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.

Angelman Syndrome Clinical Trial

— Aldebaran  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05630066
• Other study ID #: BP41315
• Secondary ID: 2022-501844-14-0
• Status: Recruiting
• Phase: Phase 2
• Start date: July 27, 2023
• Est. completion date: March 21, 2025

Study information

• Verified date: May 2024
• Source: Hoffmann-La Roche
• Contact: Reference Study ID Number: BP41315 https://forpatients.roche.com
• Phone: 888-662-6728 (U.S. Only)
• Email: global-roche-genentech-trials[@]gene.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 56
• Est. completion date: March 21, 2025
• Est. primary completion date: March 21, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Angelman Syndrome
• Syndrome

Intervention

Drug:
• 60 mg QD Alogabat
Participants aged 15-17 years or above receiving the adult 60 mg of alogabat dose. I
• 40 mg QD Alogabat
Participants aged 10-14 years receiving the equivalent of the adult 60 mg alogabat dose.
• 7 mg QD Alogabat
Participants aged 5-9 years receiving the equivalent of the adult 20 mg alogabat dose.
• 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.
• 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.
• 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.
• 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

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Queensland Children?s Hospital	South Brisbane	Queensland
France	CHRU de Brest; Pédiatrie Spécialisée et Génétique Medicale	Brest
France	Hopital la Timone Enfants; Service de Pediatrie et Neurologie Pediatrique	Marseille
France	Groupe Hospitalier Necker Enfants Malades	Paris
Germany	Dr. Von Haunersches Kinderspital	München
Italy	IRCCS Eugenio Medea; U.O. di Epilessia e Neurofisiologia clinica	Conegliano Veneto (TV)	Veneto
Italy	IRCCS Istituto G. Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari	Genova	Liguria
Italy	Ospedale Pediatrico Bambino Gesù; Dip. Neuroscienze e Neuroriabilitazione	Roma	Lazio
Spain	Hospital Sant Joan de Deu; Neurologia Pediatrica	Esplugues De Llobregat · Barcelona	Barcelona
Spain	Corporacio Sanitaria Parc Tauli	Sabadell	Barcelona
United States	Carolina Institute for Development Disabilities University of North Carolina/School of Medicine	Carrboro	North Carolina
United States	Rush Medical Center	Chicago	Illinois
United States	Vanderbilt Children's Hospital	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of treatment discontinuations due to AEs	Incidence of treatment discontinuations due to AEs in Part 1 and 2	Up to 18 Weeks
Secondary	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