Hereditary Angioedema, HAE
Conditions
Keywords
BCX7353
Brief summary
This is a phase 3, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral BCX7353 in preventing acute angioedema attacks in patients with Type I and Type II HAE who live in Japan.
Interventions
DRUGBCX7353 capsules
BCX7353 capsules administered orally once daily
DRUGPlacebo oral capsule
Matching placebo capsules administered orally once daily
Sponsors
BioCryst Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * A clinical diagnosis of hereditary angioedema (HAE) Type 1 or Type 2, defined as having a C1-INH functional level and a C4 level below the lower limit of the normal (LLN) reference range, as assessed during the Screening period. * 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 * Subjects must be medically appropriate for on-demand treatment as the sole medicinal management for their HAE during the study. * Subjects must have a specified number of expert-confirmed attacks during the run-in period of 56 days from the Screening visit. * Acceptable effective contraception * Written informed consent Key
Exclusion criteria
* Pregnancy or breast-feeding * Any clinically significant medical condition or medical history that, in the opinion of the Investigator or Sponsor, would interfere with the subject's safety or ability to participate in the study * Any laboratory parameter abnormality that, in the opinion of the Investigator, is clinically significant and relevant for this study * Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/ anaphylaxis with unclear etiology * Use of C1-INH within 14 days or use of androgens or tranexamic acid within 28 days prior to the Screening visit for prophylaxis of HAE attacks, or initiation of these drugs during the study * Current participation in any other investigational drug study or received another investigational drug within 30 days of the Screening visit * Prior enrollment in a BCX7353 study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: The Rate of Expert-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168) | 24 weeks | The angioedema event rate and the treatment comparisons between each berotralstat dose and placebo in the rate of expert-confirmed angioedema events during the entire dosing period was analyzed using a negative binomial regression model. The number of expert-confirmed angioedema events was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline monthly angioedema event rate) and study (for the combined study analysis) were included as covariates, and the logarithm of duration on treatment was included as an offset variable. The estimated rate of angioedema events for each treatment group, the treatment differences expressed as the angioedema event rate ratio (berotralstat) over placebo rate ratio), and their associated 95% confidence intervals (CIs) were provided from the negative binomial regression model. |
| Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Part 1: 24 weeks (Week 0 to 24 to 52), Part 2: 28 weeks (Week 24 to 52) | The safety data was assessed for the safety population for subjects who entered Part 2, and includes TEAEs that occurred in Part 1 and Part 2 for these subjects with a data cut-off date of 10-April-2020. TEAEs are defined as AEs that occurred on or after first dose of study treatment, whether in Part 1 or 2, and were assigned to the relevant treatment depending on when the TEAE began (Part 1 or Part 2 treatment). TEAEs were assessed for severity (graded) using the Division of Microbiology and Infectious Disease (DMID) criteria for grading AEs. TEAEs not covered by the DMID criteria were assessed as Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3) or Life-threatening (Grade 4). |
| Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | Part 3: Week 52 to up to Week 104. | The safety data was assessed for the safety population for subjects who entered Part 3, and includes TEAEs that occurred in Part 3 for these subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | 28 weeks (Week 24 to 52) | Monthly Attack Rate was defined as the total number of investigator-confirmed HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the subject was on treatment during that month. The end of Month 6 was defined as the start of Part 2 treatment. For crossover subjects receiving active treatment following placebo, months were adjusted according to the date of the first dose of active treatment. Baseline investigator-confirmed attack rate was defined as the total number of investigator-confirmed HAE attacks experienced in the period between screening and first dose of study drug adjusted for the length of a month (defined as 28 days) and the number of days during that period. |
| Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period. | 28 Weeks (Week 24 to 52) | Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL is only validated for adults; however, data were collected on all adult and adolescent study subjects. |
| Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks. | 24 weeks | Assessment of number and proportion of days subjects had angioedema symptoms from expert-confirmed angioedema events during Part 1. |
| Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period | 52 Weeks (Week 52 to 104) | Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment. |
| Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period | 52 Weeks (Week 52 to 104) | The Treatment Satisfaction Questionnaire for Medication (TSQM) was completed by subjects at baseline and at each study visit until the end of the study. TSQM scores consisted of 14 items of which 13 items were made up of 3 specific scales (Effectiveness, Side Effects, and Convenience) and 1 global satisfaction scale (Global Satisfaction). At baseline, TSQM questionnaires were completed based on subject's satisfaction with usual medications. At all other time points for collection of TSQM, subjects were asked about their level of satisfaction or dissatisfaction with the study drug. Scales scores were calculated for each scale and were transformed into scores ranging from 0 to 100, with higher scores indicating higher satisfaction. TSQM score and corresponding change from baseline values were calculated at each visit. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment. |
| Part 3: To Assess the Effectiveness of Berotralstat Over a 52- to up to 104-week Administration Period | 52 weeks (Week 52 to 104) | Adjusted subject-reported event rate was defined as (total number of adjusted subject-reported HAE events experienced in the period between the Week 52 visit and end of study \[or the last dose date/time in Part 3 + 24 hours for subjects who discontinued drug in Part 3\]) \* 28/(date of last dose in Part 3 - date of Week 52 visit + 1). |
| Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period | Day 8 through to 24 weeks | The rate of expert-confirmed angioedema events for the effective treatment period gives an analysis of the efficacy of active treatment after berotralstat had reached steady-state concentrations, given the effective half-life of 150 mg berotralstat in Study BCX7353-106 (Study 106) of 89 hours. |
| Part 1: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire at Week 24 (Total Score) | Baseline and 24 weeks | Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). |
Countries
Japan
Participant flow
Pre-assignment details
Subjects with HAE Type 1 or Type 2 were eligible for the study following assessment of data obtained from screening procedures, including demonstration of a minimum number of qualifying angioedema events documented during a prospective run-in period of 56 days from the date of the screening visit. Randomization was stratified by the angioedema event rate over the period between screening and randomization (≥ 2 angioedema events per month vs. \< 2 angioedema events per month).
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Berotralstat 110mg Once Daily Berotralstat administered as two 55mg capsules, orally QD for 24 weeks. | 6 |
| Part 1: Berotralstat 150mg Once Daily Berotralstat administered as two 75mg capsules, orally QD for 24 weeks. | 7 |
| Part 1: Placebo Placebo administered as two 2 matching capsules, orally QD for24 weeks. | 6 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1 | Study drug discontinuation due to rash | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 | Lab abnormality or AE | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 2 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
| Part 3 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 1: Berotralstat 110mg Once Daily | Part 1: Berotralstat 150mg Once Daily | Part 1: Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 15.03 | 37.3 years STANDARD_DEVIATION 9.05 | 42.3 years STANDARD_DEVIATION 13.52 | 42.1 years STANDARD_DEVIATION 12.61 |
| Baseline expert-confirmed angioedema event rate < 2 events/month | 4 participants | 3 participants | 3 participants | 10 participants |
| Baseline expert-confirmed angioedema event rate ≥ 2 events/month | 2 participants | 4 participants | 3 participants | 9 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 6 Participants | 6 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 5 Participants | 16 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 | 0 / 6 |
| other Total, other adverse events | 8 / 8 | 9 / 9 | 6 / 6 |
| serious Total, serious adverse events | 2 / 8 | 1 / 9 | 0 / 6 |
Outcome results
Primary
Part 1: The Rate of Expert-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168)
The angioedema event rate and the treatment comparisons between each berotralstat dose and placebo in the rate of expert-confirmed angioedema events during the entire dosing period was analyzed using a negative binomial regression model. The number of expert-confirmed angioedema events was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline monthly angioedema event rate) and study (for the combined study analysis) were included as covariates, and the logarithm of duration on treatment was included as an offset variable. The estimated rate of angioedema events for each treatment group, the treatment differences expressed as the angioedema event rate ratio (berotralstat) over placebo rate ratio), and their associated 95% confidence intervals (CIs) were provided from the negative binomial regression model.
Time frame: 24 weeks
Population: The intent to treat (ITT) population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy and health outcomes data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 1: The Rate of Expert-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168) | 1.961 Angioedema event rate per 28 days | Standard Deviation 1.3021 |
| Berotralstat 150mg Once Daily | Part 1: The Rate of Expert-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168) | 1.089 Angioedema event rate per 28 days | Standard Deviation 0.9168 |
| Placebo | Part 1: The Rate of Expert-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168) | 2.734 Angioedema event rate per 28 days | Standard Deviation 1.6359 |
p-value: 0.18195% CI: [-50.1, 14]negative binomial regression model
p-value: 0.00395% CI: [-67.5, -20.4]negative binomial regression model
Primary
Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE
The safety data was assessed for the safety population for subjects who entered Part 2, and includes TEAEs that occurred in Part 1 and Part 2 for these subjects with a data cut-off date of 10-April-2020. TEAEs are defined as AEs that occurred on or after first dose of study treatment, whether in Part 1 or 2, and were assigned to the relevant treatment depending on when the TEAE began (Part 1 or Part 2 treatment). TEAEs were assessed for severity (graded) using the Division of Microbiology and Infectious Disease (DMID) criteria for grading AEs. TEAEs not covered by the DMID criteria were assessed as Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3) or Life-threatening (Grade 4).
Time frame: Part 1: 24 weeks (Week 0 to 24 to 52), Part 2: 28 weeks (Week 24 to 52)
Population: The safety population included all subjects who received at least 1 capsule of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE | 3 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Investigator-identified rash (event of special interest) | 1 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Grade 3 or 4 TEAE | 0 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | SAE | 2 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related SAE | 0 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to interruption of study drug | 1 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE | 6 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related TEAE | 2 Participants |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related grade 3 or 4 TEAE | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | SAE | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related TEAE | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related SAE | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE | 1 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to interruption of study drug | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Grade 3 or 4 TEAE | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Investigator-identified rash (event of special interest) | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related grade 3 or 4 TEAE | 0 Participants |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE | 7 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | SAE | 0 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to interruption of study drug | 2 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE | 3 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related TEAE | 3 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related SAE | 0 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Grade 3 or 4 TEAE | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related grade 3 or 4 TEAE | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to discontinuation of study drug | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Investigator-identified rash (event of special interest) | 2 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE | 2 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related SAE | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related grade 3 or 4 TEAE | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE | 1 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Investigator-identified rash (event of special interest) | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to interruption of study drug | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related TEAE | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | SAE | 0 Participants |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Grade 3 or 4 TEAE | 0 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related SAE | 0 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Grade 3 or 4 TEAE | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE | 6 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to discontinuation of study drug | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related TEAE | 2 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Drug-related grade 3 or 4 TEAE | 0 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | TEAE leading to interruption of study drug | 0 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | SAE | 0 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | Investigator-identified rash (event of special interest) | 1 Participants |
| Placebo | Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE | GI abdominal related TEAE leading to discontinuation of study drug | 0 Participants |
Primary
Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE.
The safety data was assessed for the safety population for subjects who entered Part 3, and includes TEAEs that occurred in Part 3 for these subjects.
Time frame: Part 3: Week 52 to up to Week 104.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | TEAE | 6 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | SAE | 1 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | TEAE leading to interruption of study drug | 0 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | Drug-related TEAE | 0 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | Drug-related SAE | 0 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | Grade 3 or 4 TEAE | 1 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | Drug-related grade 3 or 4 TEAE | 0 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | TEAE leading to discontinuation of study drug | 0 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | Investigator-identified rash (event of special interest) | 0 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | GI abdominal related TEAE | 0 Participants |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE. | GI abdominal related TEAE leading to discontinuation of study drug | 0 Participants |
Secondary
Part 1: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire at Week 24 (Total Score)
Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score).
Time frame: Baseline and 24 weeks
Population: The ITT population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy and health outcomes data. Data were analyzed according to randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 1: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire at Week 24 (Total Score) | -9.47 AE-QoL Total Score Change from baseline | Standard Error 6.933 |
| Berotralstat 150mg Once Daily | Part 1: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire at Week 24 (Total Score) | -15.82 AE-QoL Total Score Change from baseline | Standard Error 6.424 |
| Placebo | Part 1: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire at Week 24 (Total Score) | 3.18 AE-QoL Total Score Change from baseline | Standard Error 6.832 |
Comparison: Numerical difference in change from baseline of AE-QoL total score between treatment groups. In the event that the first secondary endpoint did not meet statistical significance in the hierarchical testing scheme, testing of the third secondary endpoint of change from baseline in AE-QoL total score at Week 24 for statistical significance would not be completed. P-values that are reported are nominal.p-value: 0.21395% CI: [-33.33, 8.03]mixed-model repeated measures analysis
Comparison: Numerical difference in change from baseline of AE-QoL total score between treatment groups. In the event that the first secondary endpoint did not meet statistical significance in the hierarchical testing scheme, testing of the third secondary endpoint of change from baseline in AE-QoL total score at Week 24 for statistical significance would not be completed. P-values that are reported are nominal.p-value: 0.06195% CI: [-39, 0.99]mixed-model repeated measures analysis
Secondary
Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks.
Assessment of number and proportion of days subjects had angioedema symptoms from expert-confirmed angioedema events during Part 1.
Time frame: 24 weeks
Population: The ITT population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy and health outcomes data. Data were analyzed according to randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks. | 0.258 Proportion days with angioedema symptoms | Standard Error 0.0534 |
| Berotralstat 150mg Once Daily | Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks. | 0.118 Proportion days with angioedema symptoms | Standard Error 0.05 |
| Placebo | Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks. | 0.240 Proportion days with angioedema symptoms | Standard Error 0.0536 |
Comparison: Numerical differences from the placebo treatment in the LSM proportion of the 169 days of treatment with angioedema symptoms.p-value: 0.81495% CI: [-0.143, 0.179]ANCOVA
Comparison: Numerical differences from the placebo treatment in the LSM proportion of the 169 days of treatment with angioedema symptoms.p-value: 0.1295% CI: [-0.28, 0.036]ANCOVA
Secondary
Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period
The rate of expert-confirmed angioedema events for the effective treatment period gives an analysis of the efficacy of active treatment after berotralstat had reached steady-state concentrations, given the effective half-life of 150 mg berotralstat in Study BCX7353-106 (Study 106) of 89 hours.
Time frame: Day 8 through to 24 weeks
Population: The ITT population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy and health outcomes data. Data were analyzed according to randomized treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period | 1.988 Angioedema event rate per 28 days | Standard Deviation 1.3422 |
| Berotralstat 150mg Once Daily | Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period | 1.136 Angioedema event rate per 28 days | Standard Deviation 0.9564 |
| Placebo | Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period | 2.775 Angioedema event rate per 28 days | Standard Deviation 1.6472 |
Comparison: In the event that the first secondary endpoint did not meet statistical significance in the hierarchical testing scheme, testing of the second secondary endpoint of rate of expert-confirmed angioedema events during dosing in the effective treatment period for statistical significance would not be completed. Therefore, P-values reported are nominal.p-value: 0.18895% CI: [-14.7, 50.3]mixed-model repeated measures analysis
Comparison: In the event that the first secondary endpoint did not meet statistical significance in the hierarchical testing scheme, testing of the second secondary endpoint of rate of expert-confirmed angioedema events during dosing in the effective treatment period for statistical significance would not be completed. Therefore, P-values reported are nominal.p-value: 0.00595% CI: [17.7, 66.6]mixed-model repeated measures analysis
Secondary
Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period
Monthly Attack Rate was defined as the total number of investigator-confirmed HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the subject was on treatment during that month. The end of Month 6 was defined as the start of Part 2 treatment. For crossover subjects receiving active treatment following placebo, months were adjusted according to the date of the first dose of active treatment. Baseline investigator-confirmed attack rate was defined as the total number of investigator-confirmed HAE attacks experienced in the period between screening and first dose of study drug adjusted for the length of a month (defined as 28 days) and the number of days during that period.
Time frame: 28 weeks (Week 24 to 52)
Population: The intent to treat (ITT) population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 6 | -0.487 HAE attacks/28 days-change from baseline | Standard Deviation 1.0661 |
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 8 | -0.585 HAE attacks/28 days-change from baseline | Standard Deviation 0.5622 |
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 7 | -1.085 HAE attacks/28 days-change from baseline | Standard Deviation 0.8249 |
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 12 | -0.585 HAE attacks/28 days-change from baseline | Standard Deviation 1.0737 |
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 13 | -0.757 HAE attacks/28 days-change from baseline | Standard Deviation 0.9729 |
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 10 | -0.918 HAE attacks/28 days-change from baseline | Standard Deviation 1.0134 |
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 9 | -0.418 HAE attacks/28 days-change from baseline | Standard Deviation 0.891 |
| Berotralstat 110mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 11 | -0.585 HAE attacks/28 days-change from baseline | Standard Deviation 0.5622 |
| Berotralstat 150mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 6 | -0.686 HAE attacks/28 days-change from baseline | Standard Deviation 0.2872 |
| Berotralstat 150mg Once Daily | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 7 | -0.889 HAE attacks/28 days-change from baseline | Standard Deviation 0 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 13 | -0.733 HAE attacks/28 days-change from baseline | Standard Deviation 1.306 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 11 | -1.400 HAE attacks/28 days-change from baseline | Standard Deviation 0.9997 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 6 | -0.863 HAE attacks/28 days-change from baseline | Standard Deviation 1.3 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 7 | -1.395 HAE attacks/28 days-change from baseline | Standard Deviation 0.9127 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 8 | -1.395 HAE attacks/28 days-change from baseline | Standard Deviation 0.8016 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 9 | -0.927 HAE attacks/28 days-change from baseline | Standard Deviation 0.7645 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 10 | -0.733 HAE attacks/28 days-change from baseline | Standard Deviation 0.8068 |
| Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 12 | -0.900 HAE attacks/28 days-change from baseline | Standard Deviation 0.3925 |
| Berotralstat 150mg QD After Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 6 | -1.386 HAE attacks/28 days-change from baseline | Standard Deviation 0.5951 |
| Berotralstat 150mg QD After Placebo | Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-week Period | Month 7 | -1.403 HAE attacks/28 days-change from baseline | Standard Deviation 0.7948 |
Secondary
Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period.
Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL is only validated for adults; however, data were collected on all adult and adolescent study subjects.
Time frame: 28 Weeks (Week 24 to 52)
Population: The intent to treat (ITT) population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period. | Week 24 | -4.9 AE-QoL score -change from baseline | Standard Deviation 13 |
| Berotralstat 110mg Once Daily | Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period. | Week 52 | -7.4 AE-QoL score -change from baseline | Standard Deviation 9.4 |
| Berotralstat 150mg Once Daily | Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period. | Week 24 | -19.1 AE-QoL score -change from baseline | Standard Deviation 0 |
| Placebo | Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period. | Week 24 | -19.5 AE-QoL score -change from baseline | Standard Deviation 31.2 |
| Placebo | Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period. | Week 52 | -17.2 AE-QoL score -change from baseline | Standard Deviation 30.6 |
| Berotralstat 150mg QD After Placebo | Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period. | Week 24 | 0 AE-QoL score -change from baseline | Standard Deviation 0 |
Secondary
Part 3: To Assess the Effectiveness of Berotralstat Over a 52- to up to 104-week Administration Period
Adjusted subject-reported event rate was defined as (total number of adjusted subject-reported HAE events experienced in the period between the Week 52 visit and end of study \[or the last dose date/time in Part 3 + 24 hours for subjects who discontinued drug in Part 3\]) \* 28/(date of last dose in Part 3 - date of Week 52 visit + 1).
Time frame: 52 weeks (Week 52 to 104)
Population: The intent to treat (ITT) population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy data. The rate of adjusted subject-reported events for subjects treated in Part 3 is presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 3: To Assess the Effectiveness of Berotralstat Over a 52- to up to 104-week Administration Period | 0.883 HAE attacks per 28 days | Standard Deviation 1.1216 |
Secondary
Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period
Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.
Time frame: 52 Weeks (Week 52 to 104)
Population: The intent to treat (ITT) population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy data. QoL for subjects treated in Part 3 is presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period | Week 96 | -20.40 AE-QoL score -change from baseline | Standard Deviation 32.069 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period | Week 52 | -11.11 AE-QoL score -change from baseline | Standard Deviation 29.089 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period | Week 60 | -13.24 AE-QoL score -change from baseline | Standard Deviation 23.758 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period | Week 72 | -17.38 AE-QoL score -change from baseline | Standard Deviation 24.998 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period | Week 84 | -11.63 AE-QoL score -change from baseline | Standard Deviation 22.9 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period | Week 104 | -18.93 AE-QoL score -change from baseline | Standard Deviation 30.681 |
Secondary
Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period
The Treatment Satisfaction Questionnaire for Medication (TSQM) was completed by subjects at baseline and at each study visit until the end of the study. TSQM scores consisted of 14 items of which 13 items were made up of 3 specific scales (Effectiveness, Side Effects, and Convenience) and 1 global satisfaction scale (Global Satisfaction). At baseline, TSQM questionnaires were completed based on subject's satisfaction with usual medications. At all other time points for collection of TSQM, subjects were asked about their level of satisfaction or dissatisfaction with the study drug. Scales scores were calculated for each scale and were transformed into scores ranging from 0 to 100, with higher scores indicating higher satisfaction. TSQM score and corresponding change from baseline values were calculated at each visit. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.
Time frame: 52 Weeks (Week 52 to 104)
Population: The intent to treat (ITT) population included all randomized subjects, regardless of whether study treatment was administered. This population was the primary population for the analysis of the efficacy data. TSQM global scores for subjects treated in Part 3 is presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Berotralstat 110mg Once Daily | Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period | Week 84 | 11.7 TSQM Global score -change from baseline | Standard Deviation 34.44 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period | Week 96 | 18.8 TSQM Global score -change from baseline | Standard Deviation 26.43 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period | Week 104 | 16.1 TSQM Global score -change from baseline | Standard Deviation 23.77 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period | Week 60 | 11.7 TSQM Global score -change from baseline | Standard Deviation 37.15 |
| Berotralstat 110mg Once Daily | Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period | Week 72 | 13.6 TSQM Global score -change from baseline | Standard Deviation 37.72 |