Hereditary Angioedema, Pediatric
Conditions
Keywords
Berotralstat, BCX7353, Orladeyo, once a day, Hereditary angioedema (HAE), Pediatric, kallikrein inhibitor, Oral
Brief summary
The purpose of this study is to evaluate the pharmacokinetics (PK), safety and effectiveness of berotralstat to determine the appropriate weight-based dose for pediatric participants 2 to \< 12 years of age for prophylactic treatment to prevent attacks of hereditary angioedema (HAE).
Detailed description
This is a single-arm, 3-part, open-label study designed to evaluate the PK, safety, and effectiveness of berotralstat weight-based treatment for the prevention of HAE attacks in pediatric participants 2 to \< 12 years of age. Participation in this study is expected to be a minimum of 12 weeks in the standard of care (SOC) period, and in the berotralstat period, it is expected to be 12 weeks in Part 1, 36 weeks in Part 2, and 96 weeks in Part 3 of the study. Participants were enrolled into 4 cohorts; participant weight at baseline was 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 were then used to confirm the dose and weight bands for sequentially enrolling Cohorts 3 and 4. The safety and effectiveness of berotralstat in this population was summarized using descriptive statistical methods.
Interventions
DRUGBerotralstat
Administered orally once daily
Sponsors
BioCryst Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
This is a sequential, 3-part, open-label study. Participants were assigned a cohort based on weight at baseline.
Eligibility
Sex/Gender
ALL
Age
2 Years to 11 Years
Healthy volunteers
No
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 * 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.
Exclusion criteria
* Concurrent diagnosis of any other type of recurrent angioedema * Known family history of sudden cardiac death at a young age (\< 40 years of age) * Creatinine clearance using the modified Schwartz formula of ≤ 30 mL/min/1.73 m\^2 * Aspartate aminotransferase or alanine aminotransferase value ≥ 3 × the upper limit of the age-appropriate normal reference range value * Clinically significant abnormal electrocardiogram (ECG) including but not limited to, a corrected QT interval 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time of Last Measurable Plasma Concentration (Tlast) of Berotralstat | Predose and up to 6 hours post dose at Week 2 | Tlast is the time of the last measurable concentration (Clast) of berotralstat collected over the sampling interval. |
| Maximum Observed Plasma Concentration (Cmax) of Berotralstat | Predose and up to 6 hours post dose at Week 2 | Cmax is the maximum observed plasma concentration of berotralstat. |
| Time to Maximum Plasma Concentration (Tmax) of Berotralstat | Predose and up to 6 hours post dose at Week 2 | Tmax is the time taken to reach the maximum observed plasma concentration of berotralstat. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUC0-last) of Berotralstat | Week 2 | AUC0-last is the area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to 6 Hours Post-dose (AUC0-6) of Berotralstat | Predose and up to 6 hours post dose at Week 2 | AUC0-6 is the area under the plasma concentration-time curve from time 0 to 6 hours. |
| Concentration at the End of the Dosing Interval (Ctrough) of Berotralstat | Predose at Week 2 | Ctrough is the concentration at the end of a dosing interval of berotralstat. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of study treatment up to approximately 73 weeks | An adverse event (AE) is any untoward medical occurrence in a clinical study participant. No causal relationship with study drug or with the clinical study itself is implied. An AE could be an unfavorable and unintended sign, symptom (including an abnormal laboratory finding), syndrome, or illness that developed or worsened during the clinical study. A serious adverse event (SAE) is any untoward medical occurrence resulting in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or other medically important event. TEAEs are AEs that occurred on/after first dose of berotralstat through 30 days post discontinuation of study treatment. |
| Number of Adjusted Hereditary Angioedema (HAE) Attacks | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?",were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. |
| Rate of Adjusted HAE Attacks | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?",were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The adjusted attack rate was calculated as the number of adjusted attacks observed during a given period and standardized to number of attacks per month, where 1 month is defined as a 28-day (4 week) period. |
| Duration of Adjusted HAE Attack Symptoms | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?",were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The duration of each participant-reported attack was calculated in hours, based on the start, and stop date and time of the adjusted attack (time the attack finished). |
| Incidence of Adjusted HAE Attack Based on Anatomical Location | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks were assessed based on anatomical location. Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Anatomical locations were categorized as abdominal-only, non-abdominal peripheral, mixed, and laryngeal attacks. |
| Number of Adjusted Attacks Requiring On-Demand Treatment | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Number of adjusted attacks treated with targeted HAE medications was assessed. |
| Proportion of Adjusted Attacks Requiring On-Demand Treatment | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Proportion of adjusted attacks treated with targeted HAE medications was assessed. |
| Number of Days With Angioedema Symptoms | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc)?",were considered unique (attack began \> 24 hours from the end of the prior attack),and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The number of days with angioedema symptoms is the number of the days during the reporting period for which at least 1 symptom is reported during an adjusted HAE attack based on the start date and resolution date of an attack. |
| Proportion of Days With Angioedema Symptoms | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc)?",were considered unique (attack began \> 24 hours from the end of the prior attack),and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The proportion of days with angioedema symptoms was based on the number of days with reported symptoms and the number of days the participant was on treatment, where the number of days with angioedema symptoms is the number of the days during the reporting period for which at least 1 symptom is reported during an adjusted HAE attack based on the start date and resolution date of an attack. |
| Assessment of Adjusted HAE Attack Severity | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The severity was assessed by the parent/caregiver as negligible, mild, moderate or severe. |
| Number of Participants Who Discontinued Treatment Due to Perceived Lack of Efficacy | Week 1 through Week 12 and Week 1 through Week 48 | The total number of participants who discontinued the treatment due to perceived lack of efficacy of berotralstat were reported. |
| Number of Hospitalizations and Clinic Visits Due to HAE | Week 1 through Week 12 and Week 1 through Week 48 | Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began \> 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of \> 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Number of adjusted attacks that required hospitalization or clinic visits are reported. |
Countries
Austria, Canada, France, Germany, Israel, Italy, Poland, Romania, Spain, United Kingdom
Contacts
PRINCIPAL_INVESTIGATORJolanta Bernatoniene, MD
Bristol Royal Hospital for Children
Participant flow
Recruitment details
A total of 29 pediatric participants were enrolled in the study at a total of 11 study sites in Austria, Canada, France, Germany, Italy, Israel, Poland, Spain and the United Kingdom (UK).
Pre-assignment details
Participants were enrolled into a 12-week standard of care (SOC) period prior to initiating berotralstat. Participants were assigned to one of 4 cohorts based on body weight. Results contained herein are based on an interim analysis with data cutoff date of 11 September 2024 which was determined by the protocol defined event.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 8.3 years STANDARD_DEVIATION 2.12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 7 | 0 / 9 | 0 / 9 | 0 / 4 |
| other Total, other adverse events | 18 / 29 | 6 / 7 | 7 / 9 | 9 / 9 | 3 / 4 |
| serious Total, serious adverse events | 0 / 29 | 1 / 7 | 0 / 9 | 0 / 9 | 0 / 4 |
Outcome results
None listed