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)

• ClinicalTrials.gov Identifier: NCT05630066
• Recruitment Status: Recruiting
• First Posted: November 29, 2022
• Last Update Posted: May 3, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: November 9, 2022
• First Posted Date: November 29, 2022
• Last Update Posted Date: May 3, 2024
• Actual Study Start Date: July 27, 2023
• Estimated Primary Completion Date: March 21, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 17, 2022)

• Age-group based ratio of plasma PK parameter, area under the concentration-time curve (AUC) [ Time Frame: Up to 12 Weeks ]
  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])
• Age-group based ratio of plasma PK parameter, apparent clearance (CL/F) [ Time Frame: Up to 12 Weeks ]
  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])
• Change from baseline to Week 2, 4, and 12 in resting state EEG power in the beta band [ Time Frame: Week 2, 4, and 12 ]
  In Part 2 only

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 17, 2022)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.
• 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
• Brief 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.

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
• Study Phase: Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

There will be up to 7 cohorts. The adolescents aged 15-17 will receive the adult dose. Dosing in Part 1 is pre-specified. Cohorts in Part 1 enroll a specific age range (15-17, 10-14, 5-9), with older cohorts being initiated prior to younger ones.

Part 2 features mixed-age cohorts, with age-adjusted doses. Within each Part 2 cohort, two different doses of alogabat may be used: one up to week 2, and the other from week 2 to week 12. Part 2 opens enrolment for ages 10-17 years following analysis of the 2-week data from the Part 1 cohorts aged 15-17 years and 10-14 years. Ages 5-9 years may enroll in Part 2 following analysis of the 2-week data from the Part 1 cohort with participants aged 5-9 years. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Angelman Syndrome

Intervention

• Drug: 60 mg QD Alogabat

  Participants aged 15-17 years or above receiving the adult 60 mg of alogabat dose.

  I

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

• 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

Study Arms

• 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
  Intervention: Drug: 60 mg QD Alogabat
• 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.
  Intervention: Drug: 40 mg QD Alogabat
• 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.
  Intervention: Drug: 7 mg QD Alogabat
• 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.
  Intervention: Drug: Part 2 Adult Alogabat High Dose (aged 15-17)
• 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.
  Intervention: Drug: Alogabat
• 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.

  Intervention: Drug: Alogabat
• 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.

  Intervention: Drug: Part 2 Optional Cohort

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 17, 2022): 56
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 21, 2025
• Estimated Primary Completion Date: March 21, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, France, Germany, Italy, Spain, United States

Administrative Information

• NCT Number: NCT05630066
• Other Study ID Numbers: BP41315; 2022-501844-14-00 ( Other Identifier: EU Trial Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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).
• Supporting Materials: Study Protocol

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Hoffmann-La Roche
• Verification Date: May 2024