Berotralstat Treatment in Children With Hereditary Angioedema

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the pharmacokinetics (PK) and safety of berotralstat to determine the appropriate weight-based dose for pediatric participants 2 to < 12 years old for prophylactic treatment to prevent attacks of hereditary angioedema (HAE).

Detailed Description
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This is a single-arm, open-label study designed to evaluate the PK and safety of berotralstat weight-based treatment for the prevention of hereditary angioedema attacks in pediatric participants 2 to < 12 years of age. This study will consist of two treatment periods: a 12-week standard-of-care (SOC) treatment period followed by an open-label berotralstat treatment period lasting up to 144 weeks. Participants will be enrolled into 4 dose cohorts; participant weight will be used to determine assignment to each cohort with the higher weight cohorts (Cohorts 1 and 2) enrolling first and in parallel. Safety assessments and PK modelling from all available PK data will then be used to confirm the weight bands for sequentially enrolling Cohorts 3 and 4.The effectiveness of berotralstat in this population will be summarized using descriptive statistical methods.

Official Title
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A Phase 3 Study to Evaluate the Safety and Pharmacokinetics of Berotralstat Prophylaxis in Children With Hereditary Angioedema Who Are 2 to < 12 Years of Age

Conditions
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Hereditary Angioedema, Pediatric

Intervention / Treatment
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* Drug: Berotralstat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and non-pregnant, non-lactating females 2 to < 12 years of age Body weight ≥ 12 kg Clinical diagnosis of HAE In the opinion of the investigator, the participant would benefit from long term oral HAE prophylaxis Exclusion Criteria: Concurrent diagnosis of any other type of recurrent angioedema Known family history of sudden cardiac death Creatinine clearance using the modified Schwartz formula of ≤ 30 mL/min/1.73 m2 Aspartate aminotransferase or alanine aminotransferase value ≥ 3 × the upper limit of the age-appropriate normal reference range value Clinically significant abnormal ECG including but not limited to, a corrected QT interval calculated using Fridericia's correction > 450 msec, or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping Current participation in any other investigational drug study or received another investigational drug within 30 days of enrollment

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a sequential, three-part, open-label study. Minimum participation in this study is expected to be 24 weeks in the SOC treatment period through Part 1 of the study and up to an additional 132 weeks in Parts 2 and 3.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Berotralstat<br>Berotralstat administered once daily in 4 dose cohorts determined by participant weight. Cohorts 1 and 2 will enroll in parallel. After 4 participants from Cohort 1 and 2, with ≥ 2 subjects from Cohort 2, have reached Week 2, Cohort 3 will open for enrollment. Cohort 4 will open for enrollment, after ≥ 4 subjects in Cohort 3 have reached Week 2. Prior to dosing Cohort 3 and 4, available PK and safety data will be reviewed to confirm it is safe to proceed and the appropriate weight bands for each. BioCryst will notify sites when Cohorts 3 and 4 are open for enrollment. | Drug: Berotralstat<br>* Administered orally once daily at a weight-based dose in up to 4 cohorts<br>* Other names: Orladeyo®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Cmax | Maximum plasma concentration of berotralstat | Predose and multiple timepoints up to 24 hours postdose | 
| Pharmacokinetics: AUC0-tau | Area under the plasma concentration berotralstat time curve from time zero to the end of dosing (tau) | Predose and multiple timepoints up to 24 hours postdose | 
| Pharmacokinetics: CL/F | Apparent oral clearance of berotralstat | Predose and multiple timepoints up to 24 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) |  | Over 144 weeks | 
| Frequency and severity of hereditary angioedema (HAE) attacks |  | Over 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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berotralstat, BCX7353, Orladeyo®, once a day, Hereditary angioedema (HAE), Pediatric, oral once a day dosing, kallikrein inhibitor