This study has been transitioned to CTIS with ID 2024-514797-45-00 check the CTIS register for the current data. PRIMARY OBJECTIVE: - To assess the (long-term) safety and tolerability profile of RO7248824.SECONDARY OBJECTIVE: - To investigate the…
ID
Source
Brief title
Condition
- Other condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Health condition
ontwikkelingsstoornis door een chromosoomdeletie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Frequency and severity of adverse events, serious adverse events, treatment
discontinuations due to adverse events.
- Frequency of abnormal laboratory findings (blood and cerebrospinal fluid
[CSF]).
- Frequency of abnormal vital signs and ECG values.
- Mean changes from baseline in vital signs (temperature, systolic and
diastolic blood pressure, heartrate, respiratory rate) over time.
Endpoints measured in OOE part:
• Frequency and severity of adverse events, serious adverse events, treatment
discontinuations due to adverse events.
• Frequency of abnormal laboratory findings (blood and cerebrospinal fluid
[CSF]).
Secondary outcome
- Time to maximum concentration (Tmax)
- Maximum plasma concentration observed (Cmax)
- AUC from Time 0 to time of last sampling point or last quantifiable sample,
whichever comes first (AUClast), AUC from Time 0 to infinity (AUCinf)
Background summary
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with a
prevalence of 1 in 12,000 to 20,000 births. Individuals with AS have many
features such as global developmental delay, intellectual disability, epilepsy
(90% before age 3 years) with atypical underlying electroencephalography (EEG),
ataxia, tremor, hyperactivity, limited speech, and sleep dysregulation.
Anxiety, aggression, and self-injurious behavior may also be present. There is
a high unmet medical need and societal impact in many dimensions; affected
individuals require life-long care and cannot live independently.
In individuals with AS, the maternal UBE3A allele is not functional, thus,
UBE3A is not generally expressed in neurons. In non-neuronal cells in AS,
although expression of UBE3A from the maternal allele is lacking, the paternal
allele is active and therefore a lack of expression from the maternal allele
results in haploinsufficiency rather than complete absence of UBE3A protein in
neurons.
There is a high unmet medical need in AS patients as there are no approved
treatments for AS and no clear guidelines for symptom-based interventions in
this population.Currently available treatments are symptomatic and largely
limited to improvement ofseizures and reduction of sleep disturbances. Insight
into the mechanism of action (MoA) of the disease, however, has suggested a
path forward for disease-modifying therapies RO7248824 is an ASO that is
chemically modified with locked nucleic acids (LNA) and targets a sequence on
the 3* end of the UBE3A-ATS. An LNA is a bicyclic nucleic acid where a
ribonucleoside is linked between the 2*-oxygen and the 4*-carbon atoms with a
methylene unit to enable high affinity binding to the target RNA sequence.
RO7248824 is hereafter refered to as an LNA. It aims to unsilence expression of
the paternal Ube3a allele and enable UBE3A protein production in neurons in AS
according to the mechanism described above.
This Phase I study BP41674 is planned as a multicenter, open label,
non-randomized, adaptive, multiple ascending, intra-participant dose-escalation
study with intrathecal (IT) administration of RO7248824 in participants with
Angelman Syndrome (AS) aged 1-12 years. The primary objective of this study is
to investigate the safety and tolerability of RO7248824.
PAv6: The LTE part of the study aims to investigate long-term safety and
tolerability of RO7248824, it presents an opportunity of continued prospect for
direct clinical benefit for the participants enrolled in this Phase I trial and
will be used to inform the dosing regimen selection for future clinical
studies.
Study objective
This study has been transitioned to CTIS with ID 2024-514797-45-00 check the CTIS register for the current data.
PRIMARY OBJECTIVE:
- To assess the (long-term) safety and tolerability profile of RO7248824.
SECONDARY OBJECTIVE:
- To investigate the plasma pharmacokinetics (PK) of RO7248824.
Study design
This is a Phase I, multicenter, non-randomized, adaptive, open label, multiple
ascending,
intra-participant, dose-escalation study with a LTE part to investigate the
safety,
tolerability, PK and PD of RO7248824 administered IT in participants with AS.
Two linked sets of dose escalation cohorts are planned based on two different
age
groups, namely participants with AS aged from 5 to 12 years in cohorts A1 to A5
(with at
least 2 participants from 8 years old in each cohort) and AS participants aged
1 to 4
years in cohorts B1 to B5. The two sets of cohorts will be run in parallel,
with each cohort
A1-A5 preceding and gating the linked cohort B1-B5 (e.g., A1 precedes B1).
Each participant will receive up to three IT injections of varying dose levels
over a period
of 8 weeks, with a minimum of approximately 4 weeks between each dose
administration. It is planned to test a dose range from 15 mg to 240 mg of
RO7248824
for cohorts A and 6 mg to 240mg of RO7248824 for cohorts B, over multiple
staggered
cohorts as shown in Figure 1 of Section 1.2.1
NEW PAv6/8: Long-term Extension Part (see figure 2 of section 1.2.1 of the
protocol)
Participants whose caregivers agree to the continuation of treatment after the
MAD treatment period will transition to the LTE part during the follow-up
period of the main (MAD) part.
New participants can also be included only in the LTE
The LTE will consist of 8 cohorts (i.e., 4 dosing regimens in each age group)
with 2 dosing frequencies (every 16 weeks [Q16W], and every 24 weeks [Q24W]
Participants transitioning to an LTE cohort with Q16W dosing will receive their
first dose in the LTE part not earlier than 16 weeks after their last dose in
the main part (including bridging dose).
Participants transitioning to an LTE cohort with Q24W dosing, will receive
their first dose in the LTE part not earlier than 24 weeks after their last
dose in the main part (including bridging dose).
Protocol V9: The 240 mg dose level has not been tested as part of the MAD part
of this study, therefore Cohorts A5, B5, EA4, and EB4, have not been initiated.
Protocol V10:
Optional Open-label Extension Part
An optional OOE part will evaluate the long-term safety and tolerability of
RO7248824 for up to 48 weeks. The objective of the OOE part is to provide an
option for open-label access to RO7248824 within the context of a clinical
trial to ensure that comprehensive safety assessments and monitoring are
conducted while reducing the burden of exploratory assessments. The OOE part is
open to participants who are currently or were previously enrolled in Study
BP41674. The recommended dose and dosing interval for treatment in the OOE part
will be the same dose and dosing interval the participant last received in the
LTE part. Nonetheless, dose levels and dosing frequencies in the OOE part may
be adjusted by the Investigator and endorsed by the Dose Decision Committee
(DDC) following review of safety and tolerability data of previous doses.
Intervention
RO7248824 is a selective synthetic 20-mer oligonucleotide (see RO7248824
Investigator*s Brochure). IT injection of RO7248824 is considered to be a
potential disease modifying approach for AS.
It is planned to test a dose range from 15 mg to 240 mg of RO7248824 for
cohorts A and 6 mg to 240 mg of RO7248824 for cohorts B, over multiple
staggered cohorts as shown in Figure 1 of section 1.2.1 of the protocol.
For cohorts A, participants with planned doses of 120 mg or less will receive
up to three IT injections of varying dose levels over a period of approximately
8 weeks, with approximately 4 weeks between each dose administration.
Participants with planned doses of > 120 mg and < 240mg will receive up to two
IT injections of varying dose levels with approximately 8 weeks between each
dose administration. For the dose of 240 mg, only a single IT injection is
planned. For cohorts B, the same dosing strategy will be followed as a minimum
requirement; however, administration of two injections 8 weeks apart may be
implemented at a lower dose level than 120 mg based on emerging data.
There is currently no clinical experience with RO7248824. The evaluation of the
potential risks of RO7248824 in humans is based primarily on available data
from non-clinical toxicology, safety pharmacology studies and documented drug
class-related risk from ASO class drug candidates and approved drugs that are
administered intrathecally.
NEW PAv8:
Age 5 to 12 years (*A* cohorts):
• EA1 (60 mg Q16W): for new participants enrolling directly in the LTE part
• EA2 (120 mg Q16W): for participants continuing from cohorts A1 and A2 main
study
• EA3 (180 mg Q24W): for participants continuing from Cohort A3 and A4 main
study
• EA4 (240 mg Q24W): for participants continuing from Cohort A5 main study
Age 1 to 4 years (*B* cohorts):
• EB1 (60 mg Q16W): for new participants enrolling directly into the LTE part
• EB2 (120 mg Q16W): for participants continuing from cohorts B1 and B2 main
study
• EB3 (180 mg Q24W): for participants continuing from Cohort B3 and B4 main
study
• EB4 (240 mg Q24W): participants continuing from Cohort B3 and B4 main study
As part of the procedure and immediately after the drug is injected, a small
volume of salt solution (called a flush) may also be injected using the same
needle. The drug administration procedure (including the amount of flush),
might be modified during the study. The study doctor will inform the
participants about the drug administration procedure that your child will be
receiving.
PAv9:
With the implementation of Protocol Version 9, post-dose flush solution will
not be administered anymore as IT administration without post-dose flush has
been tested as described in the Protocol v9 and has been found safe and
well-tolerated for the 3 dose levels and in both age groups by the DDC.
The 240 mg dose level has not been tested as part of the MAD part of this
study, therefore Cohorts A5, B5, EA4, and EB4, have not been initiated.
PAv10: De dosisregimes die tijdens het OOE-gedeelte zijn toegestaan, moeten
dezelfde dosisregimes zijn die worden toegediend in het LTE-gedeelte.
Study burden and risks
Please see "aanvullende opmerkingen" for an overview of the procedures that are
done in the context of the study and which are not, or partially overlap with
the standard of care. This includes lumbal punctures, CSF sampling,
venapunctures, MRI, EEG, pregnancy testing, performance scales and fundoscopy.
Risks related to treatment with the study drug:
- Allergical reactions
- Side effects that might be related to RO7248824
Safety data have become available from this study (BP41674) for 20 participants
that received RO7248824 at doses of 6 mg to 120 mg. The most common clinical
side effects (seen in 2 or more participants) were vomiting, decreased
appetite, fever, fatigue, and ataxia (a temporary reduction in coordination
and/or balance). These side effects were generally of short duration (1 to 3
days). In addition, there was a laboratory finding of increased numbers of
white blood cells in the CSF samples of 2 participants.
Potential side effects are described in more detail in the subject information
sheet.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
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 OOE part.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-514797-45-00 |
| EudraCT | EUCTR2019-003787-48-NL |
| CCMO | NL73321.000.20 |