
embryofetal development were assessed in mated female rats and rabbits, and 

 
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reproductive studies to investigate fertility and pre- and postnatal development were 
performed in rats. Juvenile toxicity studies in post weaning rats and dogs, approximately 
equivalent to 2 to 18 years of age in humans, were completed to explore effects on the 
developing organism. Dose-range finding studies in RasH transgenic mice have been 
conducted in preparation for a planned RasH transgenic mouse carcinogenicity study. 
The genotoxic potential of basmisanil was investigated in the standard battery of in vitro 
and in vivo tests. Safety pharmacology studies were performed to assess the potential 
for any side effects related to exaggerated pharmacological action or off-target effects 
related to vital functions. Toxicokinetic parameters for basmisanil were determined in all 
pivotal in vivo safety studies and adequate exposures were achieved. 
Overall, as no serious safety concerns were identified for basmisanil nonclinically, and 
all risks can be managed clinically, the existing non-clinical package is considered to 
support BP42992 Part 1 and Part 2 study duration in individuals aged 2 years and 
above. Additional information and an overview of all non-clinical pharmacology and 
toxicology studies with basmisanil is provided in the Basmisanil Investigator’s Brochure. 
2.2.3.2 
Clinical Studies 
Information is available from 11 completed Phase I clinical studies: nine studies in 
healthy adult participants (BP25129, WP25366, WP28214, WP28978, JP29312, 
WP29393, WP29394, WP29402, and BP29784); one study enrolling both healthy adult 
participants and adults with Down syndrome (BP25611), one study in young adults with 
Down syndrome (BP25543). Two Phase II studies were conducted in Down syndrome: 
BP27832 [“CLEMATIS”] in adults and adolescents was completed and Study WP28760 
[“SEAHORSE”] in children was prematurely terminated due to the primary endpoint not 
being met in CLEMATIS. One Phase II study (BP39207) in adults was conducted to treat 
cognitive impairment associated with schizophrenia (CIAS). 
To date, basmisanil was administered to more than 500 participants including healthy 
participants, individuals with Down syndrome, schizophrenia, and stroke. Experience 
with basmisanil includes pediatric participants aged 6 to 11 years 
 
) and adolescents aged 12 to 17 years 
  
2.2.3.2.1 
Safety and Tolerability 
Overall, based on data acquired from Phase I and Phase II studies in various 
populations (healthy participants, participants with Down syndrome, participants with 
schizophrenia treated with antipsychotics, and special populations including children 
aged 6 to 11 years and adolescents 12 to 17 years), basmisanil appears safe and well 
tolerated with a favorable adverse event (AE) profile. Monitoring of hematology and 
chemistry safety laboratory data did not indicate any specific risks.  

 
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Phase II studies 
In Study BP27832 (CLEMATIS) 
 adults and adolescents (aged 12 to 30 years) with 
Down syndrome were randomized to receive placebo, or low-dose basmisanil (120 mg 
twice a day [BID] for participants aged 14-30 years and 80 mg BID for participants aged 
12-13 years), or high-dose basmisanil (240 mg BID for participants aged 14-30 years 
and 160 mg BID for participants aged 12-13 years) for 26 weeks. 
 
 
 
 
 
  
In Study WP28760 (SEAHORSE) 
 children (6 to 11 years) with Down syndrome were 
randomized to receive placebo, 
 mg basmisanil 
 for 26 weeks. No 
SAEs were reported from this study.  
In Study BP39207, 
 adults with CIAS were randomized to receive placebo, 
 mg, or 
 mg basmisanil 
 for 24 weeks. 
 
 
 
 
 
  
For more details and summary of non-SAEs reported from these 3 studies, please see 
the Basmisanil Investigator’s Brochure.  
The three Phase II studies confirmed the favorable safety and tolerability profile of 
basmisanil, which was consistent with the overall profile from the phase 1 studies, with 
no new signal noted.  
2.2.3.2.2 
Pharmacokinetics 
In adults, basmisanil is rapidly absorbed from the gastrointestinal tract after oral dosing. 
Peak plasma concentrations occur approximately 4.5 hours after administration of 
immediate-release granules with food. 
 
. The average half-life after repeated dosing ranges from 
 
. 
Food substantially increases basmisanil bioavailability in healthy adult participants. 
Basmisanil is predominantly cleared by metabolism via CYP3A4 and 
 
 

 
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. Following inhibition of CYP3A with itraconazole, the 
systemic exposure to basmisanil 240 mg BID and the maximum plasma concentration of 
basmisanil were increased 4.7- and 4.1-fold, respectively.  
 
 
 
2.3 
BENEFIT/RISK ASSESSMENT 
2.3.1 
Risk Evaluation 
Basmisanil is an orally administered drug with extensive prior clinical experience and an 
established safety and tolerability profile in more than 
 individuals without an ongoing 
medical history of seizures, aged 6 years old and above (see Section 2.2.3). 
2.3.1.1 
Identified Risks for Basmisanil  
QT corrected for heart rate (QTc) prolongation: pharmacokinetic (PK)/pharmacodynamic 
(PD) modeling using data from the itraconazole drug-drug interaction (DDI) Study 
WP29402 and from the multiple ascending dose (MAD) Study WP25366 indicates that 
basmisanil has an effect on the QT interval (QT) duration that is below the threshold 
considered to be of clinical significance by regulatory authorities (Jaminion et al 2020). 
In these studies, median concentrations (5%-95% predicted interval) are predicted to be 
well below the exposure of clinical concern for QTc interval prolongation. ECG will be 
monitored at several timepoints during the study, and additional ECGs will be performed 
in case of a dose increase of basmisanil or in case of a concomitant administration of a 
drug (or a dose increase) known to increase the QTc interval (see Section 8.3.8). 
Clinical data in more than 
 participants do not indicate the potential for proarrhythmic 
risk. 
2.3.1.2 
Potential Risks for Basmisanil 
The potential for a pro-convulsive risk was evoked with the results of the 
pentylenetetrazole (PTZ) test, a potent pro-convulsant, in which sub-threshold doses of 
PTZ given with basmisanil were associated with convulsions at the highest dose tested 
(100 mg/kg) in female rats only. However, it has been proposed that the application of 
the PTZ test to assess the pro-convulsive activity of drugs that potentiate or antagonize 
GABA either directly or indirectly (as in the case with basmisanil, which interacts with the 
same GABAA receptor) may lead to false-positive conclusions (Löscher 2009). 

 
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Beside the PTZ test, non-clinical study results support the lack of pro-convulsant effect 
for basmisanil: 
 
No convulsions and no behavioral abnormalities were observed in the in vivo 
pharmacology experiments nor in Good Laboratory Practice toxicology experiments 
including the highest dose groups. 
 
No effect on audiogenic seizures was observed in DBA/2J mice (a strain that 
exhibits age-dependent susceptibility to seizure following an auditory stimulus). 
 
There were no convulsions and no liability for anxiety in GABAA 5 knock-out mice. 
 
When basmisanil was used in clinical trials, clinical and EEG monitoring implemented in 
healthy participants (at doses of up to 1000 mg BID), in adults and children with Down 
syndrome, and in patients with stroke (at doses of up to 240 mg BID in Phase II studies) 
did not indicate an increased pro-convulsive liability.  
Because epilepsy is present in more than half of the individuals with Dup15q syndrome 
and previous clinical trials excluded participants with a history of seizures or patients 
with epilepsy, the risk for basmisanil to exacerbate or trigger de novo seizures in 
individuals with Dup15q syndrome is not established. Therefore, careful clinical 
monitoring (including AEs, EEG recording, and determination of seizure status using 
caregiver reports and diaries) is implemented in this study. 
In summary, based on cumulative clinical experience in healthy participants and in 
adults and children with Down syndrome the potential for basmisanil to trigger de novo 
seizures or increase the frequency of seizure is considered low and will be carefully 
assessed in this patient population with a high background incidence of seizures.  
Other potential risks described for basmisanil are  
 
either not expected based on previous clinical experience in adolescents and 
children with Down syndrome and in CIAS (i.e., heart rate and blood pressure 
changes, lipids and cholesterol, effect on body weight) or  
 
deemed not clinically significant for the pediatric population with Dup15q syndrome 
(i.e., modest increase in serum creatinine related to the inhibition of its tubular 
secretion by basmisanil) included in this study.  
 
For a complete summary, refer to the Basmisanil Investigator’s Brochure. 
Because of the effect of CYP3A4 inhibitors on the PK of basmisanil, there is a potential 
risk of QTc prolongation. However, because the use of strong CYP3A4 inhibitors is 
prohibited in this study (see Section 6.5.2), this risk of QTc prolongation is considered 
low for this study.  

 
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PK DDIs through inhibition of P-gp efflux are mitigated by prohibiting DOACs and 
advising that other P-gp substrates should be used with caution (see Section 2.2.3.2.2, 
Section 6.5.2, and Section 6.5.3).  
PD DDIs through interaction with GABAA receptors are mitigated by advising that drugs 
acting through GABAA receptors may require a higher dose to reach the desired effect 
when participants are taking basmisanil (see the Basmisanil Investigator’s Brochure, 
Section 6.5.3, and Table 12). 
See the Basmisanil Investigator’s Brochure for more details.  
There is currently no known immunotoxic effect or increased risk of infection under 
basmisanil treatment. However, in the setting of a pandemic or epidemic, screening for 
active infections prior to and during study participation should be considered according 
to local/institutional guidelines, and basmisanil treatment should not be administered to 
participants with active, confirmed, or suspected, COVID-19 due to potential severity of 
this infection. In case of closing of the hospital facilities due to COVID-19, investigators 
should follow up with the participants as needed and at least follow the normal dosing 
schedule (i.e., call the participant for AE recording and ask for safety laboratory tests in 
local laboratories or other investigations (e.g., ECG) as a substitute for investigations 
scheduled at investigational facility if required).  
Based on the eligibility criteria for this study protocol, and the measures that will be 
implemented to monitor participant safety (e.g., guidance regarding prohibited therapy 
[including CYP3A4 inhibitors/inducers], safety monitoring throughout the treatment 
period and follow-up period [laboratory tests, ECG, seizure status, and EEG], 
implementation of PK monitoring with dose adjustment, age-staggered approach for 
inclusion, implementation of dosing stopping rules at the individual participant level, and 
implementation of a Sponsor Internal Monitoring Committee [IMC] and Scientific 
Oversight Committee [SOC]), the risk to participants with Dup15q syndrome treated with 
basmisanil is considered small and will be re-evaluated on an ongoing basis.  
2.3.1.3 
Risk Evaluation of Measures Implemented in the Study 
The study design attempts to minimize harm or discomfort related to study assessments 
by limiting the number of direct evaluations of the participants to the minimum required 
to meet the study objectives. These include standard measures to ensure the 
participants’ safety (EEG, ECG, blood draws, physical examination), as well as two 
neurodevelopmental assessments to assess efficacy. Novel EEG equipment will be 
used to allow participants to move freely, with restrictions during limited periods used for 
quantitative analyses. Although challenging for this population, these assessments are 
minimally invasive and ordinarily encountered in routine clinical care during the 
performance of physical and psychological examinations in children and adolescents with 
Dup15q syndrome.  

 
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Repeated PK sampling (especially first two days of dosing [Day 1 and Day 2] and at 
steady state [Day 14 visit]) will be performed preferably via a cannula to avoid multiple 
blood draws. 
 
 
 
  
The study design also is equally mindful of the burden of study participation for the 
caregivers and the families, taking into account the challenges associated with travelling 
to the study site and completing long study visits with children with Dup15q syndrome. 
Specific visits can be conducted fully remotely using home nursing and telehealth 
solutions, where local regulations allow doing so. Additional flexibility is incorporated for 
the completion of caregiver-reported assessments, which may be completed at home. 
Specific clinic visits may also be split over two consecutive days (as defined in the 
schedule of activities [SoA] in Section 1.3) if required to accommodate 
participants/families. 
2.3.2 
Prospect of Direct Clinical Benefit for Pediatric Participants 
There is currently no clinical evidence with basmisanil to support a prospect of direct 
clinical benefit for patients with Dup15q syndrome. As summarized below, based on the 
mode of action, the clinically demonstrated PD effects of basmisanil at the GABAA α5R, 
as well as non-clinical efficacy data with RO4938581 (see below), a prospect of direct 
clinical benefit to the participants in this study is anticipated. 
Basmisanil is the first treatment option in development to address the underlying 
pathophysiology of Dup15q syndrome, a severe NDD with high unmet medical need 
(see Section 2.2.2). Considerable progress in our understanding of the role of the copy 
number gains of GABRB3, GABRA5 and GABRG3 genes and the downstream 
functional effects point to GABAA α5R as a valid and important target to treat Dup15q 
syndrome (see Section 2.1). 
The direct genetic link with GABAA α5R in Dup15q syndrome contrasts with the previous 
indications in which basmisanil did not show efficacy (Studies BP27832 in Down 
syndrome and BP39207 in CIAS). Indeed, the pathomechanisms of schizophrenia and 
Down syndrome are multifactorial and poorly understood. Negative allosteric modulation 
of the GABAA α5R subtype has been postulated to have cognitive-enhancing properties 
(Rudolph and Knoflach 2011, Nutt et al 2007). Selective modulation at GABAA α5R was 
thus selected as a “safe mechanism” to restore excitation-inhibition balance and improve 
cognition (reducing GABAergic function in Down syndrome; indirectly enhancing 
N-methyl-D-aspartate receptor function in CIAS) (Martinez-Cue et al 2013, 
Redrobe et al 2011), without the safety liabilities associated with GABAAa1,2,3 negative 
modulation (Rudolph and Knoflach 2011).  
By contrast, in Dup15q syndrome, GABAA α5R are proximally involved in the core 
disease pathophysiology (see Section 2.1) and the mode of action of basmisanil directly 

 
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opposes the functional consequences of the genetic duplication of GABR genes (see 
Section 2.2.3). Therefore, it is deemed unlikely that lack of efficacy in previous phase II 
studies for this mode of action reliably informs effects in the Dup15q syndrome 
population.  
Clinically, basmisanil decreases GABAA α5R function in the brain, as indexed by the 
decreases in EEG beta-band power (see the Basmisanil Investigator’s Brochure). This 
provides PD evidence that basmisanil can directly target GABAA-related 
pathomechanisms in Dup15q syndrome, namely excessive GABAA α5R activity. This 
study will use EEG beta-band power as a marker of excess GABAAR function in Dup15q 
syndrome (see Section 2.2.3). In particular, this study will test for treatment-related 
quantitative EEG (qEEG) normalizations to increase the confidence that the selected 
dose of basmisanil affects the GABAAR-related pathophysiology. In case of lack of 
effects of basmisanil treatment on the Dup15q EEG phenotype at an early interim 
analysis, which would point to lack of beneficial effects on the GABA-related 
pathophysiology, the study would be stopped to ensure that participants are not treated 
unnecessarily (see the interim analyses in Section 4.1.2.2).  
Non-clinical evidence further supports a prospect of clinical benefit in Dup15q syndrome 
following chronic GABAA α5 negative allosteric modulation. Indeed, beneficial effects 
were observed in a mouse model of Dup15q (patDp/+), following treatment with a 
GABAAα5 NAM (RO4938581). RO4938581 has a comparable pharmacological profile to 
basmisanil (potency, selectivity, and inhibition of GABA-mediated currents, see the 
Basmisanil Investigator’s Brochure). The patDp/+ mouse model shows good construct 
and face validity with duplication of syntenic mouse equivalent 15q region and models 
GABR copy number gains, as it does not over-express the UBE3A gene. In line with the 
excess GABR gene dose, the model recapitulates GABAergic signaling dysfunction in 
Dup15q syndrome with increased GABAA α5 receptor (subunits) expression and receptor 
activity, reflected in single-cell electrophysiology and an increased EEG beta-band 
power. Beneficial effects on learning inflexibility and abnormal social behavior were 
observed after chronic treatment with RO4938581 with partial normalization of 
electrophysiological phenotypes, including the EEG beta-band phenotype (see 
Basmisanil Investigator’s Brochure). This suggests that selectively targeting GABAA 
α5Rs is sufficient to rescue impairments linked to GABAAR dysfunction in Dup15q.  
The 52-week study duration in Part 1 allows for a prospect of direct benefit for pediatric 
participants receiving basmisanil in this Phase II study across core neurodevelopmental 
symptoms with anticipated slow-paced changes (see the rationale for study duration in 
Section 4.2.2). Additionally, the 2-year OLE (Part 2) allows for a prospect of direct 
benefit for all study participants who completed Part 1, including those randomized to 
placebo.  
Moreover, due to the proximal interplay between the disease mechanisms and GABAA 
α5Rs and their role in neural development and inhibitory synapse formation, early 

 
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intervention is proposed to provide prospect of clinical benefit to pediatric participants in 
the study (see the rationale for study population in Section 4.2.1 and Section 4.2.2).  
2.3.3 
Overall Benefit/Risk Assessment  
The totality of the evidence outlined in Section 2.3 indicates that treatment with 
basmisanil has the potential to affect disease pathophysiology and core 
neurodevelopmental symptoms by normalizing the excessive GABAA α5R activity in 
Dup15q syndrome, with a prospect of direct clinical benefit for pediatric participants in 
this study. The thorough safety monitoring plan in place to continuously assess risks in 
this population (as compared to the established risk profile of basmisanil), with mitigation 
of the risk of unnecessary drug exposure in absence of an impact on a biomarker of the 
GABAAR pathophysiology are in place to safeguard study participants. The benefit/risk 
balance is thus considered to favorable for pediatric participants in this study, who are 
affected by a rare disease with no treatment options. 
In addition, Study BP42992 will generate unprecedented evidence on the relative 
contribution of GABR genes to the disease and inform the development of therapeutic 
strategies in Dup15q syndrome. In the absence of natural history data, this study will 
also provide the first clinical characterization of the disease trajectory over 1 year 
(placebo arm in Part 1). Independently of study outcome, the knowledge acquired will 
inform the development of endpoints for future clinical development in this indication and 
thus contribute to promoting the health of children with Dup15q syndrome. 
3. 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints are provided in Table 5 for Part 1 and in 
Table 6 for Part 2. 

 
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obtained, and EEG recordings and relevant safety assessments will be performed (see 
SoA in Section 1.3).  
In Part 1, recruitment will be staggered as follows (see Figure 2): 
 
By age 
 
 
 to 
assess safety in participants aged 6 to 14 years before exposing participants aged 2 
to 5 years, see Figure 2. 
 
By presence or absence of epilepsy to assess the effect of basmisanil on seizures 
before enrolling participants without epilepsy (for rationale see Section 4.2.1).  
 
The study consists of two stages: 
Figure 2 Staggered Enrollment in Part 1 
 
IMC = Internal Monitoring Committee; N = number of participants; SOC = Scientific Oversight 
Committee; y = years. 
 
Staggered enrollment by age and presence or absence of epilepsy will be implemented as 
follows: 
 
Stage 1: Participants between ages 6 and 14 years (inclusive) with epilepsy will be 
enrolled. 
Data from a minimum of 9 participants enrolled in Stage 1 will be reviewed by an 
IMC + SOC as described in Section 4.1.2.2 prior to opening recruitment to 
participants aged 2 to 5 years and participants without epilepsy into Stage 2. 

 
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• 
Stage 2: The remaining participants aged 2 to 14 years with or without epilepsy will 
be enrolled following IMC + SOC recommendation to reach a total sample size of 
approximately N=90. 
Data from participants enrolled into Stage 1 and 2 will be included in periodic 
reviews by the IMC + SOC and a first interim analysis will be performed when 
approximately N=24 participants reach 4 weeks of treatment, as described in 
Section 4.1.2.2. 
 
Overall, the study aims to enroll a minimum of approximately one-third of participants 
aged 2 to 5 years and a maximum of approximately one-fifth of participants aged 12 to 
14 years.  
Treatment Groups and Duration 
Treatment with basmisanil or placebo granules, packaged in stick-packs, will be 
administered orally within 30 minutes after the start of a meal (see Section 6.4). 
Table 7 
Starting Doses According to the Age of the Participants: 
 
 
  
In Part 1, the starting dose is determined according to the participant’s age at the time 
of signing of the Informed Consent Form, and maintained for the 52-week treatment 
duration. 
In Part 2, the starting dose, dosing regimen and age-defined dose groups are initially 
the same as for Part 1 (Day 2 and onwards) and determined based on the participant’s 
age at the start of Part 2 (Day 366 visit). During Part 2, the dose will be adjusted 
according to the participant’s actual age. If applicable, the dose must be changed at the 
latest on the first dispensation visit after a participant moves into a different age group. 
Dose and dose regimen for participants aged 15 to 17 years are predicted to be similar 
to what has been determined as the starting steady state regimen in Part 1 for 10 to 
14 years old 
 
 
 

 
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4.1.1 
Length of the Study 
The planned total study duration is approximately 61 weeks for participants who 
participate in Part 1 only and 165 weeks for those participating in Parts 1 and 2, 
divided into the following periods: 
 
Screening period of up to 5 weeks (Day 35 to Day 2), which may overlap with the 
baseline period (Day 7 to Day 1) 
 
Double-blind 52-week treatment period (Day 1 to Day 365) 
 
Optional OLE treatment period of approximately 2 years/104 weeks (Day 366 to 
Day 1095/Year 3)  
 
Follow-up period of approximately 4 weeks (Part 1: Days 365 to 395 or 
Part 2: Days 1095 to 1125) 
 
The screening period starts once the first screening assessment is performed (not with 
signing the Informed Consent Form [ICF]). All screening assessments required to 
confirm participant’s eligibility for study participation need to be completed with 
results available before the Baseline visit. The Baseline visit can be done anytime 
between Day - 7 and Day -1.  
4.1.2 
Internal Monitoring Committee and Scientific Oversight 
Committee 
4.1.2.1 
Administrative Structure 
Internal Monitoring Committee 
A Sponsor IMC will be responsible for regular reviews of accumulating safety, 
tolerability, and 
 in terms of 
tolerability and exposure. The IMC will consist of internal Sponsor experts representing 
Clinical Pharmacology, Pharmacometrics, Clinical Science, Drug Safety, Statistics, as 

 
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well as Biomarkers. Attendance at IMC meetings will be determined by the purpose of 
the IMC meeting; not all members are expected to be required for all meetings.  
IMC members will review unblinded aggregated information as part of all reviews and 
interim analyses, i.e., summary information by treatment arm. As required by their 
functional expertise, selected IMC members (e.g., clinical pharmacology, drug safety) 
may be unblinded also at a participant level.  
Individual study team members outside the IMC required to prepare information for IMC 
review will be unblinded to the treatment assignment of individual participants. Access to 
treatment assignment information will follow the Sponsor’s standard procedures. 
Scientific Oversight Committee  
During Part 1 of the study, an SOC will help monitor safety and tolerability data until 
all participants have completed or were prematurely withdrawn from Part 1. 
Specifically, the SOC will help interpret any changes in seizure status and/or EEG 
findings in this patient population, to ensure that the study in its current form does not 
pose unacceptable safety risks to participants. The SOC will consist of one or more 
external neurologist/epileptologist with expertise in pediatric epilepsy in neurogenetic 
disorders and who is not an Investigator in this study. The SOC members will also 
review unblinded aggregated information and may be unblinded at the participant level if 
required.  
A separate IMC+SOC agreement will include additional details on membership and 
procedures. 
4.1.2.2 
Review Objectives and Procedures 
During Part 1, the IMC will perform periodic reviews of all available PK exposure, 
safety, and tolerability data, including up to two interim analyses as described below. As 
part of these reviews, the SOC may be consulted on the interpretation of safety and 
tolerability data if required. “IMC+SOC” is used to refer to these reviews with the focus 
as described below. 
Periodic reviews during enrollment of the first 24 participants in Part 1 Stages 1 
and 2: 
The objectives of the IMC+SOC periodic reviews of the initial PK and safety data are to: 
 
  
(2) confirm that data support opening enrollment into Stage 2.  
 

 
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The clinical pharmacologist, supported by a pharmacometrician, will review exposure 
data on a continuous basis. 
 
  
Once a minimum of 9 participants have completed their first 4 weeks of dosing in 
Stage 1, the IMC+SOC will perform a review of all available PK exposure, safety, and 
tolerability data. Based on this review, the IMC may 
 
  
Periodic reviews of PK and safety data by the IMC+SOC will continue throughout the 
course of the study.  
Interim analyses: 
In addition to the aforementioned reviews of PK and safety data, the IMC+SOC will also 
oversee up to two interim analyses: 
 
The first interim analysis occurs once approximately 24 participants (i.e., the 
participants of Stages 1 and 2), with a minimum of 9 participants aged 2 to 5 years, 
have completed 4 weeks of treatment. In addition to PK, safety, and tolerability data, 
the IMC+SOC will review the effect of basmisanil treatment on the Dup15q EEG 
phenotype (qEEG beta-band power). 
The IMC may recommend continuing the study unchanged, to adapt the dose, to 
decrease PK and/or safety assessments, or to stop the study in case of significant 
safety findings or in case of lack of effect of basmisanil treatment on the Dup15q 
EEG phenotype.  
 
A second interim analysis may occur as described in Section 9.5. Following 
review of the data, the IMC may recommend to continue the study unchanged or to 
terminate the study if benefit / risk considerations make a continuation unethical.  
 
The study will continue to enroll participants during the conduct of both interim analyses. 
Details of interim analyses will be described in a technical document, which will be 
stored in the Sponsor’s trial master file. 
4.1.3 
Stopping Rules Criteria 
Dosing will be stopped at any time during the study in a given individual participant if one 
of the following circumstances occurs:  
 
A QTc using the Fridericia’s correction factor (QTcF) value 480 msec (when 
confirmed in repeat measurement within 30 minutes) or a QTcF change from 
baseline  60 msec (when confirmed in repeat measurement within 30 minutes) for 
participants older than 10 years old;  
OR 

 
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 
A QTc using Bazett’s formula (QTcB) value  480 msec (when confirmed in repeat 
measurement within 30 minutes) or a QTcB change from baseline  60 msec (when 
confirmed in repeat measurement within 30 minutes) for participants up to, and 
including, the age of 10 years (Bazett’s correction is more appropriate in young 
children, see Section 8.2.6). 
 
Worsening of seizure frequency or occurrence of de novo seizures, which are 
considered clinically relevant in the opinion of the Investigator based on the 
following criteria: 
– 
persistent over time,  
OR 
– 
notably deviate from the expected fluctuations in seizure status based on the 
participant’s medical history,  
OR  
– 
cannot be explained by the expected natural course of the disease, 
OR 
– 
making the benefit-risk ratio non-favorable for the individual. 
 
Other AEs that may lead to discontinuation of study treatment following evaluation on a 
case-by-case basis are described in Section 8.3.8. Before permanently discontinuing 
study treatment, an interruption should be considered, and study treatment may be 
restarted as detailed in Section 6.6.1. Unless it is determined by the Investigator that the 
occurrence is not related to the administration of study treatment, study treatment should 
not be restarted (see Section 7.1).  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The study rationale is provided in Section 2.1. 
4.2.1 
Rationale for Study Population 
The study will be conducted in male and female participants with maternal duplication or 
triplication of the chromosome 15q11.2-q13.1 region, aged 2 to 14 years at the time of 
signing the Informed Consent Form. 
Participants with 3 or 4 copies of 15q11.2-q13.1 region, both int(15) and idic(15) 
The study population includes patients with Dup15q syndrome, defined by a maternal 
duplication (resulting in 3 copies) or triplication (resulting in 4 copies) containing the 
Prader-Willi/Angelman Critical Region on chromosome 15q11.2-q13.1. It includes the 
GABAA subunit gene cluster encoding for 3 receptor subunits that together form GABAA 
α5-containing receptors. Both int(15) and idic(15) genetic subtypes present with the 
characteristic EEG signature that index excess GABAA function consequent to the copy 

 
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number gains (Section 2.2.1 and Section 2.2.3) and are thus expected to benefit from 
treatment with basmisanil. The effect of copy numbers on response to treatment will be 
explored in this study if applicable.  
Participants aged 2 to 14 years 
Dup15q syndrome is an NDD with symptoms such as central hypotonia, infantile spasm 
and feeding difficulties emerging early in infancy. Motor and cognitive developmental 
delays are typically recognized in early childhood. Because of the neurodevelopmental 
nature of the disorder, early symptoms in Dup15q syndrome likely contribute to poorer 
clinical outcomes, as suggested by greater clinical severity of children with infantile 
spasms compared with children with other epilepsy types which emerge later in 
childhood (DiStefano et al 2020). Hypotonia and impaired motor skills in early childhood 
may also negatively influence learning, language, and speech acquisition, and the 
development of social skills, as in other NDDs (Wilson et al 2018). Early intervention 
offers the opportunity to affect the trajectory of the disease by altering early brain 
development and maximizing learning and socialization opportunities during key 
neurodevelopmental stages (Vivanti et al 2018). 
To which extent efficacy in adults with NDDs predicts treatment effects in children 
remains a matter of debate. Long-term neural adaptations and impact of the disease on 
brain function (e.g., decades of epilepsy for some patients), the difference in profiles of 
co-morbidities, and co-medications have been proposed as potential confounding 
factors. Early intervention during developmental stages in childhood, as early as 
possible following diagnosis (see Section 2.2.1) is thus proposed to provide greater 
prospect of benefit on neurodevelopmental outcomes in children. Greater effects may 
theoretically be expected for treatment with basmisanil at early developmental stages, 
when GABAergic control shapes inhibitory neuronal function (see Section 2.1) but are 
anticipated to be beneficial throughout neurodevelopment into early adulthood. 
Adolescents ( 11 years) may present with more variable response to treatment, due to 
greater heterogeneity in terms of developmental stages and to the interference of 
multiple factors emerging at adolescence such as the physiological changes linked to 
puberty, parent- and clinician-reported instability in symptoms (e.g., behavioral 
difficulties or anxiety), as well as important social and environmental changes during the 
teenage years. Taking into account the significant delay in development associated 
with Dup15q syndrome, and the inclusion criterion of at least “moderate” disease 
severity as measured by Dup15q-CGI-S, inclusion of young adolescents aged 12 to 
14 years is considered a reasonable extension of the pediatric study population. The 
effect of age on response to treatment will be explored in this study.  

 
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Epilepsy 
Individuals with uncontrolled epilepsy (as defined for this study in Section 5.2) are 
excluded from the study because of expected general instability from both safety and 
efficacy perspectives, and because of polypharmacy concerns, both of which may 
directly interfere with signal detection and reliable assessment of benefit/risk for the 
broader Dup15q syndrome population. 
Study population for Part 1 Stages 1 and 2 (see Figure 2)  
The good safety and tolerability profile of basmisanil has been clinically established in 
more than 500 individuals (see Section 2.2.3.2), including pediatric patients with Down 
syndrome aged  6 years, but excluded patients with an ongoing medical history of 
epilepsy. The study population in Stage 1 will be restricted to participants aged 6 to 14 
years with epilepsy, to establish the safety and tolerability profile of basmisanil in older 
participants before enrolling younger participants aged 2 to 5 years, and to establish 
the safety and tolerability profile of basmisanil in participants who have epilepsy before 
enrolling participants without epilepsy into Stage 2. 
4.2.2 
Rationale for Study Duration 
Developmental progression is slowed in children affected by severe NDDs associated 
with intellectual disability, and meaningful improvements in core neurodevelopmental 
symptoms likewise likely require time to manifest. Beneficial treatment effects on 
neurodevelopmental gains are also anticipated to increase with treatment duration. 
Longer trials, particularly in pediatric populations, have been recommended by expert 
working groups for trials in rare NDDs based on the experience in other neurogenetic 
syndromes (e.g., Berry-Kravis et al 2018). A duration of 52 weeks, as recommended by 
an expert advisory panel consulted by the Sponsor, was selected to maximize the 
detection of meaningful changes on core neurodevelopmental features of the disorder in 
the placebo-controlled part of the study, as captured by the primary measure (Vineland-
3: language, social skills and impact on daily functioning) and key secondary measures 
(Mullen Scales of Early Learning [MSEL]: motor and cognitive development). To ensure 
that the participants enrolled in this study are not treated unnecessarily for 52 weeks, at 
least one interim analysis will be performed to re-evaluate benefit/risk (see Section 
4.1.2.2). 
The 52-week study duration in Part 1 will also generate the first longitudinal 
characterization of the natural trajectory of the disease in Dup15q syndrome, which is 
needed to support the determination of meaningful improvement on core disease 
domains. 
The OLE duration will allow the collection of long-term safety and tolerability data of a 
minimum of 2 years of basmisanil treatment in all Part 2 participants, and up to 
3 years for those randomized to basmisanil in Part 1, and thus maximize the safety 

 
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information on basmisanil in this rare disorder. Additionally, it may provide supportive 
evidence of continued treatment benefit on key efficacy outcomes. 
4.2.3 
Rationale for Assessments 
4.2.3.1 
Electroencephalography  
EEG will be assessed at several timepoints throughout the study (see the SoA in 
Section 1.3), and it serves several purposes. 
Biomarker: Quantitative EEG 
The background EEG in the awake state of individuals with Dup15q syndrome shows 
markedly abnormal (excess) beta-band power and is thought to index excess GABAA 
neurotransmission (Urraca et al 2013, Frohlich et al 2016, Frohlich et al 2019). This EEG 
abnormality will be quantified (qEEG) at several timepoints (qEEG blocks) to test for 
treatment-related changes (see Section 8.6.2). 
Monitoring of Epileptiform Activity 
Approximately 60% of individuals with Dup15q syndrome have epilepsy, which affects 
patients with idic(15) (60% to 80%) more frequently than those with int(15) duplications 
(16 to 25%) (Kalsner et al 2015, Conant et al 2014, Beghi et al 2020, Battaglia et al 
2016). Participants enrolled in Stage 1 of the study will have a medical history of 
epilepsy, while participants enrolled in Stage 2 may or may not have epilepsy. 
Clinical seizures will be closely monitored during the study in all participants to ensure 
participant safety (see Section 8.2.9) and also in order to investigate potential changes 
in seizure activity (see Section 8.2.4). 
Seizure activity may be captured by the Investigator as AEs (see criteria in 
Sections 8.3.6 and 8.3.7) and/or entered in the seizure status section of the eCRF 
following joint review of the caregiver-completed seizure diary with the caregiver (see 
Section 8.1.3). 
Furthermore, EEG recordings will be reviewed by a central reader (qualified neurologist 
independent of the site personnel) for potential treatment-emergent epileptiform 
abnormalities such as sharp wave, spike, spike-wave, or polyspike, and seizures (see 
Section 8.2.9). 
4.2.3.2 
Gait Assessment 
Gait in Dup15q syndrome is impaired, characterized by poor postural control, and large 
gait variability (Wilson et al 2020). In Part 1, gait abnormalities and potential treatment-
related changes will be quantified in the home setting, using wearable devices that will 
be attached to the 
 
 
 
 
 
 

 
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4.2.4 
Rationale for Control Group 
The study is placebo controlled, as there is no approved treatment for the Dup15q 
syndrome. Given the lack of natural history data, a placebo-controlled design is required 
to assess benefits and risks of basmisanil treatment objectively. Improvements and 
developmental progress in the enrolled participants are expected over the one-year 
course of the study; therefore, in Part 1 of the study a placebo arm is essential to 
distinguish improvements due to natural development from the possible beneficial 
effects of basmisanil treatment. A placebo-controlled trial remains the most 
methodologically rigorous approach to assess the effect size of prospective new 
medicines (Di Pietro et al 2015). 
 
 
 
 
 
- in line with the envisaged mechanism 
of action of normalizing the gain-of-function of GABAA 5 receptors - the aim is to block 
RO maximally 
. 
Occupancy by basmisanil of the GABAA 5-containing receptor subtype in the brain has 
been investigated using PET imaging in healthy volunteers and in individuals with Down 
syndrome. A direct relationship between basmisanil plasma concentrations and RO was 
established, 
 
 
 
 
 
 
 
Basmisanil is predominantly cleared by metabolism via CYP3A. 
 
 
 
 
 
 
 
 
 
 
A PBPK model integrating available pediatric data from two previous studies in 
participants with Down syndrome (Study WP28760 [SEAHORSE] and Study BP27832 

 
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[CLEMATIS]) and adult information was developed (Basmisanil Investigator’s 
Brochure). 
 
 
. The pediatric PBPK model was used to simulate basmisanil 
exposure and variability in pediatric participants aged 2 to 11 years
 
 It 
predicted median AUC0-12h and Cmax values in this
 
 
 
 
 TID dosing is predicted to result in higher 
plasma exposures than what can be achieved with BID due to absorption limitation. 
 
 
 
 
 
 
 
 
 
 
 
For the starting doses according to the age of the participants, see Section 4.1 
(treatment groups and duration).  
A dosing algorithm has been defined utilizing available combinations of stick-packs with 
different dose strengths to provide a range of exposures comparable to those in adults 
across the full age range of children enrolled in this study.  
Dosing regimen 
 
 
 
 BID dosing was selected for the first dosing day (in 
clinic). In addition, to characterize the exposure–EEG relationship (both acute safety 
(safety EEGs) and PD (qEEG beta-band power), a wide concentration range will be 
covered in the first two days of dosing. The dosing regimen changes to TID from Day 2 
onwards to reach targeted exposure levels at steady state throughout the 52-week 
treatment period in Part 1 and the 2-year treatment period in Part 2. 
Further details on the justification for dose are provided in the Basmisanil Investigator’s 
Brochure. 

 
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4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he/she has completed all 
phases of the study, including the last scheduled procedure per SoA or withdrawal of 
consent.  
The end of the study is defined as the date when the last participant’s last observation 
occurs.  
5. 
STUDY POPULATION 
The study population rationale is provided in Section 4.2.1. 
The participants in this study will be female and male children and adolescents aged 2 to 
14 years at the time of signing the ICF for Part 1 with genetically confirmed maternal 
duplications (3 copies) or triplications (4 copies) of chromosome 15q11.2-q13.1 (Dup15q 
syndrome), who fulfill all of the given inclusion criteria and none of the exclusion criteria. 
The criteria to participate in Part 2 optional OLE are described in Section 6.7. 
Prospective approval of protocol deviations, also known as protocol waivers or 
exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in Part 1 of the study only if all of the following 
criteria apply: 
Informed Consent/Age 
1. 
Participants aged 2 to 14 years inclusive at the time the caregiver signs the 
informed consent.  
Type of Participants and Disease Characteristics 
2. 
In the investigator’s opinion, able to participate and deemed appropriate for 
participation in the study. 
3. 
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. 
4. 
Dup15q syndrome Clinician Global Impression of Severity scale (Dup15q 
CGI-S) overall severity score  4 (at least moderately ill). 
5. 
Stage 1 specific inclusion criterion: Participants aged 6 to 14 years with epilepsy.  
Weight 
6. 
Body weight equal to or above the third percentile for age. 

 
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Sex and Contraception/Barrier Requirements 
7. 
Male and female participants 
Some of the provisions that follow may have limited applicability based on the age range 
of study participants (i.e., up to the age of 14) and the nature of the disease under study. 
These provisions are nonetheless included for purposes of completeness to make clear 
that individuals who are pregnant or are engaging in actions that may cause them to 
become pregnant, should not participate in this study. Consent must be provided by the 
legal representative for all participants. 
a) Female Participants 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and at least one of the following conditions applies: 
 
Female participants of non-childbearing potential, as defined in Appendix 5. 
 
Female participants of childbearing potential who agree to remain abstinent (refrain 
from heterosexual intercourse) or use acceptable contraceptive methods during the 
treatment period and for at least 28 days after the final dose of study treatment. The 
following are acceptable contraceptive methods: bilateral tubal occlusion/ ligation, 
male sexual partner who is sterilized, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and 
copper intrauterine devices, male or female condom with or without spermicide; and 
cap, diaphragm, or sponge with spermicide. 
b) Male Participants 
Male contraception is not required in this study because of the minimal seminal dose 
transmitted through sexual intercourse.  
Caregiver Requirements 
8. 
The 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.  
9. 
The 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.  
10. The 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.  

 
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5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. 
Uncontrolled epilepsy at screening as indicated by: 
a) Use of rescue medication(s) to treat more than one seizure episode or seizure 
cluster per month on average in the past 6 months, 
OR 
b) Concomitant chronic use of more than 4 anti-epileptic medications, 
OR  
c) 
Status epilepticus within the past 6 months requiring hospitalization for 
treatment of the status epilepticus, 
OR 
d) Any implanted devices to treat drug-resistant epilepsy 
2. 
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. 
3. 
Clinically significant ECG abnormalities at screening, including an average triplicate 
QTcF  450 ms for participants  10 years or QTcB  450 ms for children up to and 
including age 10 years (because Bazett’s correction is more appropriate in young 
children). 
4. 
Clinically significant abnormalities in laboratory test results at screening (including 
positive results for HIV, hepatitis B and/or hepatitis C). ALT values  1.5  the upper 
limit of normal (ULN; re-testing is allowed to confirm). GFR < 90 mL/min per 1.73 
m2 (Grade 1 CKD) as estimated using Schwarz formula. 
 
Prior/Concomitant Therapy 
5. 
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.  
6. 
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). 
7. 
Concomitant use of prohibited medications (Section 6.5.2). 
Prior/Concurrent Clinical Study Experience 
8. 
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. 

 
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Other Exclusions 
9. 
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). 
10. 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).  
11. 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.  
12. 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. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Throughout the study, due to a food effect on basmisanil exposure (see 
Section 2.2.3.2.2), a meal should be given before each study treatment administration. 
In Part 1, on Day 1, Day 2, Day 14, and Day 365 study visits and in Part 2, on Day 366 
and Day 1095 study visits, the meals should be taken as per the timings given in the 
detailed SoA (Table 2 and Table 4 for Part 1 and Part 2, respectively) to allow for 
adequate characterization of PK properties. Participants are allowed to eat additional 
snacks/meals and water is allowed ad libitum.  
A ketogenic diet should be on a stable regimen for 6 weeks prior to screening and should 
not be stopped or newly started throughout the study until the Part 1 follow-up visit 
for participants who do not continue study participation in Part 2 or until the Day 548 
visit for participants who roll over to Part 2 of the study. Any other dietary restrictions 
should be documented. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants whose consent has been obtained via a 
caregiver to participate in the study but are not subsequently randomized to study 
treatment. Screen failures may be tracked separately. 
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure. 
Screen-failed participants may be re-screened with Sponsor permission (Medical 
Monitor or designee) if there is a substantial change in the participant’s general condition 

 
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(e.g., stabilization of medication or clinical status) and if recruitment for the study is still 
ongoing.  
Re-screening is also allowed for participants who were screened in the study and met all 
inclusion/exclusion criteria but failed to be randomized within the combined screening 
(Day -35 to Day -2) and Baseline (Day -7 to Day -1) window because of a study halt, or 
logistical, personal, or technical reasons (including availability of screening test results).  
Consultation with the Medical Monitor may be needed to identify whether repeat testing 
of any particular parameter is clinically relevant, on a case-by-case basis. The most 
current result prior to enrollment is the value by which study inclusion will be assessed, 
as it represents the participant’s most current clinical state.  
Re-screening is permitted once per participant. Samples of screen failures will not be 
retained for further analysis. 
5.5 
RECRUITMENT PROCEDURES  
Participants will be identified for potential recruitment using pre-screening enrollment 
logs, clinical database, referrals from other clinicians, patient groups, and Institutional 
Review Board (IRB)/Independent Ethics Committees (IEC) approved participant-facing 
recruitment materials prior to consenting to take place in this study.  
6. 
TREATMENTS 
Study treatment is defined as any investigational product (including placebo) or 
marketed product intended to be administered to a study participant according to the 
study protocol. 
The investigational medicinal products (IMP) for this study are basmisanil and placebo. 
Appendix 6 identifies all IMPs and auxiliary medicinal products (AxMPs)/non-
investigational medicinal products (NIMPs). All IMPs required for completion of this 
study will be provided by the Sponsor.  
Cases of overdose, medication error, drug abuse, or drug misuse, along with any 
associated AEs, should be reported as described in Appendix 2, Section 5.2. 
6.1 
TREATMENTS ADMINISTERED 
Table 8 and Table 9 summarize the treatments administered in Part 1 and Part 2, 
respectively. Guidelines for dosage modification and treatment interruption or 
discontinuation are provided in Section 6.6 or Section 7, respectively. 

 
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Table 9 
Summary of Treatments Administered in Part 2 
Study Treatment 
Name: 
Basmisanil (RO5186582)  
Use: 
Dose Formulation: 
Unit Dose 
Strength: 
Doseb: 
Route of 
Administration: 
oral 
Sourcing: 
Provided centrally by the Sponsor  
Packaging and 
Labeling: 
Study treatment will be provided in boxes. Each box will be labeled 
as required per country requirement. 
BID = twice a day; PBPK = physiologically-based pharmacokinetic; PK = pharmacokinetic; 
TID = three times a day. 
a Study treatment will be provided 
 
. No placebo is used in Part 2. The number of stick-packs to be taken per 
administration will depend on the participant’s actual age.  
b These are the starting doses for participants in Part 2. The starting dose will be determined 
according to the actual age of the participant at the start of Part 2 (Day 366 visit) and the 
dose must be changed at the latest on the first dispensation visit after the participant moved 
into a different age group (see Section 4.1). 
Dose and dose regimen for participants aged 15 to 17 years are predicted to be similar to 
what has been determined as the starting steady state regimen in Part 1 for 10 to 14 years 
old 
 
 
Dose or dose regimen may be adapted during the study (see Sections 4.1 and 6.6). 
 
Please see Section 6.4 for details on the requirements for study treatment administration 
as well as the Basmisanil Investigator’s Brochure for more details. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Study treatment packaging will be overseen by the Sponsor’s clinical study supplies 
department and will bear a label with the identification required by local law, the protocol 
number, drug identification, and dosage.  
The packaging and labeling of the study treatment will be in accordance with the 
Sponsor’s standard and local regulations.  

 
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The study site should follow all instructions included with each shipment of IMP. The 
investigational site will acknowledge receipt of IMPs and confirm the shipment condition 
and content. Any damaged shipments will be replaced. The investigator or designee 
must confirm that appropriate temperature conditions have been maintained during 
transit for all IMPs received, and that any discrepancies have been reported and 
resolved before use of the IMPs. All IMPs must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized staff. 
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. Study treatment will be dispensed at the study visits or 
shipped to the participant’s home (where local regulations allow for home shipments). 
Caregivers will be instructed on IMP administration, storage and return. Returned study 
treatment should not be re-dispensed to the participants. 
The study site (i.e., Investigator or other authorized personnel [e.g., pharmacist]) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each participant, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that participants are provided with 
doses specified by the protocol. The study site may also be responsible for shipping IMP 
to the participant’s home. Upon arrival of the IMPs at the site, site personnel will 
complete the following: 
 
Check the IMPs for damage. 
 
Verify proper identity, quantity, integrity of seals and temperature conditions. 
 
Report any deviations or product complaints to the Study Monitor upon discovery. 
 
The Investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment. 
All study treatments must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the Investigator and authorized site staff. 
The Investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). Unused 
IMP stick-packs will have to be returned by the caregiver at clinic visit or via the 
shipping courier to the study site for drug accountability and reconciliation.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 

 
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IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. Accurate records of all IMPs received at, dispensed from, returned to, 
and disposed of by the study site should be recorded on the drug accountability log. 
Refer to the Basmisanil Investigator’s Brochure for information on IMP formulation, IMP 
handling, including preparation and storage, and accountability. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING 
6.3.1 
Method of Treatment Assignment 
All participants will be centrally randomized to study treatment using an Interactive 
Voice/Web Response System (IxRS). Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the login information and directions for the 
IxRS will be provided to each site. 
Randomization will be stratified by  
 
Age group (2 to 5 years vs. 6 to 14 years)  
 
Number of copies of the15q11.2-q13.1 region (3 copies vs. 4 copies) 
 
Epilepsy (presence vs. absence) 
 
In Part 2 all participants are assigned to receive open-label basmisanil, regardless of 
their treatment assignment in Part 1.  
6.3.2 
Blinding 
Part 1 is a double-blind study, i.e., the study participants, the Investigators, all 
individuals in direct contact with the study participants at the investigative site, and the 
Sponsor Study Management Team (SMT) will be blinded to treatment assignment. PK 
data can be transferred and cleaned on an ongoing basis. The data will be handled and 
cleaned in a secure area that is not accessible by any blinded SMT member. 
Members of the IMC and SOC will review unblinded aggregated information. Selected 
IMC and SOC members may be unblinded also at a participant level (see 
Section 4.1.2.1). Individual study team members outside the IMC and SOC required to 
prepare information for IMC and SOC review will be unblinded to the treatment 
assignment at the participant level. Access to treatment assignment information will 
follow the Sponsor’s standard procedures. 
Emergency Unblinding 
If unblinding is necessary for participant management in the case of an SAE, the 
Investigator will be able to break the treatment code by contacting the IxRS. Treatment 
codes should not be broken except in emergency situations. If the Investigator wishes to 

 
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know the identity of the study treatment for any other reason, he/she should contact the 
Medical Monitor directly. The Investigator should document and provide an explanation 
for any premature unblinding (e.g., accidental unblinding, unblinding due to an SAE). 
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAEs (see Section 8.3.3.1) that are considered by the 
Investigator to be related to study treatment. The participant may continue to receive 
treatment, and the Investigator, participant, and Sponsor personnel, with the exception 
of the Drug Safety representative and personnel who must have access to participant 
treatment assignments to fulfill their roles (as defined above), will remain blinded to 
treatment assignment. 
Whenever disclosure of the identity of the test medication is necessary, adequate 
procedures will be in place to ensure integrity of the data. 
6.4 
TREATMENT COMPLIANCE 
The qualified individual responsible for dispensing the study treatment will write the date 
dispensed and participant number on the study treatment label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study. 
The study treatment granules are packaged in stick-packs, which have to be cut open 
with scissors and not ripped. 
 
 
 
 
 
 
 
 
 
  
On the first day of treatment in Part 1 (Day 1), the study treatment is taken BID, in 
the morning and in the evening, at the clinical study site. Thereafter, the study 
treatment is taken TID, at least 3 hours apart and within 30 minutes after the start of a 
meal.  
Caregivers will use a drug diary to record missed study treatment administration 
throughout the study (see Section 8.1.3.1). If a dose is missed (i.e., there would be less 
than 3 hours until the next dose), it must not be taken with the next dose and recorded 
as missed dose in the drug diary. The following dose should be taken at the usual time.  
6.5 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
(OTC) drugs, vaccines (including COVID-19 vaccines), approved dietary and herbal 
supplements and nutritional supplements used by a participant from 6 weeks prior to 

 
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screening until the follow-up visit. See also stability requirements for a ketogenic diet in 
Section 5.3. 
Anti-epileptic medication must be on a stable regimen 8 weeks prior to screening and 
for at least the first 4 weeks of treatment in Part 1. After the Day 28 visit, dose 
adjustments within the therapeutic range, and changes within the same class of 
anti-epileptic medication may be allowed as part of routine clinical care, upon 
consultation with the Medical Monitor. In Part 2, for the first 28 days (until Day 395) 
dose changes are not allowed. Changes in the number or the class of anti-epileptic 
medications are not allowed until the Part 1 follow-up visit for participants who do not 
continue study participation in the optional OLE or until the Day 548 visit for 
participants who roll over to Part 2 of the study. 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF) along with reason for 
use, dates of administration (including start and end dates) and dosage information 
(including dose and frequency). 
All medication administered to manage AEs should be recorded on the Adverse Event 
eCRF. 
Non-pharmacological (e.g., physiotherapy) / behavioral therapies should not be 
stopped or newly started at least 6 weeks prior to screening and are expected to remain 
stable until the Part 1 follow-up visit or until the Day 548 visit for Part 2 participants 
(excluding changes related to standard age and educational interventional programs or 
minor interruptions such as illness or vacation). 
Non-pharmacological / behavioral therapies should be reported on the appropriate eCRF 
page. 
6.5.1 
Permitted Therapy 
Permitted therapy includes all medication used by a participant to manage symptoms 
associated with Dup15q syndrome that is not specified as prohibited therapy in 
Section 6.5.2, taken from 6 weeks prior to screening until the Part 1 follow-up visit or 
until the Day 548 visit for participants in Part 2. 
Participants who use oral contraceptives with a failure rate of < 1% per year; see 
Section 5.1 and Appendix 5, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 

 
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6.5.2 
Prohibited Therapy 
The below listed therapies are prohibited and should not be administered within 2 weeks 
(or within 5-times the elimination half-life, whichever is longer) prior to dosing and until 
the Follow-up visit, unless otherwise specified. Methods of administration, which do not 
produce appreciable systemic drug exposure (e.g., topical administration for skin 
conditions), are permitted: 
Modulators of CYP3A4 Activity  
Basmisanil is predominantly cleared by metabolism via CYP3A4, and concomitant 
medications that significantly alter CYP3A4 activity will affect the pharmacokinetics of 
basmisanil.  
Strong inhibitors of CYP3A4 (e.g., itraconazole, erythromycin, fluconazole, nefazodone, 
ritonavir, verapamil, grapefruit or grapefruit juice) taken within 2 weeks (or within 5-times 
the elimination half-life, whichever is longer) prior to dosing is prohibited. Moderate 
CYP3A4 inhibitors may be used after discussion with the Medical Monitor and eventual 
use of inhibitors of CYP3A should be accompanied by dedicated safety monitoring, in 
particular the QT. 
Inducers of CYP3A4 (e.g., rifampicin, carbamazepine, pioglitazone, rifampin, modafinil, 
systemic glucocorticoids, oxycarbazepine, carbamazepine, phenobarbital, phenytoin, St 
John’s Wort) taken within 4 weeks prior to dosing (or within 5  times the elimination 
half-life, whichever is longer) are not permitted.  
Dofetilide 
Dofetilide use is not permitted because of the potential for interaction between 
basmisanil and renally cleared cationic drugs, as well as the very narrow therapeutic 
window of dofetilide. 
Benzodiazepines (chronic use) 
Based on the potential for interactions to occur between basmisanil and other 
medications whose effects are mediated via GABAA receptors, chronic use of 
benzodiazepines, including as treatment for epilepsy (e.g., clobazam) is not allowed.  
Restrictions for acute use of benzodiazepines are described in Section 6.5.3. 
 
 
  

 
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OTC Cannabidiol (CBD)  
Use of artisanal CBDs (products, derivatives, cannabis plants/extracts) is prohibited. 
Epidiolex/Epidyolex is not prohibited.  
6.5.3 
Therapy to be Used with Caution 
 
 
 
 
 
 
Concomitant medications with an effect on QT 
Drugs known to prolong the QTc interval will be allowed if stable at screening provided 
the screening QTc does not meet exclusion QTc criterion. Use of currently approved 
prokinetics (e.g. domperidone, metoclopramide) is not prohibited, but requires closer 
monitoring of QTc interval on ECG due to risk of arrhythmias. 
Benzodiazepines / GABAergic medications  
Benzodiazepines and benzodiazepine-related drugs may be exceptionally used with the 
following restrictions: 
 
For the treatment of intermittent medical conditions (e.g., for insomnia and 
anxiety / agitation, analgosedation) 
– 
Medications with a short half-life (e.g., lorazepam, alprazolam, or oxazepam) 
are preferred 
– 
Short-term use only (no more than 4 days per month)  
– 
Should not be taken within 2 days before a scheduled visit 
 
For the treatment of emergency situations (e.g., for the acute management of a 
seizure) 
– 
If benzodiazepines/benzodiazepine-related drugs are required in an emergency 
situation, the visit can be rescheduled to allow for a 2-day window between 
emergency medication and visit date (even if it falls out of the protocol defined 
visit window). 
– 
If benzodiazepines, in particular diazepam, midazolam, or clonazepam are 
used, the Investigator should be aware that a higher-than-normal dose of the 
medication may be required to achieve clinical response.  
– 
Similarly, in case of acute use of anesthetics that are GABAA positive allosteric 
modulators (e.g., volatile anesthetics or hypnotics) in a participant treated with 

 
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basmisanil, a higher dose of the anesthetics may be required to achieve the 
desired effect.  
 
As described above, these recommendations are based on the potential for competition 
(PD interaction) at the GABAA receptor level.  
6.6 
DOSE MODIFICATION, TEMPORARY INTERRUPTION AND 
RECHALLENGE 
 
 
  
 
 
 
 
 
  
 
 
6.6.1 
Temporary Interruption 
Before permanently discontinuing study treatment (regardless of whether initiated by the 
participant/caregiver, the Investigator or Sponsor), an interruption should be considered. 
Temporary study treatment interruption is an acceptable method to manage AEs related 
to the study treatment.  
Participants who have temporarily interrupted should be considered for restarting study 
treatment as soon as medically justified in the opinion of the Investigator.  
Study treatment should be interrupted if individual stopping rules are met (see 
Section 4.1.3) and to manage specific AEs and resumed as detailed in Section 8.3.8. 
Study treatment may be resumed with the joint agreement of the Investigator and the 
Sponsor’s Medical Monitor when follow-up test results show that the participant no 
longer meets the dose interruption criteria. Unless it is determined by the Investigator 
that the occurrence is not related to the administration of the study treatment, study 
treatment should not be restarted. 
6.7 
TREATMENT AFTER THE END OF PART 1 OF THE STUDY 
All participants who complete the 52 weeks of study treatment in Part 1 will be offered 
the option to roll over into an OLE to receive basmisanil treatment for a duration of 

 
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approximately 2 years (Part 2). Participants will be required to sign a separate ICF for 
participation in Part 2. 
A participant will not be eligible to receive study treatment after the end of Part 1 of the 
study if any of the following conditions are met: 
 
The study treatment is commercially marketed in the participant's country and is 
reasonably accessible to the participant (e.g., is covered by the participant's 
insurance or would not otherwise create a financial hardship for the participant). 
 
The Sponsor has discontinued development of the study treatment or data suggest 
that the study treatment is not effective for Dup15q syndrome. 
 
The Sponsor has reasonable safety concerns with regards to the study treatment. 
 
Provision of study treatment is not permitted under the laws and regulations of the 
participant's country. 
 
The participant discontinued prematurely from study treatment or withdrew from the 
study before completing 52 weeks of treatment. 
 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Participants have the right to voluntarily discontinue study treatment or withdraw from 
the study at any time for any reason.  
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study-specific procedures as outlined in this 
protocol. 
Details on study and site closures are provided in Appendix 1, Section 4. 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
For data to be collected at the time of treatment discontinuation and follow-up and for 
any further evaluations that need to be completed see the SoA (Section 1.3). 
Reasons for discontinuation of study treatment may include, but are not limited to, the 
following: 
 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues study treatment. 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant. 
 
Participant suicidal behavior or active suicidal ideation with specific plan and intent. 

 
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 
An event that meets the stopping criteria (see Section 4.1.3). 
 
Pregnancy. 
 
Specific AEs if discontinuation of study treatment is required to manage the event 
(see Section 8.3.8). 
 
Symptomatic participants with moderate or severe COVID-19 infection (as per WHO 
guidelines) with signs of pneumonia or hypoxia. 
 
Every effort should be made to obtain information on participants who discontinue study 
treatment but have not withdrawn consent. Participants who discontinue study treatment 
prematurely (Part 1 or Part 2) will be asked to return to the clinic for a study early 
termination visit (see Section 8.10.3) and will be asked to complete the follow-up visit 
(see Section 8.10.4), unless the participant withdrew consent. The primary reason for 
premature study treatment discontinuation should be documented on the appropriate 
eCRF.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY 
Participants have the right to voluntarily withdraw from the study at any time for any 
reason. 
In addition, the Investigator has the right to withdraw a participant from the study for 
medical conditions that the Investigator or Sponsor determines, may jeopardize the 
participant’s safety if he/she continues in the study. 
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn. 
This includes the follow-up assessments. 
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will be used as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of samples donated 
to the Research Biosample Repository (RBR). 
Participants who withdraw from the study will not be replaced (for sample size 
determination, see Section 9.1). 
For data to be collected at the time of study discontinuation and for any further 
evaluations that need to be completed see SoA (Section 1.3). 

 
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7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the caregiver of the participant and reschedule the 
missed visit as soon as possible.  
 
Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the caregiver of the participant. These 
contact attempts should be documented in the participant’s medical record. 
 
Should the caregiver of the participant continue to be unreachable, the participant 
will be considered to have withdrawn from the study. 
 
Discontinuation of sites or of study as a whole are handled as part of Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timepoints are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Remote visits 
The Day 92, Day 274, early termination, and follow-up visits (Part 1) can be done 
remotely at the participant’s home, if local regulations allow for it. Visits at the 
participant’s home will be conducted by a mobile nurse (MN) professional. The sponsor 
will select a healthcare company that will be responsible for providing MN services for 
participating sites. The MN vendor is responsible for ensuring that all MN professionals 
are licensed, qualified, and in good standing, as per applicable regulations, and that 
appropriate background checks have been performed.  
Visits on Day 28 (Part 1) and on Day 457 (Part 2) will be done as a telephone/video 
call. 
In addition, during Part 2, mandatory phone calls every 3 months (at minimum) will be 
done to follow up on AEs, concomitant therapies and to assess suicidality. 
Blood sampling 
The volume of blood taken will follow the recommendations from the European Union on 
ethical considerations for clinical trials on medicinal products conducted with minors, 
which states 3% of total blood volume over 4 weeks and 1% of total blood volume at a 
single time. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 

 
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Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) obtained before signing of the ICF may be utilized for screening 
purposes, provided the procedure met the protocol-specified criteria. A previously 
established genetic diagnosis of Dup15q syndrome (medical history obtained before 
signing of the ICF, see Section 8.2.1) which contains the required information to 
determine eligibility (see Section 5.1) may be utilized for screening.  
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
Requirements and Instructions for Caregivers 
To reduce variability in reporting, the same caregiver is asked to provide feedback on all 
informant-based assessments throughout the study, and the same caregiver should 
attend all on-site visits. If a visit cannot be completed as arranged (e.g., the caregiver is 
delayed in transit) visits should be rescheduled as soon as possible after the original 
appointment. The caregiver’s relationship to the child (mother, father, etc.) will be 
captured for all caregiver-reported assessments. If the caregiver changes during the 
study, this should be captured in the medical records and transcribed into the eCRF with 
a reason for the change. 
The caregiver must be able to attend the on-site visits and be available for the home 
visits when required. The caregiver must oversee the participant’s compliance with 
protocol-specified procedures, including compliance to study treatment and report on the 
participant’s status via completion of study diaries and assessments. Caregiver-reported 
assessments can be completed at applicable clinic visits or remotely/at home throughout 
the study, if the requirements described in Section 8.1.4.2 can be fulfilled. 
8.1.2 
Caregiver Expectations Guidance 
Because of the important role of the caregiver as respondent in several key 
assessments, they will be provided with a short training on their role in the study prior to 
the administration of clinical scales. The training can be provided either by the 
Investigator or as a self-read document on TrialMax (see the SoA in Section 1.3). This 
aims to help caregivers accurately report on the participant’s health and behaviors.  
8.1.3 
Equipment for Home Measurements 
8.1.3.1 
Dedicated Website (TrialMax)  
Diaries and outcome assessments can be completed at home or at site through a 
dedicated website (TrialMax) where caregivers can log in. The login will be created at 
screening by the site personnel. The TrialMax website can be accessed either through 
the caregiver’s personal device or, if required, on a dedicated digital device 
(Section 8.1.3.2). TrialMax contains:  

 
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 
the seizure diary (see Section 8.2.4) 
 
the drug diary to record missed study medication (Section 6.4) 
 
the meal record to answer questions about whether the doses were given with the 
meal (see Section 8.5) 
 
caregiver-reported assessments (see Table 10 and Section 8.1.5) 
 
Caregiver expectation guidance (see Section 8.1.2) 
 
8.1.3.2 
Devices 
To access the dedicated website (TrialMax) (Section 8.1.3.1) for diary entries or 
completion of caregiver-reported assessments, caregivers may use an appropriate 
personal device (with restrictions) or a dedicated digital device provided by the electronic 
clinical outcome assessment (eCOA) vendor for the duration of the study.  
Two wearable devices will be provided to all caregivers of all participants who are able to 
walk 10 meters without assistance at screening. These wearable devices record the leg 
movements of the participant. One device will be worn on each ankle (see 
Section 8.1.5.12).  
The equipment will be issued to the caregivers during the screening visit, as will 
educational materials and an instruction manual. Caregivers will be trained on the 
correct use of all devices.  
All dedicated digital devices must be returned to the clinic upon completion of study 
Part 1 for those who do not continue study participation in Part 2, or upon completion 
of study Part 2, or upon early termination. 
8.1.4 
Data Collection Methods for Clinical Outcome Assessments 
Clinical outcome assessments will be completed in the clinic or remotely at home as 
shown in Table 10.  
To decrease the study burden for participants and their families and for the sites, some 
study visits can be performed entirely remotely (at Day 28 [Part 1] and Day 457 [Part 2] 
 telephone call only; and at Day 92, Day 274, Day 395 [Part 1] follow up, and early 
termination [Part 1] with home nursing and via telemedicine) (see the SoA in 
Section 1.3). Furthermore, caregiver-reported assessments scheduled at in-clinic visits 
(as specified in the SoA and per footnote “c” in Table 10) may also be performed 
remotely, consistently across visits, if all the requirements described in Section 8.1.4.2 
can be fulfilled. 

 
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b Performed in the clinic by the clinician, except Day 28 which will be a phone call visit and Day 92, 
Day 274, Day 395 (follow up), and early termination visits which can be remote, if local regulations allow 
for it and if home nursing service is available in the country/region, via video call. 
c Vineland-3 interview and completion of caregiver-reported scales can be done either at the clinic visit or 
at home under remote site supervision. The preferred method should be determined at Baseline and kept 
consistent throughout the study.  
d Included in this outcome assessment table for completeness; but not used as efficacy assessment in this 
study (Section 8.2 and Section 8.1.5.13). 
 
Training, guidance on rater qualifications, rating, and scoring procedures are described 
separately in the Rater Manual. An external company and external consultant will 
provide training to all site raters on the various scales and will provide all sites with the 
relevant record forms (paper or rater station device), instruction manuals, and kits as 
appropriate. Training and certification on the ADOS-2 will have to be performed through 
the scale owner (Western Psychological Services) directly, Roche may facilitate access 
to ADOS-2 training. 
Rater qualification will be reviewed per the criteria established by the Sponsor. Only 
raters certified by the vendor to be qualified on those assessments should rate in this 
study. Efforts should be made to have the same rater or clinician perform the 
assessments for a given participant throughout the study as established at the 
screening and/or baseline visit. 
8.1.4.1 
Clinician-Reported Outcome Assessments 
Clinician-reported outcome (ClinRO) data will be collected through use of the following 
instruments: Dup15q CGI-S, Dup15q CGI-C, hypotonia assessment, and suicidality 
questions (completed by the clinician); MSEL and ADOS-2 completed by a certified rater 
(site personnel), and Vineland-3 completed by a certified remote central rater 
(independent from the site personnel, see Table 10 and Section 8.1.5). ClinRO 
instruments will be completed at the clinic or remotely during the study as specified in 
the SoA (see Section 1.3).  
The Vineland-3 interview may be completed remotely/at home or during the clinic visit, 
consistently throughout the study, based on the caregiver’s preference as stated at 
Baseline. For interviews completed remotely/at home, the criteria for remote 
assessments described in Section 8.1.4.2 also apply. 
Remote centralized administration for the Vineland-3 (see Section 8.1.5.2) will be carried 
out via telephone and may be audio recorded. If a remote administration session cannot 
occur for an unforeseen reason, it will be rescheduled. 
ADOS-2 and MSEL administration by a certified rater on site will be video recorded for 
quality control purposes. 
A rater station device provided by the eCOA vendor will be used by site staff to capture 
or transcribe all ClinRO data. The instructions and training for completing the 

 
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assessments electronically will be provided by the eCOA vendor. The data will be 
transmitted to a centralized database maintained by the eCOA vendor. Paper booklets 
may be used to capture clinical outcome assessment data (if the digitalized scale 
version is not available or in case of technical issues).  
8.1.4.2 
Caregiver-Reported Assessments 
Caregiver-reported data about the participants’ health and behaviors will be collected 
through completion of the following instruments: ABC-2-C, ORCA, RBS-R, CSHQ, 
Dup15q CaGI-S, and Dup15q CaGI-C. Caregiver-reported data about caregiver and 
family functioning will be collected through administration of the PedsQL-FIM (see 
Table 10 and Section 8.1.5). 
The caregiver-reported assessments will be completed through a dedicated website 
(TrialMax) on an appropriate personal device, or a dedicated digital device provided by 
the eCOA vendor (see Section 8.1.3), or paper-based if the digital device is not available 
or feasible for a selected assessment and a paper-based alternative is available. 
Caregiver-reported data will also be collected through use of a seizure diary 
(Section 8.2.4) and a drug diary (Section 6.4) via TrialMax. 
The assessments may be completed remotely/at home or during the clinic visit, 
consistently throughout the study, based on the caregiver’s preference as stated at 
Baseline. For caregiver assessments completed remotely/at home, the following 
requirements apply: 
 
The caregiver must be able to dedicate sufficient time for completion (total 
approximately 2 hours, see Table 10). 
 
The caregiver must have access to a location with limited distractions where 
privacy can be ensured. 
 
The assessments must be performed within a time window of 5 days before the 
scheduled clinic visit (see Section 8.10 and SoA in Section 1.3). 
 
The assessments can be performed with remote support from the site as needed. 
 
Detailed guidance will be provided by the eCOA vendor to the study sites for remote 
assessment completion/administration. 
8.1.5 
Clinical Outcome Assessments  
8.1.5.1 
Dup15q Syndrome Clinician Global Impression of Severity and 
Clinician Global Impression of Change  
The Dup15q CGI-S is a 10-domain, clinician-rated measure, which measures global 
severity of illness at a given point in time. Nine domains are seizures, expressive 
communication difficulties, fine motor skills difficulties, gross motor skills difficulties, 
cognitive/intellectual impairment, impairment in activities of daily living/self-care, 
socialization, maladaptive behavior, and sleep difficulties. The tenth domain is a score 
for overall severity. The Dup15q CGI-S is a 6-point scale with response options of none, 

 
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very mild, mild, moderate, severe, and very severe. Guidelines for rating will be provided 
to ensure consistency. 
The Dup15q CGI-C is also a 10-domain, clinician-rated measure, assessing the 
clinician’s impression of change in illness compared with baseline. The 10 domains are 
the same as the domains specified for the Dup15q CGI-S. The Dup15q CGI-C is a 7-
point scale, with response options of very much improved, much improved, minimally 
improved, no change, minimally worse, much worse, and very much worse. Guidelines 
for rating will be provided to ensure consistency. 
8.1.5.2 
Vineland Adaptive Behavior Scales–Third Edition  
The Vineland-3 is an instrument that measures communication, daily living skills, 
socialization, and motor skills (Sparrow et al 2016). The maladaptive behavior domain is 
not administered in this study. The Comprehensive Interview Form (i.e., a 
semi-structured interview) will be administered via telephone to the participant’s 
caregiver by a certified remote central rater independent of the site personnel (see 
Section 8.1.4.1). The central rater will ask the caregiver open-ended questions relating 
to the participant’s activities and behavior. Items are either scored as 2 = Usually, 
1 = Sometimes, 0 = Never, or scored as 2 = Yes, 0 = No in the case of items that require 
a binary response. Lower scores indicate lower adaptive behavior abilities.  
8.1.5.3 
Mullen Scales of Early Learning  
The MSEL are designed for a certified rater to provide an assessment of cognitive ability 
and motor development of typically developing children from birth through age 
68 months (Mullen 1995). The MSEL will be administered to all participants in the 
study, irrespective of their chronological age. They have previously been used outside of 
the standardized age norms to characterize the cognitive and developmental profiles of 
children and adolescents with Dup15q syndrome (DiStefano et al 2020). The 
instrument consists of 124 items across five scales measuring Gross Motor, Visual 
Reception, Fine Motor, Expressive Language, and Receptive Language. Each scale is 
comprised of interactive tasks that can be completed by the child or can be scored by 
the certified rater through interview of, or with assistance from, the caregiver. The 
scoring for each item ranges from 0 to 5 points. Lower scores indicate lower 
developmental abilities.  
8.1.5.4 
Autism Diagnostic Observational Schedule, Second Edition  
The ADOS-2 is a diagnostic tool used to document the presence of ASD (Gotham et al 
2007, Lord et al 2000). During a semi-structured evaluation, the individual is observed in 
a naturalistic social situation and assessed by a certified rater across areas of social 
communication, imagination, and restricted and/or repetitive behaviors. The ADOS-2 
includes four modules for use with different age groups and language levels. 

 
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8.1.5.5 
Aberrant Behavior Checklist-Community – Second Edition  
The ABC-2 is an updated, empirically derived, validated 58-item caregiver-completed 
rating scale that measures the severity of a range of maladaptive behaviors commonly 
observed in children, adolescents, and adults with intellectual and developmental 
disabilities (Aman et al 2010, Aman and Singh 2017). The Community version of the 
scale (ABC-2-C) will be used. It is designed for use in individuals who are not residing in 
institutional settings. The checklist assesses symptoms across five domains: irritability, 
social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate 
speech. Items are scored on a 4-point scale from 0 (never) to 3 (severe problem). Sub-
scale scores and a total score can be calculated with higher scores indicating greater 
severity.  
8.1.5.6 
Pediatric Quality of Life InventoryFamily Impact Module 
The PedsQL-FIM, Version 2, (Varni et al 2007) is a 36-item, informant-based measure 
that will be completed by the caregiver. The instrument was developed to measure 
parent and family functioning. It encompasses 6 scales covering Physical Functioning 
(6 items), Emotional Functioning (5 items), Social Functioning (4 items), Cognitive 
Functioning (5 items), Communication (3 items), and Worry (5 items) and 2 scales 
measuring parent-reported family functioning, Daily Activities (3 items) and Family 
Relationships (5 items). The acute form, using a recall period of 7 days, will be employed 
in this trial. Items are scored on a 5-point scale from 0 (never a problem) to 4 (almost 
always a problem) with higher scores indicating greater severity. 
8.1.5.7 
Observer-Reported Communication Ability 
The ORCA assesses the communication ability of an individual from the perspective of a 
caregiver. The instrument consists of 73 items representing 22 conceptual areas of 
communication capturing expressive, receptive and pragmatic communication skills, 
alongside a set of communication specific descriptive items that capture information 
about the individual’s unique ways of communicating. All items, except “turns in 
conversation”, have the same three response options of “No or only once”, “Sometimes”, 
and “Yes, almost all the time”. “Turns in conversation” has 5 response options: 0, 1, 2, 3, 
4 or more turns. A hierarchical ordering of communication ability level differentiates 
which behaviors represent lower ability (level 1) versus higher ability (greater than level 
1) within each concept. 
8.1.5.8 
Repetitive Behavior Scale–Revised  
The RBS-R is a 43-item informant-based caregiver-reported questionnaire, assessing 
the variety of restricted and repetitive behaviors observed in individuals with ASD 
(Bodfish et al 2000). The scale is grouped into six subscales: Stereotyped, Self-Injurious, 
Compulsive, Ritualistic, Sameness, and Restricted Behaviors. Each item uses a 4-point 
response scale assessing the presence and severity of a restricted or repetitive 
behavior. Response options range from "Behavior does not occur" (0) to "Behavior 
occurs and is a severe problem" (3). A total score is generated for each subscale and an 
overall total score encompasses all the subscales.  

 
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8.1.5.9 
Assessment of Hypotonia  
The Investigator or designee will perform an assessment of hypotonia (head control and 
truncal stability) including absence or presence of hypotonia, severity grading, and 
changes since the last visit at the timepoints specified in the SoA (Section 1.3).  
8.1.5.10 
Children’s Sleep Habit Questionnaire 
The Children’s Sleep Habit Questionnaire (CSHQ), which includes 45-items assessing 
sleep habits and possible difficulties with sleep, was developed for typically developing 
children aged 4 to 10 years (Owens et al 2000). The CSHQ will be administered to all 
participants in the study, irrespective of their chronological age. The CSHQ has 
previously been used outside of the standardized age norms to characterize the sleep 
parameters of children and adolescents with ASD aged 5 to 20 years (Schnapp et al 
2022). The past week is the recall period, however if the last week is unusual for a 
specific reason, the most recent typical week will be chosen. Unless noted, “Always” 
refers to something occurring every night, “Usually” if it occurs 5 or 6 times a week, 
“Sometimes” if it occurs 2−4 times a week, “Rarely” if it occurs once a week, and “Never” 
if it occurs less than once a week. The questionnaire will be completed by the caregiver. 
Individual subscale scores as well as a total score can be calculated, with higher scores 
indicating more severe sleep disturbance. 
8.1.5.11 
Dup15q Syndrome Caregiver Global Impression of Severity 
and Caregiver Global Impression of Change 
The Dup15q CaGI-S is a nine domain, caregiver-rated measure, assessing the 
caregiver’s impression of the impact of a participant’s condition, in this case Dup15q 
syndrome (no other conditions/co-morbidities). This scale mirrors the Dup15q CGI-S 
described in Section 8.1.5.1. The nine concept-specific domains are seizures, non-
verbal and verbal expressive communication, fine motor skills, gross motor skills, 
cognition, self-care, socialization, disruptive behavior, and sleep. The tenth domain is a 
score for overall severity. Guidelines will be provided to ensure consistency of rating. 
The Dup15q CaGI-C is a 10-domain, caregiver-rated measure, assessing the caregiver’s 
impression of change in the participant’s condition, in this case Dup15q Syndrome (no 
other conditions or co-morbidities), compared with baseline. This scale includes the 
same domains as the Dup15q CaGI-S, and mirrors the Dup15q CGI-C described in 
Section 8.1.5.1. Guidelines for rating will be provided to ensure consistency of rating. 
8.1.5.12 
Wearable device 
Participants who are able to walk should wear a movement monitor during periods 
specified in the SoA in Section 1.3. All efforts should be made to ensure that 
participants who are able to walk 10 meters without assistance at screening and can 
tolerate the wearable device wear the device throughout the specified periods. The 
purpose of this device is to measure daily movement and activity levels of the participant 
accurately during normal daily living, outside of investigational site visits. The device 
consists of two sensors, one of which is worn on each ankle. As the device battery 

 
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requires recharging overnight, the device will not be worn at night. The device is not 
waterproof and must not be worn during bathing, swimming, or showering. The 
participant and caregiver will be trained on the correct use of the device, including 
correct fitting and wearing of the device, how to dock the device on the battery charging 
station, and when to return the wearable devices to the site. Detailed instructions as to 
use of the device are provided in the User Manual and Quick Start Guide.  
8.1.5.13 
Palatability questionnaire 
Palatability will be indirectly assessed by asking caregivers about the child’s reaction to 
the administration of the study treatment and ease of drug administration: 
1. 
On the basis of the reaction ⁄ facial expression of your child, do you think that the 
medication is: pleasant, not sure, or unpleasant? 
2. 
Do you sometimes have problems in giving the medication to your child because 
he/she refuses to take it or throws it up? Yes/No 
 
8.1.5.14 
Caregiver Exit Interview 
If consent is provided, caregivers of study participants may be invited to participate in an 
optional, 1-hour, one-to-one interview, which will be recorded and transcribed. Interviews 
will be completed via telephone, in the caregiver’s native language, and as soon as 
possible but no later than 4 weeks after the Day 365 visit (during follow-up period if 
participant does not enter Part 2 or during the first 4 weeks of Part 2). Interviews are 
optional, and if a caregiver initially consents to participate in the interview, they can 
subsequently decide not to participate at a later time without any implications for their 
participation in the overall study. If a caregiver declines to participate at the start of the 
study this will not have any implication for the participation in the overall study. 
These interviews will provide qualitative insights regarding among others: the daily life 
impact of Dup15q syndrome for the study participant; any key areas of change over the 
duration of the study; and the real-world impact of the changes that are most important. 
Caregivers will be asked to specifically consider areas such as developmental skills 
(including communication, motor function, cognition, behavior, and self-care), and 
seizures. Additionally, these interviews will capture information regarding how any 
change in Dup15q syndrome symptoms or functional ability may affect the daily life of 
the participant’s caregivers and family. These interviews will be performed by a trained 
interviewer independent of the site personnel to explore whether there were additional 
Dup15q syndrome concepts that were not captured in the standard efficacy 
assessments. A semi-structured interview guide will be administered, including both 
open-ended and closed-ended questions.  
8.2 
SAFETY ASSESSMENTS 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 

 
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Safety assessments will consist of monitoring and recording AEs, including SAEs and 
AEs of special interest (AESIs); and measurement of protocol-specified safety laboratory 
assessments, vital signs, ECGs, seizure status, and other protocol-specified tests that 
are deemed critical to the safety evaluation of the study. 
8.2.1 
Medical History and Demographic Data 
Medical history includes lifetime clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), including infantile hypotonia and 
infantile spasms and date of diagnosis of Dup15q syndrome. Medical history should be 
recorded in the eCRF.  
The following information will also be collected and recorded in the eCRF: 
 
All medications (e.g., prescription drugs, OTC drugs, herbal or homeopathic 
remedies, nutritional supplements)  
 
Non-pharmacological interventions, including e.g., behavioral, physical, or speech 
therapies, within 6 weeks prior to the screening visit  
 
Demographic data will include age, sex, and caregiver-reported race/ethnicity  
 
Level of education and participation in special educational or day programs 
8.2.2 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
Weight, height and head circumference: Body weight (using calibrated scales) will be 
measured to the nearest 100 g at the timepoints specified in the SoA (Section 1.3). Head 
circumference will be measured in children below the age of 5 years to the nearest 0.1 
cm using a flexible, non-stretchable tape.  

 
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Abnormal changes from baseline should be recorded in participant’s notes. New or 
worsened clinically significant abnormalities should be recorded as AEs on the Adverse 
Event eCRF. 
8.2.3 
Tanner Staging 
Tanner staging for pubertal status will be determined at the timepoints listed in the SoA 
(Section 1.3). In Part 1, Tanner staging will be assessed for participants aged 9 years or 
above at the time of signing the Informed Consent Form. In Part 2, Tanner staging will 
be assessed for participants aged 9 or above at the time of the assessment. 
Tanner staging will not be performed after participants achieve Stage 5. 
8.2.4 
Seizure Status 
The seizure diary (see Section 8.1.3) will be provided to caregivers for completion at 
home after initial training at the clinic. The diary entries are event driven, i.e., have to be 
completed retrospectively after a seizure occurred, and contain information on seizure 
type, duration, and frequency based on guidance from the International League Against 
Epilepsy (ILAE; Scheffer et al 2017, Fisher et al 2017). A list of seizure types is 
provided for selection by the Investigator based on the “ILAE 2017 Classification of 
Seizure Types Expanded Version“ (Appendix 7) to support the seizure diary entries.  
In addition, the seizure diary asks to confirm accurate entries at regular intervals. 
The Investigator will determine the participant’s recent seizure status at the timepoints 
specified in the SoA (in Part 1 and for the first 6 months in Part 2; see Section 1.3), 
based on caregiver report (time since last visit) and review of the information in the 
seizure diary (see Table 11 for review period for each assessment).  

 
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8.2.5 
Vital Signs 
Blood pressure, pulse rate, respiratory rate, and body temperature (oral or tympanic) will 
be recorded at the timepoints specified in the SoA (Section 1.3). Blood pressure, pulse 
rate, and respiratory rate should be obtained in a quiet room at a comfortable 
temperature, with the participant's arm unconstrained by clothing or other material. The 
participant should be asked to remove all clothing that covers the location of cuff 
placement. All measurements will be obtained from the same arm and, with the 
appropriate cuff size, using a well-calibrated automatic instrument with a digital readout, 
throughout the study (the “ideal” cuff should have a bladder length that is 80% and a 
width that is at least 40% of arm circumference [a length-to-width ratio of 2:1]). The 
individual should be comfortably in a semi-supine/supine position, with the legs 
uncrossed. 
8.2.6 
Electrocardiograms 
At each specified timepoint, 12-lead ECG recordings must be obtained in triplicate (i.e., 
three useful ECGs without artifacts 2 to 3 minutes apart), per the SoA (see Section 1.3). 
The average of the three readings will be used to determine ECG intervals (e.g., PR, 
QRS complex [QRS], and QT). Whenever possible, the same brand/model of a standard 
high-quality, high-fidelity electrocardiograph machine equipped with computer-based 
interval measurements should be used for each participant. The conditions should be as 
close as possible to pre-dose timepoints; this includes but is not limited to food intake, 
activity level, stressors, and room temperature. To minimize variability, every effort 
should be made that participants be in a resting position for  10 minutes prior to each 
ECG evaluation. Body position should be consistently maintained for each ECG 
evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, 
radio, conversation) should be avoided during the pre-ECG resting period and during 
ECG recording. ECGs should be performed prior to any scheduled vital sign 
measurements and blood draws. In some cases, it may be appropriate to repeat 
abnormal ECGs to rule out improper lead placement as contributing to the ECG 
abnormality.  
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory. ECG characteristics, including heart 
rate, QRS duration, and PR, and QT, will be recorded on the eCRF. QTcB (Bazett’s 
correction; Phan et al 2015), QTcF (Fridericia’s correction), and RR will be recorded on 
the eCRF. 
Both corrections of QTc will be tabulated and analyzed, although, in children, Bazett’s 
formula appears to provide a better correction of the QT. Changes in T-wave and U-
wave morphology and overall ECG interpretation will be documented on the eCRF. T-
wave information will be captured as normal or abnormal, U-wave information will be 

 
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captured in two categories: absent/normal or abnormal. Any medically relevant changes 
occurring during the study should be recorded in the AE section of the case report form 
(CRF). 
8.2.7 
Clinical Safety Laboratory Assessments 
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of clinical laboratory tests to be performed is provided in 
Appendix 4, and these assessments must be conducted in accordance with the 
laboratories process. If analysis is required to be done centrally, the samples and assays 
should be clearly identified, and instructions may be provided by the central laboratory 
manual according to the requirements from the SoA (Section 1.3). 
At any time, safety laboratory samples will be given priority over any other sample, such 
that the volume of blood taken at any single timepoint will not exceed 1% of total blood 
volume, and the volume collected over any 4-week period throughout the study will not 
exceed 3% of total blood volume, as per recommendations by the European Union. The 
Investigator must review the laboratory report, document this review, and record any 
medically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Medically relevant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant's 
condition. 
 
In the event of unexplained, abnormal, medically relevant laboratory test values, the 
tests should be repeated immediately and followed up until values have returned to 
the normal range and/or an adequate explanation of the abnormality is found. 
 
If such values do not return to normal/baseline within a period judged reasonable by 
the Investigator, the etiology should be identified and the Sponsor notified. 
 
If laboratory values from non-protocol–specified laboratory assessments performed 
at the local laboratory require a change in participant management or are 
considered medically relevant by the Investigator (e.g., SAE or AE or dose 
modification), the results must be recorded in the CRF. 
 
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory.  
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges or clinical symptoms necessitate 
additional testing to monitor participant safety. 
Where the clinical significance of abnormal laboratory results at screening is considered 
uncertain, screening laboratory tests may be repeated before randomization to confirm 
eligibility. 

 
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Based on continuous analysis of the data in this study and other studies, any sample 
type not considered critical for safety may be stopped at any time if the data from the 
samples collected do not produce useful information. 
8.2.8 
Clinical Assessment of Suicidality  
In Part 1, suicidality will be assessed for participants aged 6 years and above at the 
time of signing the Informed Consent Form. In Part 2, suicidality will be assessed for 
participants aged 6 years and above at the time of the assessment. The Investigator or 
designee will ask the caregiver of participants the following questions adapted from the 
C-CASA: 
 
Suicidal ideation: Has the participant wished he/she were dead or wished they could 
go to sleep and not wake up?  
 
Suicidal behavior: Has the participant made a suicide attempt? Has the participant 
done anything to harm him or herself? 
 
Self-injurious behavior: Has the participant engaged in non-suicidal self-injurious 
behavior? 
 
If the Investigator determines that any of these questions can be asked directly to the 
participant, based on the participant’s ability to understand and to react to the questions, 
then those questions should be directed to the participant; if not, these should be 
directed to the caregiver. If the answer to any of these three questions is “yes”, then the 
investigator will further evaluate the suicidal risk of the participant. 
8.2.9 
Seizures (EEG Monitoring) 
EEG will be measured according to the SoA (Section 1.3).  
EEG monitoring will be implemented in this study as a safety parameter to detect 
treatment-emergent or changes in seizure activity. Abnormal changes in EEG recordings 
will be compared to baseline with a focus on: 
 
Treatment-emergent epileptiform abnormalities 
 
Occurrence of subclinical seizures and nonconvulsive status epilepticus  

 
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The EEG safety report will indicate if any findings require the Investigator’s attention 
in order to ensure patient safety and may be further discussed with the Medical 
Monitor if deemed necessary by the Investigator on a case-by-case basis. 
Findings from the EEG safety report are to be considered within the full clinical context 
of the participant presentation for decision making on the continuation of dosing 
during the study, based on the stopping rules criteria listed in Section 4.1.3. 
For EEG to determine PD and biomarker parameters, see Section 8.6.2. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of an AE or SAE can be found in Appendix 2. The AESIs are discussed 
in Section 8.3.6. 
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity, and causality; see Appendix 2) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2. 
Procedures used for recording AEs are provided in Appendix 3. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the Adverse Event eCRF as follows: 
After informed consent has been obtained, but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). Any other AE should not be reported. 
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until 28 days after the final dose of study treatment.  
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period of 28 days after the final 
dose of study treatment or until the start of another treatment, whichever comes first. 
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 
time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study 

 
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participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all participant evaluation timepoints. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
8.3.3.1 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study treatment or study-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the participant’s medical record to facilitate source data 
verification. If, after follow up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5. 
8.3.3.2 
Sponsor Follow Up 
For SAEs, AESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional event details 
and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) to perform an independent medical assessment of the reported event. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Immediate notification by the Investigator to the Sponsor of an SAE regardless of 
relationship to study drug is essential so that legal obligations and ethical responsibilities 
toward the safety of participants and the safety of a study treatment under clinical 
investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 

 
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investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.  
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded 
to investigators as necessary.  
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements. 
For immediate (i.e., no more than 24 hours after learning of the event) and expedited 
reporting requirements from Investigator to Sponsor and from Sponsor to Health 
Authority, investigators, IRB and EC, see Appendix 2, Section 5. 
8.3.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours a day 7 days a week. Details will be available separately. 
8.3.5 
Pregnancy 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5. All pregnancies reported during the study should be followed until 
pregnancy outcome, with follow-up information on the infant collected according to 
procedures outlined in Appendix 5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5). 
8.3.6 
Adverse Events of Special Interest 
AESIs are required to be reported by the Investigator to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Appendix 2 for reporting 
instructions). 
AESIs for this study include the following: 
 
De novo seizure in participants who had no prior history of seizure 
 
New seizure type not reported prior to baseline  
 
Confirmed QTcF  480 msec or confirmed QTcF change from baseline  60 msec for 
participants older than 10 years.  
 
Confirmed QTcB  480 msec or confirmed QTcB change from baseline  60 msec for 
participants up to and including the age of 10 years. 

 
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 
Confirmed increase of serum creatinine  1.5  ULN or eGFR <90 mL/min per 
1.73 m2 (Grade 1 CKD). 
 
Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Appendix 3. 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a participant exposed to a medicinal product. This term applies only when a 
contamination of the study treatment is suspected. 
 
8.3.7 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events 
Seizure activity (i.e., convulsive and non-convulsive seizures) which are in line with 
the known medical history of the patient should not be reported as AEs unless they meet 
the seriousness criteria (see Appendix 2). Only convulsions requiring hospitalization or 
intubation should be reported as SAEs. 
8.3.8 
Management of Specific Adverse Events 
Treatment of specific AEs will be considered on a case-by-case basis according to local 
standard of care. Several measures are taken to ensure the safety of participants 
participating in this study. Eligibility criteria have been designed to exclude participants 
at potentially higher risk. Participants will undergo safety monitoring during the study. In 
addition, guidelines for managing AEs, including criteria for treatment interruption or 
discontinuation, are provided in Table 12. 
 
Increases in heart rate and blood pressure observed in pre-clinical studies and 
Phase I studies were not observed in subsequent clinical trials with basmisanil, 
including trials in children with Down syndrome. Vital signs will be monitored 
throughout the study. 
 
Increased in QTcF interval at supra-therapeutic plasma concentrations has been 
observed in the context of the basmisanil DDI study with itraconazole, a strong 
CYP3A4 inhibitor. In this study, basmisanil concentrations are predicted to be well 
below the exposure of clinical and regulatory concern for QTcF interval (see Section 
2.3). ECG recordings are part of the safety monitoring of this study.  
 
Increase in serum creatinine has been reported previously and appears to reflect 
inhibitory effects of basmisanil on the tubular creatinine transporters since changes 
of other glomerular filtration rate markers remained unchanged. Serum creatinine 
and eGFR will be measured at various timepoints throughout the study. 
 
Seizure risk: The risk for basmisanil to exacerbate or trigger de novo seizures in 
individuals with Dup15q syndrome will be assessed but is considered low based on 

 
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non-clinical data and clinical experience in the patient population previously treated 
with basmisanil (see Section 2.3 and the Basmisanil Investigator’s Brochure).  
 
Suicidality: clinical experience does not point to any suicidality liability of basmisanil. 
However, monitoring for suicidality is mandatory in clinical trials of CNS-active 
molecules and will be implemented as described in Section 8.2.8.  

 
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Table 12 Guidelines for Managing Specific Adverse Events (cont.)  
Elevated liver 
enzymes 
 
ALT or AST  3  ULN: 
o 
Monitor weekly until ALT and AST return to  1.2  ULN. 
o 
Further investigation into the liver enzyme elevations may 
include hepatitis serologies and other diagnostic tests at 
the discretion of the investigator in consultation with the 
Medical Monitor. 
 
Interrupt the study treatment in the event of liver enzymes that meet 
the following criteria): 
o 
ALT or AST 5 ULN 
o 
ALT or AST  3  ULN and either total bilirubin > 2 × ULN 
or INR 1.5  
o 
ALT or AST  3  ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or 
hypersensitivity 
o 
Such abnormalities should be followed by repeat testing 
within 48 to 72 hours and repeated two to three times 
weekly based on the participant’s clinical state. An 
evaluation by a hepatologist may be required if the 
abnormalities do not stabilize. All participants with possible 
drug-induced liver injury should be followed until 
abnormalities return to normal, even if the study treatment 
has been discontinued. 
o 
Discontinue study medication permanently if levels do not 
return to baseline after 30 days 
 
8.4 
TREATMENT OF OVERDOSE 
Overdose is the accidental or intentional use of the study drug in an amount higher 
than the assigned dose throughout the treatment period. 
An overdose or incorrect administration of study treatment is not an AE unless it results 
in untoward medical effects (see Sections 5 and 5.2 of Appendix 2 for further details). 
Decisions regarding dose-interruptions or modifications (if applicable) will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the participant. 
In the event of an overdose, the Investigator should: 
1. 
Contact the Sponsor’s Medical Monitor immediately. 

 
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2. 
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved  
3. 
Obtain a blood sample for PK and ECG analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. 
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the CRF. 
 
Appropriate supportive treatment should be initiated according to the individual's clinical 
signs and symptoms and in accordance with best medical practices. In vitro studies have 
shown that benzodiazepines compete with basmisanil for binding to GABAA, and 
flumazenil was able to block the inhibitory effect of basmisanil on GABA-induced 
currents. 
Benzodiazepines may therefore be considered as a treatment option for the 
management of basmisanil overdose.  
8.5 
PHARMACOKINETICS 
Mandatory blood samples to evaluate plasma concentrations of basmisanil and its major 
metabolite, M1, will be collected from a vein. The date and time of each sample 
collection will be recorded in the eCRF. Basmisanil and M1 levels will be analyzed. The 
PK samples will be taken as outlined in the SoA (Section 1.3). 
 
 
 Additional PK samples will be taken at the time of treatment 
discontinuation or if an AE leading to dose-reduction or delay of basmisanil 
administration is reported (Section 6.6 Dose Modifications). 
Due to the food effect of basmisanil the information on the meals will be recorded by 
parent/caregiver at defined timepoints (tied to PK sampling, see SoA, Section 1.3). 
The PK blood samples will be destroyed no later than 2 years after the date of final 
clinical study report (CSR). Details on sampling procedures, sample storage, and 
shipment are given in the sample documentation. For participants who consent to RBR, 
leftover samples will be transferred to RBR (see Section 8.8). 
A Sponsor IMC will perform unblinded reviews of PK data as described in Section 4.1.  
Drug concentration information that would unblind the study, will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of timepoints for any planned study assessments 
must be documented and approved by the relevant study team member and archived in 
the Sponsor and site study files. This will not constitute a protocol amendment. The 

 
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IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF. 
8.6 
PHARMACODYNAMICS AND BIOMARKERS ANALYSES 
8.6.1 
Genetic and Genomic Analyses 
Genetic tests can be performed within the study in cases where the required genetic 
information is not available in the participant’s medical history (Section 8.2.1). In this 
case, the Investigator must ensure that the appropriate test(s) are performed within the 
study to obtain all of the following genetic information: 
 
the number of copies of the 15q11.2-13.1 chromosomal region as well as 
breakpoints coordinates in the human reference genome, and the segment size, 
determined by chromosomal microarray (CMA). CMA will be performed only if 
permitted by local regulations.  
 
the parental origin of the duplication or triplication of 15q11.2-13.1 chromosomal 
region, determined using methylation specific-multiplex ligation dependent probe 
amplification (MS-MLPA)  
 
the int(15) vs. idic(15) nature of the copy number gain of the 15q11.2-13.1 
chromosomal region, determined by fluorescence in situ hybridization (FISH)  
 
Where required, samples will be collected for DNA extraction at timepoints specified in 
the SoA (see Section 1.3).  
Data arising from all biosamples, including samples for analyses of inherited DNA, will 
be subject to the confidentiality standards described in Section 1.4 of Appendix 1.  
8.6.2 
Effect of Basmisanil on the EEG (qEEG) Assessments 
EEG will be measured at clinic visits according to the SoA (see Section 1.3) using a 
clinical EEG system (10/20 montage comprising up to 32 electrodes plus auxiliary 
channels such as electrooculogram [EOG] or ECG). 
Sections of the EEG data at pre-defined times (qEEG blocks, see Table 2 and Table 4 
for Part 1 and Part 2, respectively) will be used for quantitative analyses. The 
impedance of electrodes will be checked before starting each block and participants will 
be instructed to remain as calm as possible and awake during the qEEG block with the 
goal to achieve good data quality for quantitative analysis. Recording good quality EEG 
data will be challenging but should be attempted. The EEGs will be used to evaluate the 
effect of basmisanil treatment on EEG beta-band power, acutely and at steady state, and 
to relate these signals to the PK data. In particular, the treatment-related change in the 
EEG beta-band power from Baseline to Day 2 and to Day 14 will be investigated (see 
Section 9.3.5). 
 
 
 

 
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For EEG to monitor safety see Section 8.2.9. 
8.7 
PHARMACODYNAMICS AND BIOMARKER SAMPLES 
If required, blood and buccal swab samples may be taken for DNA extraction for a full 
characterization of the Dup15q genotype (Section 8.6.1). Where required, samples will 
be collected according to the SoA (see Section 1.3). Additional samples may be 
requested in case of technical issues with the initial samples. 
Blood and buccal swab samples will be destroyed no later than 2 years after the date of 
final CSR. For participants who consent to RBR, an additional whole blood sample will 
be taken at Baseline and transferred to the RBR (see Section 8.8). Leftover blood and 
buccal swab samples will be transferred to the RBR (Section 8.8). 
Details on processes for collection and shipment of these samples can be found in a 
separate sample documentation. 
8.8 
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY 
8.8.1 
Overview of the Research Biosample Repository 
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic samples, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage, and analysis of the RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional RBR. Collected RBR samples can be used (but not limited to) 
to achieve the following objectives: 
 
To study the association of biomarkers with efficacy or progressive disease. 
 
To identify safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE monitoring or investigation. 
 
To increase knowledge and understanding of disease biology and drug safety. 
 
To study treatment response, including drug effects and the processes of drug 
absorption and disposition.  
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays. 
 
8.8.2 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to study treatment, 
diseases, or drug safety: 

 
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 
Leftover PK plasma samples 
 
Leftover genetic test sample prepared from whole blood and buccal swab (DNA) 
 
RBR whole blood sample 
 
The sample collected for DNA extraction include, but is not limited to, genomic analysis 
and may be sent to one or more laboratories for analysis of germline or somatic 
mutations via whole genome sequencing (WGS), whole exome sequencing (WES), next-
generation sequencing, or other genomic analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but may also be explored 
in aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents. 
Samples, upon RBR consent, may be used for DNA extraction to enable WGS/WES and 
other genomic analysis.  
Samples may be sent to one or more laboratories for analysis of germline or somatic 
mutations via WGS or WES, or other genomic analysis methods. Genomics is 
increasingly informing researchers’ understanding of disease pathobiology. WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop AE. 
Participants will not be identified by name or any other personally identifying information. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies. The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.  
If allowed by local laws, the caregiver may request access to the non-interpreted WGS 
and WES raw data from blood samples. Such a request must be conveyed to the 
Sponsor by the Investigator, using the email address: global.return-genomics-
results@roche.com. The information, if available at the time of the request, would be 
shared with the Investigator in the form of a data file of raw genomic sequencing data. 
The Sponsor will not provide any interpretation of this raw genomic sequencing data. 
The interpretation of these data will require expertise in genomic and genetic analysis 
and an understanding of the variability of the technology used for data generation.  

 
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For all samples, dates of consent and sample collection should be recorded on the 
associated RBR page of the eCRF. Details on processes for collection and shipment of 
these samples can be found in separate sample documentation. 
RBR samples will be stored and used until no longer needed, until they are exhausted 
but no longer than 15 years. The RBR storage period will be in accordance with the 
IRB/EC‑approved ICF and applicable laws (e.g., Health Authority requirements). 
The repository samples will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1). 
 
8.9 
HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
8.10 
TIMING OF STUDY ASSESSMENTS 
All assessments must be performed as per SoA (see Section 1.3). 
As a rule, efficacy assessments supporting primary and secondary objectives (Table 5) 
are to be prioritized over exploratory assessments. As much as possible the sequence of 
assessments established for a given participant and their caregiver at the Baseline visit 
should be kept the same on the Day 183 and Day 365 visits. Specifically, for MSEL 
administration, all efforts should be made to perform the assessments at about the same 
time of day. 
The timings of the qEEG blocks (first block starts 30 minutes before the morning meal 
and lasts until the start of this meal as specified in the SoA) should be recorded at about 
the same time of day at every visit. 
Assessments listed in Table 2 and Table 4 of the SoA (see Section 1.3) must be 
performed as specified at all indicated visits as these assessments will be important to 
confirm the PK model and to establish the exposure-qEEG relationship in Dup15q 
syndrome.  
Caregiver-reported questionnaires can be completed either in the clinic or remotely 
within a 5-day window before the scheduled clinic visit, with remote support from the site 
as needed (see the SoA in Section 1.3). 
The Baseline, Day 183, Day 365 (Part 1) and Day 548, Day 730, Day 1095 (Part 2), 
Day 1125, and early termination (Part 2) visits can be split over 2 days if required to 
accommodate participants and families.  

 
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8.10.1 
Screening and Pre-treatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. ICFs for enrolled 
participant and for participants who are not subsequently enrolled will be maintained at 
the study site. Assent should be obtained for participants who, in the opinion of the 
investigator, are judged to be capable of giving assent.  
All screening, and all pre-treatment assessments (related to entry criteria), must be 
completed and reviewed by the Investigator to confirm that participants meet all eligibility 
criteria. The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure. 
The seizure diary and the wearable device should be handed out to the caregiver at 
screening to record baseline data as described in Section 8.2.4 and Section 8.1.5.12.  
 
 
 
8.10.2 
Assessments during Treatment 
Under no circumstances will participants who enroll in this study and complete treatment 
as specified be permitted to be allocated a new randomization number and re-enrolled in 
the study. 
All assessments must be performed as per SoA (Section 1.3).  
8.10.3 
Assessments at Early Termination Visit 
Participants who discontinue from the study early will be asked to complete early 
termination assessments as per the SoA (Section 1.3) as soon as possible after the final 
dose of study treatment.  
8.10.4 
Follow-Up Assessments 
Participants who complete or who withdraw early from the study will be asked to attend 
a safety follow-up visit as described in the SoA (Section 1.3). For participants who 
consent to Part 2 OLE, the follow-up assessments will be completed at the end of Part 2 
(see Section 4.1.1). 
After the study completion/early termination visit, AEs should be followed as outlined in 
Sections 8.3.1 and 8.3.3. 

 
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9. 
STATISTICAL CONSIDERATIONS 
9.1 
SAMPLE SIZE DETERMINATION 
Approximately 90 participants with Dup15q syndrome are planned to be randomized 2:1 
to basmisanil or placebo. Assuming approximately 10% of randomized participants may 
not be evaluable for efficacy, there will be approximately 81 evaluable participants. The 
sample size may be increased in case of higher-than-expected rates of early study 
withdrawals or number of participants requiring dose adjustments due to exposures 
substantially deviating from target trough plasma concentrations. 
The primary efficacy analysis will compare the change in Vineland-3 Adaptive Behavior 
Composite score from Baseline to Week 52 of treatment between the basmisanil and the 
placebo arm. 
9.2 
SETS FOR ANALYSES 
For purposes of analysis, the following analysis sets are defined in Table 13. 
Table 13 Analysis Sets 
Analysis Set 
Description 
Intent-to-treat (ITT) 
All randomized participants who received at least one dose of study 
treatment. The ITT population will be the primary population for the 
analysis of all efficacy endpoints. Participants will be allocated to the 
treatment arm they were randomized to.  
Safety 
The safety analysis population equals the ITT population assuming 
treatment is received as assigned at randomization. 
Pharmacokinetic (PK) 
All participants who have received at least one dose of study 
treatment and who have data from at least one postdose sample will 
be included in the PK analysis population. Participants will be 
excluded from the PK analysis population if they significantly violate 
the inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete which may influence 
the PK analysis. Excluded cases will be documented with the reason 
for exclusion. All decisions on exclusions from the analysis will be 
made prior to database closure. 
 
If, at any time during Part 1 of the study, participants receive treatment different from the 
one they were randomized to, manual re-assignments of participants to treatment arms 

 
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for the purpose of the analysis of safety data may be made depending on the duration of 
such incorrect treatment. Such re-assignments, if any, can only be made after unblinding 
and will be described in detail. 
9.3 
STATISTICAL ANALYSES OF PART 1 
9.3.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group using 
means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate. Analyses will be performed in all 
randomized participants and in the intent-to-treat (ITT), if different. 
Baseline will be defined as the latest available value prior to the first dose of study 
treatment.  
9.3.2 
Efficacy Analyses 
The primary efficacy analysis will take place after all participants complete 52 weeks of 
double-blind treatment or are prematurely withdrawn.  
In addition, results for the primary and secondary efficacy endpoints in Part 1 will be 
presented in descriptive summary tables and graphs, as appropriate. Listings will be 
prepared as required. Change from baseline for continuous endpoints will be analyzed 
using the same methodology as that for the primary endpoint. All statistical analysis 
methodologies will be described in detail and documented in the Sponsor’s trial master 
file prior to performing any of the planned interim or final analyses.  

 
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In addition to the primary analysis in the ITT, selected endpoints may be analyzed in 
subgroups, including by key demographic variables and stratification factors.  
9.3.3 
Safety Analyses 
All safety analyses will be based on the safety analysis population. Safety endpoints will 
be described in appropriate summary tables and graphs. Individual outputs will be 
presented if required.  
Descriptive summaries of exposure to study treatment will be prepared by treatment 
group (including treatment duration, total dose received, dose intensity).  
Verbatim AE terms recorded in the eCRF will be mapped to MedDRA thesaurus terms. 
AE severity will be graded according to National Cancer Institute Common Terminology 
Criteria for AEs (v5.0). Data on AEs, SAEs, and deaths will be presented by treatment 
group in summary tables and in individual outputs, as appropriate.  
Abnormal changes in EEG recordings compared to baseline will be presented in 
summaries and individual outputs with a focus on treatment-emergent epileptiform 
abnormalities. Seizure status as derived from the seizure diary entries by caregivers will 
be used to analyze changes from baseline in seizure types, frequency, and duration.  
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Laboratory test values will be presented in International System of Units 
(Système International d’Unités [SI] units;). Individual outputs will show flags for 
abnormal results. Summaries and shift tables will be prepared for selected laboratory 
tests to describe baseline and maximum post baseline severity grade. 
Vital sign data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of abnormalities.  
ECG data as well as data for height, weight, and head circumference will be presented 
using appropriate summaries and/or listings. 
Suicidality questions adapted from the C-CASA will be analyzed descriptively in 
participants aged 6 years and above. 
Tanner staging over time will be described in participants from age 9. 
Concomitant Medications: The original terms recorded on the participants’ eCRF by the 
Investigator for concomitant medications will be standardized by the Sponsor by utilizing 
a mapped term and appropriate drug dictionary level. Concomitant medications will be 
presented using appropriate outputs. 

 
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9.3.4 
Pharmacokinetic Analyses 
Analyses will be carried out on the PK analysis population. PK parameters will be 
estimated using a population PK model and presented by listings and descriptive 
summary statistics (mean, standard deviation, coefficient of variation, median, minimum, 
and maximum). 
The plasma concentration of basmisanil and its major metabolite M1 will be determined. 
PK parameters for basmisanil are AUCtau,ss, Cmax,ss, Ctrough,ss, CL/F, and Vd/F will be 
estimated by using population PK analysis. Plasma concentration ratio of M1 to 
basmisanil at trough will be determined as well as other PK parameters as appropriate. 
Estimates for these parameters will be tabulated and summarized.  
The population PK analysis analyses will be presented separately from the main CSR. 
9.3.5 
Pharmacodynamic Analyses  
The main PD endpoint is the change in the characteristic Dup15q EEG phenotype, 
acutely and at steady state. 
Results for change in EEG beta-band power from baseline will be presented in summary 
tables, graphs, and listings. 
9.4 
STATISTICAL ANALYSES OF PART 2 
Analyses using the complete database including both Parts 1 and 2 of the study will be 
performed when all participants complete the protocol-defined assessments or are 
prematurely withdrawn. Details on the statistical methodology will be described in a 
separate technical document prior to the analysis.  
9.5 
INTERIM ANALYSES 
Interim analyses in Part 1 will be conducted as described in Section 4.1.2.2.  
A first interim analysis is planned once approximately 24 participants (Stage 1 and 
Stage 2) have completed 4 weeks of treatment or withdrawn from treatment prior to that.  
The Sponsor may choose to conduct an additional interim analysis during Part 1. The 
decision to conduct an optional interim analysis and the timing of the analysis will be 
documented in the Sponsor’s trial master file prior to the conduct of the interim analysis.  
The interim analyses will be performed and interpreted by members of the IMC and may 
be shared with the SOC as needed and as described in Section 4.1.2. Access to 
treatment assignment information will follow the Sponsor’s standard procedures. 
All statistical analysis methodologies will be described in detail and documented in the 
Sponsor’s trial master file prior to performing any of the planned interim analyses. 

 
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After completion of the primary analysis of Part 1 and prior to the end of the study, the 
Sponsor may conduct additional interim analyses combining the data collected in both 
Part 1 and Part 2. The timing of and the methods used in such analyses will be 
documented in the Sponsor’s trial master file prior to the analysis. 
9.6 
SUMMARIES OF CONDUCT OF STUDY 
Protocol deviations will be summarized by treatment group; a participant listing will also 
be available.  
Participant disposition, including number of participants randomized and 
discontinuations from study treatment or study will be reported. 
Terms for concomitant medications recorded on the eCRF by the Investigator will be 
mapped to preferred terms by the Sponsor. Data on concomitant medication will be 
summarized and listed.  

 
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10. 
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 

 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
1.1. 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC) or Clinical Trials Regulation 
(536/2014) (EEA sites only), and all other applicable local regulations. 
1.2. 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the participant or caregiver (e.g. 
advertisements, diaries, etc.), and relevant supporting information must be submitted to 
the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/EC 
before the study is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this appendix). 
The Investigator should follow the requirements for reporting all adverse events (AEs) to 
the Sponsor. Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file. 
1.3. 
INFORMED CONSENT 
The Sponsor’s Master Informed Consent Form including the consent form for the 
optional open-label extension part of the study (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participant’s caregiver or participant’s legally authorized representative must be 
informed that participation is voluntary. Participant’s caregiver or legally authorized 

 
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representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. The Sponsor or its designee must review and approve any 
proposed deviations from the Sponsor’s sample ICFs or any alternate consent forms 
proposed by the site (collectively, the “Consent Forms”) before IRB/EC submission. The 
final IRB/EC‑approved Consent Forms must be provided to the Sponsor for Health 
Authority submission purposes according to local requirements. Participant’s caregiver 
or participant’ legally authorized representative must be re-consented to the most 
current version of the ICF(s) during the participant’s participation in the study. A copy of 
the ICF(s) signed by all parties must be provided to the participant’s caregiver or the 
participant’s legally authorized representative. 
Due to the nature of Dup15q syndrome, participants in this study will not be asked to 
provide their own informed consent. The Informed Consent Form included in this study is 
for the caregiver or the legally authorized representative of the participant. The 
participant’s ability to provide assent will not be dependent on their age. Assent should 
be obtained for all participants who, in the opinion of the Investigator, are judged 
capable of giving assent. 
The ICFs must be signed and dated by the participant’s caregiver or legally authorized 
representative before the participant’s participation in the study. The case history or 
clinical records for each participant shall document the informed consent process from 
the caregiver or participant’s legally authorized representative and that written informed 
consent was obtained prior to participation in the study. 
The ICFs should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the participant’s 
caregiver or participant’s legally authorized representative to take part. The final 
revised IRB/EC-approved ICFs must be provided to the Sponsor for Health Authority 
submission purposes if required as per local regulations. 
If the ICFs are revised (through an amendment or an addendum) while a participant is 
participating in the study, the participant’s caregiver or a legally authorized 
representative may be re-consented by signing the most current version of the ICFs or 
the addendum, in accordance with applicable laws and IRB/EC policy. For any updated 
or revised ICFs, the case history or clinical records for each participant shall document 
the informed consent process and that written informed consent was obtained using the 
updated/revised ICFs for continued participation in the study. The study team will 
provide guidance for which participants need to re-consent in the event of an update to 
the ICF. 
A copy of each signed ICF must be provided to the participant’s caregiver or 
participant’s legally authorized representative. All signed and dated ICFs must remain in 

 
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each participant’s study file or in the site file and must be available for verification by 
study monitors at any time. 
If a participant is re-screened, the caregiver or the participant’s legally authorized 
representative is not required to sign another ICF if the re-screening occurs within 30 
days from the previous ICF signature date. 
Consent to Participate in the Research Biosample Repository 
The ICF will contain a separate section that addresses participation in the RBR. The 
Investigator or authorized designee will explain to each participant’s caregiver or 
participant’s legally authorized representative the objectives, methods, and potential 
hazards of participation in the RBR. Participant’s caregiver or participant’s legally 
authorized representative will be told that they are free to refuse to participate and may 
withdraw their samples at any time and for any reason during the storage period. A 
separate, specific signature will be required to document a participant’s caregiver or 
participant’s legally authorized representative agreement to provide optional RBR 
samples. Participant’s caregiver or participant’s legally authorized representative who 
declines to participate will not provide a separate signature. 
The Investigator should document whether or not the participant’s caregiver or 
participant’s legally authorized representative has given consent to participate by 
completing the RBR Sample Informed Consent eCRF. 
In the event of death or loss of competence of a participant who is participating in the 
research, the participant's samples and data will continue to be used as part of the RBR. 
For sites in the United States, each ICF may also include participant’s caregiver's or 
participant’s legally authorized representative’s authorization to allow use and 
disclosure of personal health information in compliance with the U.S. Health Insurance 
Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a separate 
Authorization Form for participant’s caregiver’s or participant’s legally authorized 
representative’s authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study-site policies. 
Approval by the Institutional Review Board or Ethics Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the ICF by each site's 
IRB/EC and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol will not be applicable at that site. 
Withdrawal from the Research Biosample Repository 
Participants whose caregiver or legally authorized representative gives consent to 
provide samples for the RBR have the right to withdraw their samples at any time for any 

 
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reason. If consent is withdrawn for the testing of the samples, the Investigator must 
inform the Medical Monitor and Site Monitor in writing of the decision taken using the 
RBR Withdrawal Form and, if the study is ongoing, must enter the date of withdrawal on 
the RBR Withdrawal of Informed Consent eCRF. The participant’s caregiver or 
participant’s legally authorized representative will be provided with instructions on how 
to withdraw consent after the study is closed. A participant's withdrawal from Study 
BP41992 does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 
participant’s withdrawal from the RBR does not constitute withdrawal from Study 
BP41992. Data already generated before time of withdrawal of consent to RBR will still 
be used. 
1.4. 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participant’s caregiver or participant’s legally authorized representative must be 
informed that the participant’s personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes. 
The participant’s caregiver or participant’s legally authorized representative must be 
informed that the participant’s medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study. These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease. In addition, redacted clinical study reports and 
other summary reports will be provided upon request. 

 
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Confidentiality for Research Biosample Repository 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Participant medical information associated with RBR samples is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the participant’s caregiver 
or participant’s legally authorized representative, unless permitted or required by law. 
Data derived from RBR sample analysis on individual participants will generally not be 
provided to study Investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication. 
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or participants unless required by law. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR sample data will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
Monitoring and Oversight Research Biosample Repository 
Samples collected for the RBR will be tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of samples as specified in this protocol and in the ICF. 
The Sponsor’s monitors and auditors will have direct access to appropriate parts of 
records relating to participant participation in RBR for the purposes of verifying the data 
provided to the Sponsor. The site will permit monitoring, audits, IRB/EC review, and 
Health Authority inspections by providing direct access to source data and documents 
related to the samples. 
1.5. 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLO). 

 
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2. 
DATA HANDLING AND RECORD 
2.1. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
2.1.1. 
Data Quality Assurance 
All participant data relating to the study will be recorded on electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH Good Clinical Practice (GCP), and all applicable regulatory 
requirements. 
2.1.2. 
Clinical Outcome Assessment Data 
2.1.2.1 
Electronic Clinical Outcome Assessment 
For this study, eCOA devices (dedicated digital device [Section 8.1.3.2] and a rater 
station device [Section 8.1.4.1]) provided by an eCOA vendor and through the dedicated 
website (TrialMax) on the caregiver’s personal device will be used to capture COA 
data. The data will be transmitted to a centralized database maintained by the eCOA 
vendor. The data may be reviewed by site staff via secure access to a web server. 
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations for 
electronic records (21 CFR Part 11). System backups for data stored by the Sponsor 
and records retention for the study data will be consistent with the Sponsor’s standard 
procedures. 
2.1.2.2. 
Paper Clinical Outcome Assessment Data 
If paper booklets are used to capture COA data (e.g. ADOS-2, MSEL), all original forms 
on which responses are recorded are source documentation as described in Section 
2.1.3 of this appendix. 

 
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2.1.3. 
Source Data Records 
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, COAs (paper or eCOA), 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
participant files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical study. 
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below. 
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities. 
2.1.4. 
Use of Computerized Systems 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
2.2. 
RETENTION OF RECORDS 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion or 
discontinuation of the study, or for the length of time required by relevant national or 
local Health Authorities, whichever is longer. After that period, the documents may be 
destroyed, subject to local regulations. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local Health Authorities. 

 
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Audio and video recordings will be maintained on a secure server throughout the 
duration of the study and destroyed 2 years after study completion on approval by the 
Sponsor. 
For countries where Ethics Committees or the Ministry of Health will not approve video 
or audio recording of participant interviews, review of the scale worksheets, submitted as 
part of the assessment source information, will be performed to verify accuracy of 
scoring and compliance to study conventions. 
2.3. 
STUDY RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval.  
Roche shall also submit an Annual Safety Report once a year to the IEC and competent 
authorities (CAs) according to local regulatory requirements and timelines of each 
country participating in the study. 
2.3.1. 
Protocol Amendments 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements. 
2.3.2. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator. 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multi-center trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel. 

 
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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
2.3.3. 
Dissemination of Clinical Study Data 
The results of the study may be communicated in scientific meetings and/or 
peer-reviewed literature. In addition, results of the study will also be included in 
submissions to regulatory agencies and other Health Authorities. 
2.3.4. 
 
Management of Study Quality 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity. 
Prior to first participant entry into the study, the Sponsor will identify and evaluate 
potential risks associated with critical study processes and data and will implement 
controls for the communication, review, and reporting these risks. Details regarding the 
applied approach for the study will be provided in the integrated Risk Based Quality 
Management Plan. 
2.3.5. 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ medical records, and eCRFs. The Investigator will 
permit national and local Health Authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
3. 
ADMINISTRATIVE STRUCTURE 
An IMC and a SOC will used in this study, see Section 4.1.2. 
4. 
STUDY AND SITE CLOSURE 
The Sponsor (or designee) has the right to close the study site or terminate this study at 
any time. Reasons for terminating the study may include, but are not limited to, the 
following: 
 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to participants. 
 
Participant enrollment is unsatisfactory. 
 
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program. 

 
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Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines. 
 
Inadequate recruitment of participants by the Investigator. 
 
Discontinuation of further study treatment development. 
 

 
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Appendix 2  
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting 
1. 
DEFINITION OF ADVERSE EVENTS 
According to the E2A ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An adverse event can therefore be: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
 
Events Meeting the AE Definition: 
 
Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) or 
other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to a 
change in study treatment or concomitant treatment or discontinuation from study 
treatment (see Appendix 3, Section 4). 
 
Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies). 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE unless the progression is unexpectedly accelerated and 
not in line with the natural history of the disease. If the “Lack of efficacy” would not 
require safety reporting such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
  
Events NOT Meeting the AE Definition: 
 
Any medically relevant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 

 
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 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
2. 
DEFINITION OF SERIOUS ADVERSE EVENTS 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that at any 
dose: 
 
Results in death. 
 
Is life-threatening. 
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(see Appendix 3). 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
 
Results in persistent or significant disability/incapacity 
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly/birth defect. 

 
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 
Other significant events: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
development of drug dependency or drug abuse. 
As epilepsy is part of the clinical presentation of Dup15q syndrome, only 
convulsions requiring hospitalization or intubation should be reported as SAEs.  
 
3. 
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
The Investigator will then record all relevant AE/SAE information in the CRF. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
3.1. 
ASSESSMENT OF SEVERITY 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

 
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Table 1 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily livinga 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily livingb,c 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to adverse eventd 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the NCI CTCAE (v5.0), which can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 6 of this appendix for reporting instructions), per the definition of 
serious adverse event in Section 2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 6 for reporting 
instructions), per the definition of serious adverse event in Section 2. Grade 4 laboratory 
abnormalities would only be reported as SAEs if these meets one or more of the conditions 
outlined in Section 2 (Definition of Serious Adverse Events) of Appendix 2. 
 
3.2. 
ASSESSMENT OF CAUSALITY 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the study 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration: 
 
Temporal relationship of event onset to the initiation of study treatment. 
 
Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment.  
 
Known association of the event with the study treatment or with similar treatments. 
 
Known association of the event with the disease under study. 
 
Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event. 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 

 
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For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
4. 
FOLLOW-UP OF AES AND SAES 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, when possible, the Investigator will provide the Sponsor with a copy of any 
postmortem findings including histopathology. 
New or updated information will be recorded in the originally completed eCRF. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
5. 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events 
 
Adverse events of special interest (AESI) 
 
Pregnancies (see Section 8.3.5) 
 
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis. 
 
Significant new diagnostic test results. 
 
Change in causality based on new information. 
 
Change in the event’s outcome, including recovery. 
 
Additional narrative information on the clinical course of the event. 
 

 
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Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC. 
5.1 
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS, AND ADVERSE EVENTS OF SPECIAL INTEREST  
Events that Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event). 
Events that Occur after Study Treatment Initiation 
For reports of serious adverse events and adverse events of special interest 
(Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department. 
In the event that the EDC system is unavailable, the Clinical Trial Adverse Event/ 
Special Situations Form provided to Investigators should be completed and submitted to 
the Serious Adverse Event Responsible immediately (i.e., no more than 24 hours after 
learning of the event). 
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system. 
Reporting of Post-Study Adverse Events and Serious Adverse Events 
If the Investigator becomes aware of any other SAE occurring after the end of the AE 
reporting period, and if the event is believed to be related to prior study treatment, the 
event should be reported directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the Clinical Trial Adverse Event/Special Situations Form using 
the fax number or email address provided to Investigators. 

 
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5.2 
SPECIAL SITUATIONS (OVERDOSE, MEDICATION ERROR, DRUG 
ABUSE, AND/OR DRUG MISUSE) 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose: accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose: intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error: accidental deviation in the administration of a drug (e.g., wrong 
drug, expired drug, accidental overdose, underdose, wrong dosing schedule, 
incorrect route of administration) 
 
Drug abuse: intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse: intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the participant, drug misuse 
could involve the drug being administered to someone other than the 
participant. 
 
After initiation of study drug, special situations associated with basmisanil/matching 
placebo and any associated AEs will be reported until 28 days after the final dose of 
study treatment. 
Special situations, regardless of whether they result in an AE, should be reported on the 
Special Situations eCRF. If there are any associated AEs, each event should be recorded 
separately on the Adverse Event eCRF. 
Special situations and any associated AEs should be reported within 30 days after the 
Investigator becomes aware of the situation. However, if an associated AE fulfills 
seriousness criteria or qualifies as an AESI, both the event and the special situation 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after the 
Investigator becomes aware of the event), as described in Section 5.1 of this appendix. 
6. 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and AESI against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation. 

 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
Basmisanil 
Basmisanil Investigator’s Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
 

 
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Appendix 3  
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
1. 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
2. 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
3. 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation timepoints. Such events should only be recorded once on the 

 
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Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this. 
A recurrent adverse event is one that resolves between participant evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
4. 
ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
 
Accompanied by clinical symptoms. 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy. 
 
Medically relevant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a medically relevant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF. 
If a medically relevant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same medically relevant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 

 
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5. 
ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
 
Accompanied by clinical symptoms. 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
 
Results in a medical intervention or a change in concomitant therapy. 
 
Medically relevant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a medically relevant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same medically relevant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
6. 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total 
bilirubin  2  ULN. 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice. 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Appendix 2) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event or an adverse event of special interest (see 
Section 8.3.6). 
7. 
DEATHS 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to study treatment, must be recorded 

 
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on the Adverse Event eCRF and immediately reported to the Sponsor. This includes 
death attributed to progression of Dup15q syndrome. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF. If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
8. 
PREEXISTING MEDICAL CONDITIONS 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
9. 
LACK OF EFFICACY OR WORSENING OF DUP15Q SYNDROME 
Medical occurrences or symptoms of deterioration that are anticipated as part of Dup15q 
syndrome should be recorded as an adverse event if judged by the Investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study. When recording an unanticipated worsening of Dup15q syndrome on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., “accelerated Dup15q syndrome”). 
10. 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 2), except as outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol  

 
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 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
o The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease. 
o The participant has not suffered an adverse event. Prolonged 
hospitalization due to psychosocial issues such as lack of home care 
facilities, caregiver issues, transport issues, etc.  
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available. 
 
11. 
OBSERVER-REPORTED OUTCOME DATA (COA DATA 
REPORTED DIRECTLY BY CAREGIVER) 
Adverse event reports will not be derived from patient-reported outcome (PRO) data by 
the Sponsor, and safety analyses will not be performed using PRO data. However, if any 
PRO responses suggestive of a possible adverse event are identified during site review 
of the PRO data, the Investigator will determine whether the criteria for an adverse event 
have been met and, if so, will report the event on the Adverse Event eCRF. 

 
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Appendix 4  
Clinical Laboratory Tests 
The tests detailed in Table 1 will be performed by the central laboratory.  
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study treatment administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis be obtained at the same time. Additionally, if the local laboratory results are 
used to make either a study treatment decision or response evaluation, the results must 
be captured in source documentation and entered as a comment into the eCRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 

 
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Table 1 
Protocol-Required Safety Laboratory Assessments 
All study-required laboratory assessments will be performed by a central laboratory, with 
the exception of urine pregnancy test and urinalysis: 
Laboratory Assessments 
Parameters 
Hematology 
 
Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes)  
Clinical chemistry 
 
Sodium, potassium, chloride, bicarbonate, glucose, 
urea, creatinine, eGFR, total protein, albumin, 
phosphate, calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, -GT, CPK, total cholesterol 
(with HDL and LDL), triglycerides, urate, LDH 
Coagulation 
 
PT (INR), aPTT 
Viral serology 
 
HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, 
HIV-2 antibody), hepatitis B surface antigen, total 
hepatitis B core antibody, hepatitis C virus antibody 
Thyroid hormones  
 
Free T4, TSH  
Pregnancy test 
 
Female participants of childbearing potential will have 
urine pregnancy tests. If a urine pregnancy test is 
positive, it must be confirmed by a blood pregnancy 
test. 
Urinalysis 
 
Dipstick: pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase 
 
If there is a medically relevant positive result, urine will 
be sent to the laboratory for microscopy and culture. If 
there is an explanation for the positive dipstick results 
(e.g., menses), it should be recorded and there is no 
need to perform microscopy and culture. 
 
Microscopic examination (RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria), if blood or protein is abnormal. 
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; CPK = creatine phosphokinase; -GT = gamma-glutamyltransferase; 
HDL = high-density lipoproteins; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LDH = lactate dehydrogenase; LDL = low-density lipoproteins; 
PT = prothrombin time; RBC = red blood cell; TSH = thyroid-stimulating hormone; 
WBC = white blood cell. 
 
The results of each test may be entered into the CRF. 
Investigators must document their review of each laboratory safety report. 

 
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Additional Statistical Considerations for Clinical Laboratory Data 
 
Standard Reference Ranges and Transformation of Data 
Potential analysis considerations for analyzing Laboratory data includes the use of 
Standard Reference Ranges and potential transformation of data for specific laboratory 
tests.  
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the Investigator, can be used for specific parameters. For these parameters, the 
measured laboratory test result will be assessed directly using the Roche standard 
reference range. Certain laboratory parameters will be transformed to Roche’s standard 
reference ranges. 
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Because the 
standard reference ranges for these parameters have a lower limit of zero, only the 
upper limits of the ranges will be used in transforming the data. 
 
Definition of Laboratory Abnormalities 
For all laboratory parameters included in the analysis described above, there exists a 
Roche pre-defined standard reference range. Laboratory values falling outside this 
standard reference range will be labeled “H” for high or “L” for low in participant 
statistical outputs of laboratory data. 
In addition to the standard reference range, a marked reference range has been pre-
defined by Roche for these laboratory parameters. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially medically relevant. If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low. 

 
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Appendix 5  
Contraceptive and Barrier Guidance 
1. 
DEFINITIONS 
Female Participants of Childbearing Potential  
A female participant is considered fertile following menarche and until becoming 
postmenopausal unless permanently sterile. The definition of childbearing potential may 
be adapted for alignment with local guidelines or requirements. 
Female participants in the following categories are considered to be 
Female Participants of Non-Childbearing Potential  
a) Pre-menarchal 
b) Pre-menopausal female with one of the following: 
– 
Documented hysterectomy. 
– 
Documented bilateral salpingectomy. 
– 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
2. 
CONTRACEPTION GUIDANCE 
Female Participants 
Female participants of childbearing potential are eligible to participate if the caregiver 
agrees that the participant must use highly effective method of contraception 
consistently and correctly as described in Table 1 below.  
Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly as described in Table 1 below. 

 
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Table 1 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User-Dependenta 
(Failure rate of  1% per year when used consistently and correctly) 
 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable  
Highly Effective Methods That Are User-Independent 
(Failure rate of  1% per year) 
 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa 
 
Intrauterine device  
 
Intrauterine hormone-releasing system  
 
Bilateral tubal occlusion/ ligation 
Azoospermic partner (vasectomized or due to medical cause) 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the female participant of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
Effective Birth Control Methods Which May Not Be Considered As Highly Effective 
(Failure rate of  1% per year when used consistently and correctly) 
 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
 
Male or female condom with or without spermicide b 
 
Cap, diaphragm or sponge with spermicide b 

 
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Table 1 
Highly Effective Contraceptive Methods (cont.) 
a) Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method. 
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
b) A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are also considered acceptable, but not highly effective, birth control 
methods. i.e., when the risk of teratogenicity and genotoxicity is unlikely. 
 
3. 
PREGNANCY TESTING 
For female participants of childbearing potential enrolled in the study, urine pregnancy 
tests will be performed according to Schedule of Activity tables (see Section 1.3). If a 
urine pregnancy test is positive, it must be confirmed by a blood pregnancy test. 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice. 
4. 
COLLECTION OF PREGNANCY INFORMATION 
Male participants with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy). This applies only to male participants who receive study 
treatment. 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 

 
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reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Additionally, attempts should be made to collect and report infant health information. 
When permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant. If the authorization has been signed, the infant's health 
status at birth should be recorded on the Clinical Trial Pregnancy Reporting Form. In 
addition, the Sponsor may collect follow-up information on the infant's health status at 
6 and 12 months after birth. 
Female participants who become pregnant 
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the Clinical Trial Pregnancy Reporting Form and 
submitted to the Sponsor within 24 hours of learning of a participant's pregnancy. The 
participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, which will be 
forwarded to the Sponsor. Monitoring of the participant should continue until conclusion 
of the pregnancy. Any termination of pregnancy will be reported, regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor as described in Appendix 2. 
While the Investigator is not obligated to actively seek this information in former study 
participants, he/she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
Additionally, attempts should be made to collect and report infant health information. 
When permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant. If the authorization has been signed, the infant's health 
status at birth should be recorded on the Clinical Trial Pregnancy Reporting Form. In 
addition, the Sponsor may collect follow-up information on the infant's health status at 
6 and 12 months after birth. 

 
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5 
ABORTIONS 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5 of Appendix 2). 
Any induced abortion due to maternal toxicity and/or embryofetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5 of Appendix 2). 
Elective or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form. 
6 
CONGENITAL ANOMALIES/BIRTH DEFECTS 
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male participant exposed to study treatment should be classified as a 
serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). 
 

 
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Appendix 6  
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations 
 
Table 1 
Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations for European 
Economic Area 
Product Name 
IMP/AxMP 
Designation 
Marketing 
Authorization Status 
in EEA  
Used within 
Marketing 
Authorization 
GABAA 5 
negative 
allosteric 
modulator 
(RO5186582) 
IMP (test product) 
Unauthorized 
Not applicable 
AxMP = auxiliary medicinal product; EEA = European Economic Area; IMP = investigational 
medicinal product. 
 
 
Table 2 
Investigational and Non-Investigational Medicinal Product 
Designations for the United Kingdom 
Product Name 
IMP/NIMP 
Designation 
Marketing 
Authorization Status 
in UK 
Used within Marketing 
Authorization 
GABAA 5 
negative 
allosteric 
modulator 
(RO5186582) 
IMP (test product)  
Unauthorized 
Not applicable 
IMP = investigational medicinal product; NIMP  = non-investigational medicinal product; 
UK = United Kingdom. 
 
 
 
 
 

 
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Appendix 7  
International League against Epilepsy 2017 Classification of 
Seizure Types  
(Fisher et al. 2017, Figure 2) 
 
 
 
References: 
Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the 
International League Against Epilepsy: Position Paper of the ILAE Commission 
for Classification and Terminology. Epilepsia 2017;58:522–30. 

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