Clinical trial NCT05630066: A Study to Investigate the Pharmacokinetics (PK) 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Angelman Syndrome
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2022-11-29
Enrollment: 56
Sex: ALL
Minimum age (years): 5
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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 (Dose A), and the other from Week 3 to Week 12 (Dose B). 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. Part 2 Cohort 2 will open enrollment across ages following the review of Week 2 and Week 4 data in Part 2 Cohort 1. A total of two optional cohorts may be utilized in this study, allocated to Part 1 and/or Part 2.
Primary purpose: TREATMENT

Brief summary: This is a two-part, Phase IIa, multicenter, 12-week, open-label study. Up to 56 participants with deletion 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, electroencephalography (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 Dose B), and at the end of the 12-week treatment period after daily administration of alogabat.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of AS and a genetic subtype of deletion on chromosome 15q11q13 confirmed by a historical molecular diagnosis
* The participant's general health status, in the context of the disease under study, allows them to participate in a clinical trial in the opinion of the investigator
* 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 (MI) within 12 months of screening or uncompensated heart failure
* Confirmed clinically significant abnormality on 12-lead electrocardiogram (ECG), including:
* a QT corrected for heart rate using the Fridericia's correction factor (QTcF) of \>/= 450 ms (based on the average of 3 consecutive measurements) for participants older than 10 years old
* a QT corrected for heart rate using Bazett's formula (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 QT corrected for heart rate (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 ribonucleic acid (HCV RNA) may be considered eligible for entry into the study

Primary outcomes:
measure: Part 1: Age-group Based Ratio of Plasma PK Parameter, Area Under the Concentration-time Curve (AUC)
timeFrame: Up to 12 Weeks
measure: Part 1: Age-group Based Ratio of Plasma PK Parameter, Apparent Clearance (CL/F)
timeFrame: Up to 12 Weeks
measure: Part 2: Change From Baseline to Week 2, 4, and 12 in Resting State EEG Power in the Beta Band
timeFrame: Week 2, 4, and 12
Secondary outcomes:
measure: Parts 1 and 2: Plasma PK Parameter of Alogabat, Maximum Concentration (Cmax)
timeFrame: Up to 12 Weeks
measure: Parts 1 and 2: Plasma PK Parameter of Alogabat, AUC
timeFrame: Up to 12 Weeks
measure: Parts 1 and 2: Plasma PK Parameter of Alogabat, CL/F
timeFrame: Up to 12 Weeks
measure: Parts 1 and 2: Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 18 Weeks
measure: Parts 1 and 2: Incidence of Treatment Discontinuations due to AEs
timeFrame: Up to 18 Weeks
measure: Parts 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
timeFrame: Up to 12 Weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: Chicago
country: United States
facility: Rush Medical Center
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Carrboro
country: United States
facility: Carolina Institute for Development DisabilitiesUniversity of North Carolina/School of Medicine
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt Children's Hospital
state: Tennessee
city: Tacoma
country: United States
facility: Multicare Institute for Research and Innovation
state: Washington
city: South Brisbane
country: Australia
facility: Queensland Children?s Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Brest
country: France
facility: CHRU de Brest
city: Dijon
country: France
facility: CHU Dijon Bourgogne Hôpital François Mitterand
city: Marseille
country: France
facility: Hopital la Timone Enfants
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: München
country: Germany
facility: Dr. Von Haunersches Kinderspital
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
state: Lazio
city: Genova
country: Italy
facility: IRCCS Istituto G. Gaslini
state: Liguria
city: Conegliano Veneto (TV)
country: Italy
facility: IRCCS Eugenio Medea
state: Veneto
city: Esplugues De Llobregat · Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
state: Barcelona
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Puerta De Hierro Majadahonda
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: