A Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of RO7248824 In Participants With Angelman Syndrome

Brief Title

A Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of RO7248824 In Participants With Angelman Syndrome

Official Title

An Open-Label, Multicenter Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of RO7248824 In Participants With Angelman Syndrome

Brief Summary

      This is a Phase I, multicenter, non-randomized, adaptive, open label, multiple ascending,
      intra-participant, dose-escalation study using IT administration to investigate the safety,
      tolerability, PK and PD of RO7248824 in participants with AS.

      Two linked sets of dose escalation cohorts are planned based on two different age groups,
      namely participants with AS aged ≥ 5 to ≤ 12 years in cohorts A1 to A4 (with at least 2
      participants ≤ 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-A4
      preceding and gating the linked cohort B1-B5 (e.g., A1 precedes B1).
    


Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Frequency And Severity Of Adverse Events

Secondary Outcome

 Time to Maximum Concentration (Tmax) for RO7248824

Condition

Angelman Syndrome

Intervention

RO7248824

Study Arms / Comparison Groups

 Cohort A1 RO7248824
Description:  Participants 5-12 Years

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

66

Start Date

August 19, 2020

Completion Date

September 13, 2022

Primary Completion Date

September 13, 2022

Eligibility Criteria

        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 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.

          -  Body weight of ≥ 7 kg

          -  Participant must be ≥ 1 to ≤ 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 UBE3A mutation of the maternal allele or deletion on the
             maternally inherited chromosome 15q11q13 that includes the UBE3A gene and is less than
             7 Mb in size.

        Reproductive Status:

        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 12) and the nature of the disease understudy.
        These provisions are nonetheless included for purposes of completeness in order:

        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.

          -  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 (RG6091). 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.

        Male Participants

        During the treatment period and for at least 6 months after the final dose of RO7248824
        (RG6091), consent has to be provided to:

          -  Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures
             such as a condom, with a female partner of childbearing potential, or pregnant female
             partner, to avoid exposing the embryo.

        The reliability of sexual abstinence for male and/or female enrollment eligibility needs to
        be evaluated in relation to the duration of the clinical study and the preferred and usual
        lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation,
        symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of
        preventing drug exposure.

        Exclusion Criteria:

        Diagnostic Assessments

          -  Clinically-significant laboratory, vital sign or electrocardiography (ECG)
             abnormalities at Screening

        Type of Participants and Disease Characteristics

          -  Molecular diagnosis of AS with genotypic classification:

        UBE3A missense mutation of maternal allele Paternal Uniparental Disomy (UPD) of 15q11-13
        UBE3A Imprinting center defect (ID) A partial molecular diagnosis of AS, that cannot
        exclude UPD or ID despite appropriate genetic testing.

        Medical history and concurrent disease

          -  Clinically relevant hematological, hepatic, cardiac or renal disease or event, in the
             judgement of the investigator. Pre-existing abnormal hepatic, renal or hematology lab
             tests must be discussed with the Sponsor Medical Monitor.

          -  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 LP process,
             cerebrospinal fluid (CSF) circulation or safety assessment

          -  History of clinically significant 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.

        Prior Therapy

          -  Allowed sleep medications have not been stable for 4 weeks prior to screening and at
             the time of enrollement.

          -  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.

        Other Exclusion Criteria: Prior/Concurrent Clinical Study Experience

          -  Received an investigational drug within 90 days or 5 times the half-life 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 and non-interventional studies) without approval of the Sponsor Medical
             Monitor. At the discretion of the Sponsor, participants may enroll into non-drug
             observational studies.

          -  Previous participation in a cellular therapy, or gene therapy, or gene editing
             clinical study.
      

Gender

All

Ages

1 Year - 12 Years

Accepts Healthy Volunteers

No

Contacts

Clinical Trials, 888-662-6728 (U.S. and Canada), [email protected]

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT04428281

Organization ID

BP41674

Secondary IDs

2019-003787-48

Responsible Party

Sponsor

Study Sponsor

Hoffmann-La Roche


Study Sponsor

Clinical Trials, Study Director, Hoffmann-La Roche


Verification Date

November 2021