AN OPEN-LABEL, MULTICENTER STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF RO7248824 IN PARTICIPANTS WITH ANGELMAN SYNDROME

Recruiting

• Conditions: ontwikkelingsstoornis door een chromosoomdeletie; Angelman syndrome; developmental disorder; 10083624

• Registration Number: NL-OMON54298
• Lead Sponsor: Roche Nederland B.V.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 19 August 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: Not specified
• Target Recruitment: 10

Inclusion Criteria

• The participant has a parent, caregiver or legal representative (hereinafter
*caregiver*) who is reliable, competent and at least 18 years of age. The
caregiver is willing and able to accompany the participant to clinic visits and
to be available to the Investigational Site by phone or email if needed and who
(in the opinion of the investigator) is and will remain sufficiently
knowledgeable of participant*s ongoing condition to respond to any inquiries
about the participant from personnel from the Study Site.
• A caregiver must be able to consent for the participant according to
International Council on Harmonisation (ICH) and local regulations.
• Ability to comply with all study requirements.
• Have adequate supportive psychosocial circumstances.
• Able to undergo MRI scans (e.g., no metal implants including MRI incompatible
intrauterine devices (IUDs), or any condition that renders testing intolerable
for the participant), under sedation or anesthesia if needed and as determined
appropriate by the Investigator.
• Able to tolerate blood draws.
• Able to undergo LP and IT injection, under sedation or anesthesia if needed
and as determined appropriate by the Investigator.
• Stable medical status for at least 4 weeks prior to Screening and at the time
of enrollment.
• Bodyweight of >= 7 kg.
• Participant must be >= 1 and <= 12 years of age at the time of signing of the
informed consent by the caregiver.
• Clinical diagnosis of AS confirmed by a molecular diagnosis with genotypic
classification of either:
o UBE3A truncation mutation of maternal allele
o 15q11-15 deletion of maternal allele
o Deletion on the maternally inherited chromosome 15q11q13 that includes the
UBE3A gene and is less than 7 Mb in size.
• 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: Women of non-childbearing potential or Women 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 6 months after the final dose of RO7248824
• Male Participants: During the treatment period and for at least 6 months
after the final dose of RO7248824, consent has to be provided to remain
abstinent or use contraceptive measures with a female partner of childbearing
potential, or pregnant female partner.

Inclusion Criteria for Optional Open-label Extension Part:
If a participant continues directly from the LTE part, only OOE informed
consent is required, and eligibility reassessments are not required. If a
participant has completed the LTE part of the BP41674 study or has discontinued
participation in the BP41674 study for reasons not related to safety,
reassessment of eligibility will be required along with the OOE informed
consent.
11. Current or prior participations in the LTE part of Study BP41674.
12. Signed OOE Informed Consent Form
13. Continue to meet the inclusion criteria 1 to 8 and reproductive status as
stated in the protocol at the time of entry into the OOE and met the inclusion
criteria 9 (age) and 10 (disease characteristics) at the time of enrollment
into the MAD part of the study.

Exclusion Criteria

• Clinically-significant laboratory, vital sign or electrocardiography (ECG)
abnormalities at Screening.
• Molecular diagnosis of AS with genotypic classification of:
o UBE3A missense mutation of maternal allele
o Paternal UPD of 15q11-13
o UBE3A ID
o A partial molecular diagnosis of AS that cannot exclude UPD or ID despite
appropriate genetic testing.
• Clinically relevant hematological, hepatic, cardiac, renal disease event or
laboratory abnormality, in the judgement of the Investigator.
• Any concomitant condition that might interfere with the clinical evaluation
of AS and that is not related to AS.
• Known history of human immunodeficiency virus (HIV) or hepatitis B virus
(HBV) or hepatitis C virus (HCV).
• Any condition that increases risk of meningitis.
• History of bleeding diathesis or coagulopathy.
• A medical history of brain or spinal disease that would interfere with the
lumbar puncture process, CSF circulation or safety assessment.
• History of post-lumbar-puncture headache of moderate or severe intensity
and/or blood patch.
• Malignancy within 5 years of Screening.
• Hospitalization for any major medical or surgical procedure involving general
anesthesia within 12 weeks of Screening or planned during the study.
• Have any other conditions which, in the opinion of the Investigator, would
make the participant unsuitable for inclusion or could interfere with the
participant participating in or completing the study, including any
contraindication to administration of intrathecal therapy.
• Premature birth with gestational age at birth below 34 weeks.
• History of hypersensitivity to the investigational medicinal product (IMP),
antisense oligonucleotides, or any excipients.
• Allowed sleep medications have not been stable for 4 weeks prior to screening
and at the time of enrollment.
• Allowed medications for treatment of epilepsy have not been stable for 12
weeks prior to screening and at the time of enrollment.
• Use of antiplatelet or anticoagulant therapy for 2 weeks prior to screening
and at the time of enrollment.
• Concurrent psychotropic medications have not been stable for 4 weeks prior to
screening and at the time of enrollment.
• Received an investigational drug within 90 days or 5 times the halflife of
the investigational drug (whichever is longer) or participation in a study
testing an investigational medical device within 90 days prior to first dosing
or if the device is still active.
• Concurrent or planned concurrent participation in any clinical study
(including observational, non-drug and non-interventional studies) without a
signed data sharing agreement covering the participant in place between other
clinical study and the Sponsor.
• Previous participation in a cellular therapy, or gene therapy or gene
editing, or any other gene expression modulating clinical study.

Exclusion Criteria for Optional Open-label Extension Part:
22. The participants re-entering the study to participate in the OOE must
continue to comply with exclusion criteria 1 to 21 as stated in the protocol at
the time of enrollment in the OOE.
a. ECG will be waived for participants who are re-entering the study.
23. Participants who never enrolled in Study BP41674, or who discontinued
participation due to safety reasons, are not eligible for the

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p> - Frequency and severity of adverse events, serious adverse events, treatment<br /><br>discontinuations due to adverse events.<br /><br>- Frequency of abnormal laboratory findings (blood and cerebrospinal fluid<br /><br>[CSF]).<br /><br>- Frequency of abnormal vital signs and ECG values.<br /><br>- Mean changes from baseline in vital signs (temperature, systolic and<br /><br>diastolic blood pressure, heartrate, respiratory rate) over time.<br /><br><br /><br>Endpoints measured in OOE part:<br /><br>• Frequency and severity of adverse events, serious adverse events, treatment<br /><br>discontinuations due to adverse events.<br /><br>• Frequency of abnormal laboratory findings (blood and cerebrospinal fluid<br /><br>[CSF]). </p><br>

Secondary Outcome Measures

Name	Time	Method
<p> - Time to maximum concentration (Tmax)<br /><br><br /><br>- Maximum plasma concentration observed (Cmax)<br /><br><br /><br>- AUC from Time 0 to time of last sampling point or last quantifiable sample,<br /><br>whichever comes first (AUClast), AUC from Time 0 to infinity (AUCinf)</p><br>