Evaluation of the Safety and Pharmacokinetics of Oral Berotralstat in Pediatric Patients Aged 2 to <12 Years with Hereditary Angioedema
- Trial ID
- 2024-511257-22-00
- Protocol
- BCX7353-304
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to describe the **pharmacokinetic** parameters of berotralstat when administered orally to pediatric subjects with **Hereditary Angioedema (HAE)** aged 2 to less than 12 years and weighing at least 12 kg. Understanding the pharmacokinetics is crucial for determining the appropriate dosing regimen, ensuring efficacy, and minimizing potential adverse effects in this vulnerable population.
Secondary objectives include:
- Assessing the safety and tolerability of berotralstat in the specified pediatric population, which is essential for ensuring that the treatment is not only effective but also safe for long-term use.
- Summarizing the effectiveness of berotralstat in preventing HAE attacks in these pediatric subjects, which will provide insights into the clinical benefits of the treatment in reducing the frequency and severity of attacks.
Participants
The clinical trial involves a total of **11 participants** diagnosed with **Hereditary Angioedema (HAE)**. The study population consists of both male and non-pregnant, non-lactating female subjects aged between 2 to less than 12 years, with a minimum weight of 12 kg. Participants were selected based on a confirmed clinical diagnosis of HAE, which includes specific laboratory criteria or genetic mutations associated with the condition. The trial includes a vulnerable population, as it involves pediatric subjects. Participants are required to have access to acute medications for HAE attacks and, if not currently on prophylaxis, must have a documented history of at least two HAE attacks in the six months prior to enrollment. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the participants are those who would potentially benefit from long-term oral prophylaxis, as determined by the investigator.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and pharmacokinetics of **berotralstat** in pediatric patients with **Hereditary Angioedema (HAE)**, aged 2 to less than 12 years. This is a Phase 3, randomized, double-blind, controlled study. The trial aims to characterize the pharmacokinetic profile of berotralstat when administered orally to children with HAE, ensuring the participants weigh at least 12 kg. The study is expected to run from April 25, 2022, to February 26, 2027, with a maximum treatment period of 144 weeks.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, weight, and a clinical diagnosis of HAE. The screening will include laboratory tests to document C1-INH levels and genetic testing for SERPING-1 mutations if necessary. Following the screening, eligible participants will be enrolled and randomized to receive either berotralstat or a control treatment. The study will include regular follow-up visits to monitor safety and efficacy, assess the frequency and severity of adverse events, and evaluate the effectiveness of the treatment in reducing HAE attack frequency and severity. The end-of-study visit will conclude the trial, where final assessments will be conducted.
The expected length of participant involvement is up to 144 weeks, depending on individual response and adherence to the study protocol. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, lack of efficacy, or withdrawal of consent by the participant or their caregiver. The primary endpoint focuses on the pharmacokinetic profile of berotralstat, while secondary endpoints include safety assessments and the effectiveness of the treatment in managing HAE symptoms. Participants will be required to have access to acute medications for HAE attacks and must agree to use effective contraception if applicable.
Treatment
The clinical trial involves the administration of **Berotralstat**, a chemical compound developed by BioCryst Pharmaceuticals, Inc., in the form of granules. The pharmaceutical form is specified as granules, and the medication is administered orally. The trial includes several dosage regimens: 96 mg, 78 mg, 66 mg, and 108 mg, with a maximum treatment period of 144 days. The granules are not formulated specifically for pediatric use, and the maximum daily dose corresponds to the total dose amount for each regimen. The administration is conducted once daily, ensuring consistent exposure to the active substance throughout the study period.
Additionally, the trial includes the use of **Orladeyo 150 mg hard capsules**, which also contain the active substance **Berotralstat**. These capsules are manufactured by BioCryst Ireland Limited and are administered orally. The maximum daily dose for this formulation is 150 mg, with a total treatment period of 144 days. The capsules are designed for patients who can swallow them, and it is noted that subjects younger than 12 years may be able to take the 150 mg capsule if they weigh at least 40 kg. The administration of Orladeyo is also conducted once daily.
Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is solely on evaluating the safety and pharmacokinetics of Berotralstat in pediatric subjects with hereditary angioedema (HAE) aged 2 to less than 12 years old, weighing at least 12 kg.
Efficacy
The efficacy of Berotralstat in the clinical trial will be assessed through several parameters. The primary endpoint focuses on the characterization of the pharmacokinetic (PK) profile of **Berotralstat** in pediatric subjects aged 2 to less than 12 years. This involves measuring the drug's absorption, distribution, metabolism, and excretion in the body. Secondary endpoints include the effectiveness of the treatment, which will be evaluated by monitoring the frequency of attacks, duration of symptoms, anatomical location of attacks, on-demand treatment usage, number of days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of efficacy, and the number of hospitalizations and clinic visits from Week 1 through Weeks 12 and 48.
Data collection will involve various methods, including patient-reported outcomes and clinical assessments. The frequency and severity of adverse events (AEs) and serious adverse events (SAEs) will also be recorded, alongside laboratory analyses such as clinical chemistry, hematology, coagulation, and other vital signs. Electrocardiograms (ECGs) and physical examination findings will be part of the safety assessments. These measurements will be taken at specified intervals throughout the trial to ensure comprehensive data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and non-pregnant, non-lactating females 2 to < 12 years of age and weighing ≥ 12 kg.
- Parent/caregiver willing and able to provide written, informed consent (with assent from the child where appropriate).
- Subjects with a clinical diagnosis of HAE. A clinical diagnosis of HAE is defined as: a. Screening results that document immunogenic C1-INH antigenic level below the lower limit of normal (LLN) reference range or C1-INH function < 50% and a complement 4 (C4) level below LLN reference range. OR b. Laboratory documentation of historical C1-INH functional level below the assay lower limit of normal OR c. For subjects with C1-INH function ≥ 50% but less than the assay LLN, a SERPING-1 gene mutation known or likely to be associated with HAE Type I or II, as assessed during the screening period OR a repeat C1-INH functional level < 50% will be considered acceptable for enrollment. OR d. Historical or new laboratory documentation of a SERPING-1 mutation known or likely to be associated with HAE OR e. For subjects who currently use plasma-derived or recombinant C1-INH-based prophylactic therapies, a confirmed family history of C1-INH deficiency.
- For subjects who are not currently receiving prophylaxis for HAE, documented history of ≥ 2 HAE attacks in the 6 months prior to the enrollment visit.
- Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE.
- In the opinion of the investigator, the subject would benefit from long-term oral prophylaxis.
- Females who had started their menses and males must be either: Sexually abstinent (Section 9.2.1.1 of the protocol ); OR b. If sexually active , or become sexually active during the study, must agree to the use of effective contraception (Section 9.2.1.1 of the protocol)
Exclusion Criteria
- Concurrent diagnosis of any other type of recurrent angioedema.
- Any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, myocarditis, pericarditis, congenital heart defects, or any other clinically significant cardiovascular abnormality such as poorly controlled hypertension.
- Known family history of sudden cardiac death at a young age (ie, < 40 years of age). Family history of sudden death from HAE is not exclusionary.
- History of or current implanted defibrillator or pacemaker.
- Moderate to severe hepatic impairment (Child-Pugh B or C).
- A calculated creatinine clearance using the Modified Schwartz formula of ≤ 30 mL/min/1.73 m2 or aspartate aminotransferase or alanine aminotransferase value ≥ 3 × the upper limit of the age-appropriate normal reference range value.
- History of severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis with unclear etiology.
- Current participation in any other investigational drug study or received another investigational drug within 30 days of enrollment; not willing to refrain from participation in another clinical study after enrollment and for the duration of the study. [Note: drugs/vaccines approved under FDA emergency use authorization (or country-specific analogous regulations) are not considered excluded or prohibited under this criterion.]
- An immediate family relationship to either sponsor employees, the investigator, or employees of the study site named on the delegation log.
- Any clinically significant medical condition or medical history (including altered mental status) that, in the opinion of the investigator or sponsor, would interfere with the subject's safety or ability to participate in the study. Examples include but are not limited to active malignancy under treatment, uncontrolled cardiovascular disease, organ dysfunction requiring supportive care.
- Clinically significant abnormal ECG including but not limited to, a corrected QT interval calculated using Fridericia's correction (QTcF = QT/RR0.33) > 450 msec, or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping.
- Any result at screening that, in the opinion of the investigator, is clinically significant and relevant for this study.
- Known hypersensitivity to berotralstat or any of its formulation excipients
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 25 Apr 2022 | 3 |
 France | Not Recruiting | 25 Apr 2022 | 3 |
 Germany | Not Recruiting | 25 Apr 2022 | 3 |
 Italy | Not Recruiting | 25 Apr 2022 | 4 |
 Poland | Not Recruiting | 25 Apr 2022 | 2 |
 Spain | Not Recruiting | 25 Apr 2022 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Berotralstat | Test | GRANULES | ORAL USE | 78 | 144 | PRD11180355 |
Berotralstat | Test | GRANULES | ORAL | 96 | 144 | PRD11180383 |
Orladeyo 150 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 150 | 144 | PRD8911647 |
Berotralstat | Test | GRANULES | ORAL USE | 66 | 144 | PRD11180324 |
Berotralstat | Test | GRANULES | ORAL USE | 108 | 144 | PRD11180418 |