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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
29
Administered orally once daily
Investigative Site #1
Vienna, Ontario, Austria
Investigative Site #1
Ottawa, Ontario, Canada
Investigative Site #3
Grenoble, France
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUC0-last) of Berotralstat
AUC0-last is the area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration.
Time frame: Week 2
Area Under the Plasma Concentration-Time Curve From Time 0 to 6 Hours Post-dose (AUC0-6) of Berotralstat
AUC0-6 is the area under the plasma concentration-time curve from time 0 to 6 hours.
Time frame: Predose and up to 6 hours post dose at Week 2
Concentration at the End of the Dosing Interval (Ctrough) of Berotralstat
Ctrough is the concentration at the end of a dosing interval of berotralstat.
Time frame: Predose at Week 2
Maximum Observed Plasma Concentration (Cmax) of Berotralstat
Cmax is the maximum observed plasma concentration of berotralstat.
Time frame: Predose and up to 6 hours post dose at Week 2
Time of Last Measurable Plasma Concentration (Tlast) of Berotralstat
Tlast is the time of the last measurable concentration (Clast) of berotralstat collected over the sampling interval.
Time frame: Predose and up to 6 hours post dose at Week 2
Time to Maximum Plasma Concentration (Tmax) of Berotralstat
Tmax is the time taken to reach the maximum observed plasma concentration of berotralstat.
Time frame: Predose and up to 6 hours post dose at Week 2
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
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Investigative Site #2
Marseille, France
Investigative Site #1
Paris, France
Investigative Site #1
Berlin, Germany
Investigative Site #2
Frankfurt, Germany
Investigative Site #2
Haifa, Israel
Investigative Site #1
Tel Aviv, Israel
Investigative Site #1
Padova, Italy
...and 5 more locations
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.
Time frame: From first dose of study treatment up to approximately 73 weeks
Number of Adjusted Hereditary Angioedema (HAE) Attacks
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Rate of Adjusted HAE Attacks
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Duration of Adjusted HAE Attack Symptoms
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).
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Incidence of Adjusted HAE Attack Based on Anatomical Location
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Number of Adjusted Attacks Requiring On-Demand Treatment
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Proportion of Adjusted Attacks Requiring On-Demand Treatment
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Number of Days With Angioedema Symptoms
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Proportion of Days With Angioedema Symptoms
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Assessment of Adjusted HAE Attack Severity
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Number of Participants Who Discontinued Treatment Due to Perceived Lack of Efficacy
The total number of participants who discontinued the treatment due to perceived lack of efficacy of berotralstat were reported.
Time frame: Week 1 through Week 12 and Week 1 through Week 48
Number of Hospitalizations and Clinic Visits Due to HAE
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.
Time frame: Week 1 through Week 12 and Week 1 through Week 48