Study to Investigate the Pharmacokinetics and Safety and to Provide Proof of Mechanism of Alogabat in Children and Adolescents Aged 5-17 Years With Angelman Syndrome (AS) With Deletion Genotype. (Aldebaran)

A Phase IIa Multicenter, Open-Label, 12-Week Study to Investigate the Pharmacokinetics and Safety and to Provide Proof of Mechanism of Alogabat in Children and Adolescents Aged 5-17 Years With Angelman Syndrome (AS) With Deletion Genotype

This is a two-part, Phase IIa, multicenter, 12-week, open-label study. Up to 56 participants with deletion Angelman Syndrome (AS) aged 5-17 years (inclusive) will be enrolled in the study.

Study Overview

• Status: Recruiting
• Conditions: Angelman Syndrome
• Intervention / Treatment: Drug: 60 mg QD Alogabat; Drug: 40 mg QD Alogabat; Drug: 7 mg QD Alogabat; Drug: Part 2 Adult Alogabat High Dose (aged 15-17); Drug: Alogabat; Drug: Alogabat; Drug: Part 2 Optional Cohort

Detailed Description

The study will have Part 1-dose confirmations and Part 2 with dose levels to be decided based on the cumulative PK, EEG, and safety data emerging from Part 1.

The dose levels for the first cohort of Part 2 will be decided based on the cumulative PK, EEG, and safety data emerging from Part 1.

Part 2 will explore the change in EEG beta-band power relative to baseline at Week 2, Week 4 (i.e., approximately 2 weeks after the start of the second dose), and at the end of the 12-week treatment period after daily administration of Alogabat.

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: BP41315 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. Only); Email: global-roche-genentech-trials@gene.com

Study Locations

• Australia
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Recruiting
      • Queensland Children?s Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Recruiting
      • Flinders Medical Centre
• France
  • Brest, France, 29609
    • Recruiting
    • CHRU de Brest; Pédiatrie Spécialisée et Génétique Medicale
  • Marseille, France, 13005
    • Recruiting
    • Hopital la Timone Enfants; Service de Pediatrie et Neurologie Pediatrique
  • Paris, France, 75015
    • Recruiting
    • Groupe Hospitalier Necker Enfants Malades
• Germany
  • München, Germany, 80337
    • Recruiting
    • Dr. von Haunersches Kinderspital
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00165
      • Recruiting
      • Ospedale Pediatrico Bambino Gesù; Dip. Neuroscienze e Neuroriabilitazione
  • Liguria
    • Genova, Liguria, Italy, 16147
      • Recruiting
      • IRCCS Istituto G. Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari
  • Veneto
    • Conegliano Veneto (TV), Veneto, Italy, 31015
      • Recruiting
      • IRCCS Eugenio Medea; U.O. di Epilessia e Neurofisiologia clinica
• Spain
  • Barcelona
    • Esplugues De Llobregat · Barcelona, Barcelona, Spain, 08950
      • Recruiting
      • Hospital Sant Joan de Deu; Neurologia Pediatrica
    • Sabadell, Barcelona, Spain, 08208
      • Active, not recruiting
      • Corporacio Sanitaria Parc Tauli
• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Rush Medical Center
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center
  • North Carolina
    • Carrboro, North Carolina, United States, 27510
      • Recruiting
      • Carolina Institute for Development Disabilities University of North Carolina/School of Medicine
  • Tennessee
    • Nashville, Tennessee, United States, 37232-9119
      • Recruiting
      • Vanderbilt Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical diagnosis of AS and a genetic subtype of deletion on the maternally inherited chromosome 15q11q13 confirmed by a historical molecular diagnosis. The deletion must include UBE3A, GABRB3, GABRA5, and GABRG3 genes, and be less than 7 Mb in size.
• Body mass index (BMI) below the 97th percentile and above the 3rd percentile for the same age and sex
• 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.
• Female participants:

A female participant is eligible to participate if she is not pregnant, not breastfeeding, and non-childbearing or remain abstinent and/or Hormonal contraceptive methods must be supplemented

-Male participants: Male contraception is not required in this study because of the minimal seminal dose transmitted through sexual intercourse

Exclusion Criteria:

• A molecular diagnosis of AS with genotypic classification of any type besides the molecular diagnosis as specified in Inclusion Criterion
• Concurrent cardiovascular disease considered not well controlled by drug treatment, including participants with clinically significant hypertension, bradycardia and arrhythmias, myocardial infarction within 12 months of screening or uncompensated heart failure
• Confirmed clinically significant abnormality on 12-lead ECG, including:
• a QTcF of >/= 450 ms (based on the average of 3 consecutive measurements) for participants older than 10 years old
• a QTcB of >/= 450 ms (based on the average of 3 consecutive measurements) for participants up to, and including, the age of 10 years old
• Congenital heart diseases not treated and congenital QTc prolongation or family history of Long QT Syndrome
• Medical history of malignancy if not considered cured or if occurred within the last 5 years with the exception of fully excised non-melanoma skin cancers or in-situ carcinoma of the cervix that has been successfully treated
• Concomitant disease, condition, or treatment that would either interfere with the conduct of the study or pose an unacceptable risk to the participant in the opinion of the Investigator.
• Known active or uncontrolled bacterial, viral, or other infection (excluding fungal infections of nail beds) or any major episode of infection or hospitalization (relating to the completion of the course of antibiotics) within 6 weeks prior to the start of drug administration. Rescreening is allowed once the infection is cured and if the rescreening criteria are met.
• 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)
• Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study. Rescreening is allowed not earlier than 12 weeks after the surgery and if the rescreening criteria are met.
• Use of prohibited medications within 6 weeks or 5 half-lives (t1/2) prior to start of study medication on Day 1 (whichever is longer)
• Clinically significant loss of blood within 3 months prior to screening defined by participant age and weight per recommendations from Duke University (2012)
• Any prior or current treatment with an investigational study drug within 6 weeks or 5 times the t1/2 of the investigational molecule (whichever is longer) prior to baseline or prior or current use of an investigational medical device within 6 weeks prior to baseline 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 Investigator.
• Previous participation in a cellular therapy, gene therapy, or gene editing clinical study
• Clinically significant vital sign or ECG abnormalities at Screening
• Confirmed clinically significant abnormality in hematological, chemistry or coagulation laboratory parameters
• Uncorrected hypokalemia or hypomagnesaemia
• Positive test result at screening for hepatitis B surface antigen (HBsAg), HCV (untreated), or HIV-1/2. Participants with HCV who have been successfully treated and who test negative for HCV RNA may be considered eligible for entry into the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Age adjusted high dose (age 10-14); In Part 1 of the study, participants will receive age-adjusted dose 60 mg QD alogabat.	Drug: 40 mg QD Alogabat; Participants aged 10-14 years receiving the equivalent of the adult 60 mg alogabat dose.
Experimental: Part 1 Age Adjusted Low Dose (age 5-9); In Part 1 of the study, participants will receive age-adjusted dose 20 mg QD alogabat.	Drug: 7 mg QD Alogabat; Participants aged 5-9 years receiving the equivalent of the adult 20 mg alogabat dose.
Experimental: Part 2 Cohort 1; In Part 2 of the study, the dosing will depend upon the results of Part 1, with age-adjusted dose equivalents of up to 100 mg being administered.	Drug: Part 2 Adult Alogabat High Dose (aged 15-17); In Part 2 of the study, the dosing will depend upon the results of Part 1, with age-adjusted dose equivalents of up to 100 mg being administered.
Experimental: Part 2 Cohort 2; In Part 2 of the study, the dosing will depend upon the results of Part 1, with age-adjusted dose equivalents of up to 100 mg being administered.	Drug: Alogabat; In Part 2 of the study, the dosing will depend upon the results of Part 1, with age-adjusted dose equivalents of up to 100 mg being administered.; Drug: Alogabat; If dose adjustments (e.g., increase or decrease in dose) are required, particularly due to uncertainty of the clearance estimates (e.g., due to high variability) or over-/underprediction of the pediatric clearance versus adult clearance, additional participants may be recruited in any of the of the 3 age-groups in order to confirm the exposure equivalence. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2.
Experimental: Part 1 Adult Alogabat High Dose (aged 15-17); In Part 1 of the study, participants will receive age-adjusted dose 60 mg QD alogabat	Drug: 60 mg QD Alogabat; Participants aged 15-17 years or above receiving the adult 60 mg of alogabat dose. I
Experimental: Part 1 Optional Cohort; If dose adjustments (e.g., increase or decrease in dose) are required, particularly due to uncertainty of the clearance estimates (e.g., due to high variability) or over-/underprediction of the pediatric clearance versus adult clearance, additional participants may be recruited in any of the of the 3 age-groups in order to confirm the exposure equivalence. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2.	Drug: Alogabat; In Part 2 of the study, the dosing will depend upon the results of Part 1, with age-adjusted dose equivalents of up to 100 mg being administered.; Drug: Alogabat; If dose adjustments (e.g., increase or decrease in dose) are required, particularly due to uncertainty of the clearance estimates (e.g., due to high variability) or over-/underprediction of the pediatric clearance versus adult clearance, additional participants may be recruited in any of the of the 3 age-groups in order to confirm the exposure equivalence. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2.
Experimental: Part 2 Optional Cohort; If dose adjustments (e.g., increase or decrease in dose) are required, particularly due to uncertainty of the clearance estimates (e.g., due to high variability) or over-/underprediction of the pediatric clearance versus adult clearance, participants from any of the 3 age-groups may enroll in order to confirm the exposure equivalence. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2.	Drug: Part 2 Optional Cohort; If dose adjustments (e.g., increase or decrease in dose) are required, particularly due to uncertainty of the clearance estimates (e.g., due to high variability) or over-/underprediction of the pediatric clearance versus adult clearance, participants from any of the 3 age-groups may enroll in order to confirm the exposure equivalence. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age-group based ratio of plasma PK parameter, area under the concentration-time curve (AUC)	In Part 1 only. Age-group based ratio of plasma PK parameters in pediatric participants with AS versus data collected from adult healthy volunteers and participants with ASD (area under the concentration-time curve [AUC])	Up to 12 Weeks
Age-group based ratio of plasma PK parameter, apparent clearance (CL/F)	In Part 1 only. Age-group based ratio of plasma PK parameters in pediatric participants with AS versus data collected from adult healthy volunteers and participants with ASD (apparent clearance [CL/F])	Up to 12 Weeks
Change from baseline to Week 2, 4, and 12 in resting state EEG power in the beta band	In Part 2 only	Week 2, 4, and 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma pharmacokinetic parameter of alogabat, maximum concentration (Cmax)	In Part 1 and 2. Plasma pharmacokinetic parameter of alogabat maximum concentration (Cmax) as derived using a population-pharmacokinetic (popPK) model	Up to 12 Weeks
Plasma pharmacokinetic parameters of alogabat area under the concentration-time curve (AUC)	In Part 1 and 2. Plasma pharmacokinetic parameter of alogabat area under the concentration-time curve (AUC) as derived using a population-pharmacokinetic (popPK) model	Up to 12 Weeks
Plasma pharmacokinetic parameter of alogabat, apparent clearance (CL/F)	In Part 1 and 2. Plasma pharmacokinetic parameter of alogabat apparent clearance (CL/F) derived using a population-pharmacokinetic (popPK) model	Up to 12 Weeks
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs).	In Part 1 and 2. Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	Up to 18 Weeks
Incidence of treatment discontinuations due to AEs	Incidence of treatment discontinuations due to AEs in Part 1 and 2	Up to 18 Weeks
Incidence of daytime sleepiness assessed with the Karolinska Sleepiness Scale (KSS), and incidence of sudden onset of sleep assessed with somnolence diary	Incidence of daytime sleepiness assessed with the Karolinska Sleepiness Scale (KSS), and incidence of sudden onset of sleep assessed with somnolence diary in Part 1 and 2.	Up to 21 Weeks

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2023
• Primary Completion (Estimated): March 21, 2025
• Study Completion (Estimated): March 21, 2025

Study Registration Dates

• First Submitted: November 9, 2022
• First Submitted That Met QC Criteria: November 17, 2022
• First Posted (Actual): November 29, 2022

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: May 2, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Imprinting Disorders; Syndrome; Angelman Syndrome
• Other Study ID Numbers: BP41315; 2022-501844-14-00 (Other Identifier: EU Trial Number)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No