Trial Outcomes & Findings for Study to Evaluate the Efficacy and Safety of BCX7353 as an Oral Treatment for the Prevention of HAE Attacks in Japan (NCT NCT03873116)

Last Updated: 2024-07-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

19 participants

Primary outcome timeframe

24 weeks

Results posted on

2024-07-19

Participant Flow

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).

Participant milestones

Participant milestones
Measure	Berotralstat 110mg Once Daily Berotralstat administered as two 55mg capsules, orally QD in parts 1, 2 \& 3.	Berotralstat 110mg QD, Followed by Berotralstat 150 mg QD Subjects were treated with 110 mg berotralstat QD in part 1 \& 2 (up to 52 weeks) \& 150 mg berotralstat QD in part 3 (52-104 weeks).	Berotralstat 110mg QD After Placebo Subjects were treated with placebo for 24 weeks in Part 1 and 110 mg berotralstat QD in part 2 (24-52 weeks) \& part 3 (52-104 weeks).	Berotralstat 110mg QD, Followed by Berotralstat 150 mg QD, After Placebo Subjects were treated with placebo for 24 weeks in Part 1, 110 mg berotralstat QD in part 2 (24-52 weeks) \& 150 mg berotralstat QD in part 3 (52-104 weeks).	Berotralstat 150mg Once Daily Berotralstat administered as two 75mg capsules, orally QD in parts 1, 2 \& 3.	Berotralstat 150mg QD After Placebo Subjects were treated with placebo for 24 weeks in Part 1 and 150 mg berotralstat QD in part 2 (24-52 weeks) \& part 3 (52-104 weeks).
Part 1 STARTED	3	3	2	1	7	3
Part 1 COMPLETED	3	3	2	1	7	2
Part 1 NOT COMPLETED	0	0	0	0	0	1
Part 2 STARTED	3	3	1	1	7	2
Part 2 COMPLETED	3	3	0	1	6	2
Part 2 NOT COMPLETED	0	0	1	0	1	0
Part 3 STARTED	0	3	0	1	6	1
Part 3 COMPLETED	0	3	0	1	5	1
Part 3 NOT COMPLETED	0	0	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Berotralstat 110mg QD After Placebo Subjects were treated with placebo for 24 weeks in Part 1 and 110 mg berotralstat QD in part 2 (24-52 weeks) \& part 3 (52-104 weeks).	Berotralstat 150mg Once Daily Berotralstat administered as two 75mg capsules, orally QD in parts 1, 2 \& 3.	Berotralstat 150mg QD After Placebo Subjects were treated with placebo for 24 weeks in Part 1 and 150 mg berotralstat QD in part 2 (24-52 weeks) \& part 3 (52-104 weeks).
Part 1 Study drug discontinuation due to rash	0	0	1
Part 2 Withdrawal by Subject	1	0	0
Part 2 Lab abnormality or AE	0	1	0
Part 3 Withdrawal by Subject	0	1	0

Baseline Characteristics

Study to Evaluate the Efficacy and Safety of BCX7353 as an Oral Treatment for the Prevention of HAE Attacks in Japan

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Part 1: Berotralstat 150mg Once Daily n=7 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Part 1: Placebo n=6 Participants Placebo administered as two 2 matching capsules, orally QD for24 weeks.	Total n=19 Participants Total of all reporting groups
Age, Continuous	47.3 years STANDARD_DEVIATION 15.03 • n=5 Participants	37.3 years STANDARD_DEVIATION 9.05 • n=7 Participants	42.3 years STANDARD_DEVIATION 13.52 • n=5 Participants	42.1 years STANDARD_DEVIATION 12.61 • n=4 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	16 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants	6 Participants n=7 Participants	6 Participants n=5 Participants	18 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Baseline expert-confirmed angioedema event rate ≥ 2 events/month	2 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	9 participants n=4 Participants
Baseline expert-confirmed angioedema event rate < 2 events/month	4 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants	10 participants n=4 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily n=7 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo n=6 Participants Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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	1.089 Angioedema event rate per 28 days Standard Deviation 0.9168	2.734 Angioedema event rate per 28 days Standard Deviation 1.6359	—	—

PRIMARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily n=2 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo n=7 Participants Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo n=2 Participants Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo n=6 Participants Subjects were treated with Placebo in Part 1
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	0 Participants	1 Participants	0 Participants	1 Participants
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	0 Participants	1 Participants	0 Participants	1 Participants
Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE TEAE	6 Participants	1 Participants	7 Participants	2 Participants	6 Participants
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	0 Participants	3 Participants	0 Participants	2 Participants
Part 2: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE SAE	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants
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	0 Participants	0 Participants	0 Participants	0 Participants
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	0 Participants	1 Participants	0 Participants	0 Participants
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	0 Participants	2 Participants	0 Participants	0 Participants
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	0 Participants	2 Participants	0 Participants	1 Participants
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	1 Participants	3 Participants	1 Participants	1 Participants
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	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=11 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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 outcome

Timeframe: 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.

Assessment of number and proportion of days subjects had angioedema symptoms from expert-confirmed angioedema events during Part 1.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily n=7 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo n=6 Participants Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks.	0.258 Proportion days with angioedema symptoms Standard Error 0.0534	0.118 Proportion days with angioedema symptoms Standard Error 0.0500	0.240 Proportion days with angioedema symptoms Standard Error 0.0536	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily n=7 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo n=6 Participants Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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	1.136 Angioedema event rate per 28 days Standard Deviation 0.9564	2.775 Angioedema event rate per 28 days Standard Deviation 1.6472	—	—

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily n=7 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo n=6 Participants Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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	-15.82 AE-QoL Total Score Change from baseline Standard Error 6.424	3.18 AE-QoL Total Score Change from baseline Standard Error 6.832	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily n=2 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo n=7 Participants Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo n=2 Participants Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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	-0.686 HAE attacks/28 days-change from baseline Standard Deviation 0.2872	-0.863 HAE attacks/28 days-change from baseline Standard Deviation 1.3000	-1.386 HAE attacks/28 days-change from baseline Standard Deviation 0.5951	—
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	-0.889 HAE attacks/28 days-change from baseline Standard Deviation 0	-1.395 HAE attacks/28 days-change from baseline Standard Deviation 0.9127	-1.403 HAE attacks/28 days-change from baseline Standard Deviation 0.7948	—
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	—	-1.395 HAE attacks/28 days-change from baseline Standard Deviation 0.8016	—	—
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 0.8910	—	-0.927 HAE attacks/28 days-change from baseline Standard Deviation 0.7645	—	—
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	—	-0.733 HAE attacks/28 days-change from baseline Standard Deviation 0.8068	—	—
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	—	-1.400 HAE attacks/28 days-change from baseline Standard Deviation 0.9997	—	—
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	—	-0.900 HAE attacks/28 days-change from baseline Standard Deviation 0.3925	—	—
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	—	-0.733 HAE attacks/28 days-change from baseline Standard Deviation 1.3060	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=6 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily n=1 Participants Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo n=7 Participants Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo n=1 Participants Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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 13.0	-19.1 AE-QoL score -change from baseline Standard Deviation 0	-19.5 AE-QoL score -change from baseline Standard Deviation 31.2	0 AE-QoL score -change from baseline Standard Deviation 0	—
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	—	-17.2 AE-QoL score -change from baseline Standard Deviation 30.6	—	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=11 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=11 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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 22.900	—	—	—	—
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	—	—	—	—
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 outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Berotralstat 110mg Once Daily n=11 Participants Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.	Berotralstat 150mg Once Daily Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.	Placebo Placebo administered as two matching capsules, orally QD for 24 weeks.	Berotralstat 150mg QD After Placebo Subjects were treated with 150 mg berotralstat QD in part 2 (24-52 weeks), following part 1 placebo treatment.	Placebo Subjects were treated with Placebo in Part 1
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—
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	—	—	—	—

Adverse Events

Berotralstat 110mg Once Daily

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

Berotralstat 150mg Once Daily

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Berotralstat 110mg Once Daily n=8 participants at risk Berotralstat administered as two 55mg capsules, orally QD	Berotralstat 150mg Once Daily n=9 participants at risk Berotralstat administered as two 75mg capsules, orally QD	Placebo n=6 participants at risk Placebo administered as two matching capsules, orally QD
Infections and infestations Pneumonia	12.5% 1/8 • Number of events 1 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	0.00% 0/9 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	0.00% 0/6 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.
Congenital, familial and genetic disorders Hereditary angioedema	12.5% 1/8 • Number of events 1 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	0.00% 0/9 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	0.00% 0/6 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/8 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	11.1% 1/9 • Number of events 1 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	0.00% 0/6 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.
Injury, poisoning and procedural complications Fibula fracture	0.00% 0/8 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	11.1% 1/9 • Number of events 1 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.	0.00% 0/6 • Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed until the last follow-up visit, approximately 3 weeks following the last dose of study drug, or until the AE was resolved or the subject was in a clinically stable condition with regard to the AE. AEs were assigned to the relevant treatment depending on when the AE began; i.e., Part 1 or Part 2 and 3 treatment.

Other adverse events

Additional Information

Study Director

BioCryst Pharmaceuticals Inc

Phone: +1 919-859-1302

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place