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Efficacy and Safety of BCX7353 to Prevent Angioedema Attacks in Subjects With Hereditary Angioedema (APeX-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02870972
Recruitment Status : Completed
First Posted : August 18, 2016
Results First Posted : March 4, 2021
Last Update Posted : March 23, 2021
Sponsor:
Information provided by (Responsible Party):
BioCryst Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Condition Hereditary Angioedema (HAE)
Interventions Drug: BCX7353
Drug: Placebo
Enrollment 75
Recruitment Details  
Pre-assignment Details HAE subjects attended a Screening Visit up to 21 days before the baseline visit, for assessment of eligibility to participate in the study.
Arm/Group Title Part 1: Berotralstat 350 mg Parts 2 & 3: Berotralstat 250 mg Parts 2 & 3: Berotralstat 125 mg Part 3: Berotralstat 62.5 mg Parts 1, 2 & 3: Placebo
Hide Arm/Group Description Berotralstat capsules, 350 mg dose administered once per day for 28 days Berotralstat capsules, 250 mg dose administered once per day for 28 days Berotralstat capsules, 125 mg dose administered once per day for 28 days Berotralstat capsules, 62.5 mg dose administered once per day for 28 days Placebo capsules, administered once per day for 28 days
Period Title: Overall Study
Started 18 14 14 7 22
Completed 17 14 14 7 22
Not Completed 1 0 0 0 0
Reason Not Completed
Adverse Event             1             0             0             0             0
Arm/Group Title Part 1: Berotralstat 350 mg Parts 2 & 3: Berotralstat 250 mg Parts 2 & 3: Berotralstat 125 mg Part 3: Berotralstat 62.5 mg Parts 1, 2 & 3: Placebo Total
Hide Arm/Group Description Berotralstat capsules, 350 mg dose administered once per day for 28 days Berotralstat capsules, 250 mg dose administered once per day for 28 days Berotralstat capsules, 125 mg dose administered once per day for 28 days Berotralstat capsules, 62.5 mg dose administered once per day for 28 days Placebo capsules, administered once per day for 28 days Total of all reporting groups
Overall Number of Baseline Participants 18 14 14 7 22 75
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants 14 participants 14 participants 7 participants 22 participants 75 participants
43.8  (11.6) 40.9  (13.4) 48.1  (12.6) 38.9  (16.6) 46.8  (11.1) 44.5  (12.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 14 participants 14 participants 7 participants 22 participants 75 participants
Female
11
  61.1%
6
  42.9%
10
  71.4%
6
  85.7%
13
  59.1%
46
  61.3%
Male
7
  38.9%
8
  57.1%
4
  28.6%
1
  14.3%
9
  40.9%
29
  38.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 14 participants 14 participants 7 participants 22 participants 75 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   5.6%
1
   7.1%
0
   0.0%
0
   0.0%
0
   0.0%
2
   2.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
15
  83.3%
12
  85.7%
14
 100.0%
7
 100.0%
20
  90.9%
68
  90.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
  11.1%
1
   7.1%
0
   0.0%
0
   0.0%
2
   9.1%
5
   6.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 18 participants 14 participants 14 participants 7 participants 22 participants 75 participants
Austria 1 2 0 2 1 6
Hungary 1 0 0 0 2 3
North Macedonia 2 0 5 0 2 9
Denmark 1 0 3 1 3 8
United Kingdom 6 2 2 0 1 11
Italy 2 1 0 2 2 7
Australia 0 2 1 0 0 3
Switzerland 2 1 0 0 2 5
Germany 2 2 3 0 5 12
Spain 1 1 0 1 3 6
France 0 3 0 1 1 5
Adjusted qualifying HAE attack rate  
Mean (Standard Deviation)
Unit of measure:  HAE attacks/week
Number Analyzed 18 participants 14 participants 14 participants 7 participants 22 participants 75 participants
0.84  (0.35) 0.91  (0.43) 0.94  (0.40) 1.05  (0.44) 0.87  (0.45) 0.90  (0.41)
1.Primary Outcome
Title Number of Confirmed HAE Attacks
Hide Description Efficacy was evaluated by the number of acute angioedema attacks. To ensure that consistent, objective assessments were used in accepting subject-reported attack data, a panel of expert physicians in the treatment of HAE patients adjudicated all subject-reported attacks prior to their inclusion in primary efficacy analyses.
Time Frame Investigators collected data from patient diaries from the first day of dosing through to Day 29 or last day of dosing +24 hrs (the effective dosing period).
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post baseline HAE diary data recorded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Berotralstat Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Berotralstat capsules administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 18 14 14 7 53 22
Least Squares Mean (Standard Error)
Unit of Measure: HAE attacks per week
0.519  (0.115) 0.527  (0.130) 0.249  (0.130) 0.852  (0.185) 0.494  (0.067) 0.952  (0.104)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.458
Confidence Interval (2-Sided) 95%
-0.703 to -0.214
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.433
Confidence Interval (2-Sided) 95%
-0.740 to -0.127
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.012
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.425
Confidence Interval (2-Sided) 95%
-0.755 to -0.095
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.703
Confidence Interval (2-Sided) 95%
-1.033 to 0.373
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.639
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.10
Confidence Interval (2-Sided) 95%
-0.52 to 0.32
Estimation Comments [Not Specified]
2.Primary Outcome
Title Proportion of Subjects Who Were HAE Attack-free During the Entire Dosing Period
Hide Description Assessment of the proportion of subjects who had no HAE attacks during the entire dosing period
Time Frame Investigators collected data from patient diaries from the first day of dosing through to Day 29 or last day of dosing +24 hrs (the effective dosing period).
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post-baseline HAE diary data recorded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Berotralstat Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Berotralstat capsules administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 18 14 14 7 53 22
Measure Type: Number
Unit of Measure: participants
HAE Attack Free Number Analyzed 18 participants 14 participants 14 participants 7 participants 53 participants 22 participants
4 3 4 0 11 1
HAE Attack Free (missing diary = attack) Number Analyzed 18 participants 14 participants 14 participants 7 participants 53 participants 22 participants
2 3 4 0 9 1
HAE Attack Free (missing diary = exclude) Number Analyzed 14 participants 13 participants 14 participants 7 participants 48 participants 22 participants
2 3 4 0 9 1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.155
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference vs placebo (%)
Estimated Value 17.7
Confidence Interval (2-Sided) 95%
-3.4 to 38.8
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.277
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference vs placebo (%)
Estimated Value 16.9
Confidence Interval (2-Sided) 95%
-6.3 to 40.1
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.064
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference vs placebo (%)
Estimated Value 24.0
Confidence Interval (2-Sided) 95%
-1.2 to 49.2
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference vs placebo (%)
Estimated Value -4.5
Confidence Interval (2-Sided) 95%
-13.2 to 4.2
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Berotralstat, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.097
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference vs placebo (%)
Estimated Value -16.2
Confidence Interval (2-Sided) 95%
-30.2 to -2.2
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Confirmed Abdominal HAE Attacks
Hide Description A prespecified secondary endpoint analyzed confirmed attacks by anatomical location; abdominal HAE attacks included any abdominal symptoms (i.e. swelling in the stomach/gut, or any symptoms of nausea, vomiting, or abdominal pain)
Time Frame Investigators collected data from patient diaries from the first day of dosing through to Day 29 or last day of dosing +24 hrs (the effective dosing period).
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post baseline HAE diary data recorded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Berotralstat Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Berotralstat capsules administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 18 14 14 7 53 22
Least Squares Mean (Standard Error)
Unit of Measure: HAE attacks per week
0.366  (0.073) 0.324  (0.082) 0.173  (0.083) 0.404  (0.117) 0.309  (0.042) 0.370  (0.066)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.439
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.061
Confidence Interval (2-Sided) 95%
-0.216 to 0.094
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.968
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.004
Confidence Interval (2-Sided) 95%
-0.198 to 0.190
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.667
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.045
Confidence Interval (2-Sided) 95%
-0.254 to 0.164
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.065
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.197
Confidence Interval (2-Sided) 95%
-0.406 to 0.012
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.797
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value 0.035
Confidence Interval (2-Sided) 95%
-0.232 to 0.301
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Number of Confirmed Peripheral HAE Attacks
Hide Description A prespecified secondary endpoint analyzed confirmed attacks by anatomical location; peripheral attacks included any with peripheral symptoms only (i.e. peripheral swelling or erythema marginatum).
Time Frame Investigators collected data from patient diaries from the first day of dosing through to Day 29 or last day of dosing +24 hrs (the effective dosing period).
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post baseline HAE diary data recorded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Berotralstat Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Berotralstat capsules administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 18 14 14 7 53 22
Least Squares Mean (Standard Error)
Unit of Measure: HAE attacks per week
0.160  (0.086) 0.143  (0.097) 0.098  (0.097) 0.463  (0.138) 0.179  (0.050) 0.543  (0.078)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.364
Confidence Interval (2-Sided) 95%
-0.547 to -0.181
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.384
Confidence Interval (2-Sided) 95%
-0.613 to -0.154
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.401
Confidence Interval (2-Sided) 95%
-0.647 to -0.154
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.445
Confidence Interval (2-Sided) 95%
-0.692 to -0.198
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.614
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.080
Confidence Interval (2-Sided) 95%
-0.394 to 0.234
Estimation Comments [Not Specified]
5.Secondary Outcome
Title HAE Attacks Requiring Treatment
Hide Description A prespecified secondary endpoint analyzed the number of attacks requiring treatment with acute HAE medication (Berinert, Firazyr, Cinryze or Ruconest)
Time Frame Investigators collected data from patient diaries from the first day of dosing through to Day 29 or last day of dosing +24 hrs (the effective dosing period).
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post baseline HAE diary data recorded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Berotralstat Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Berotralstat capsules administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 18 14 14 7 53 22
Least Squares Mean (Standard Error)
Unit of Measure: HAE attacks per week
0.483  (0.109) 0.449  (0.123) 0.218  (0.1231) 0.833  (0.174) 0.450  (0.063) 0.776  (0.098)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.326
Confidence Interval (2-Sided) 95%
-0.557 to -0.095
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.047
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.293
Confidence Interval (2-Sided) 95%
-0.582 to 0.004
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.040
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.327
Confidence Interval (2-Sided) 95%
-0.638 to -0.016
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.558
Confidence Interval (2-Sided) 95%
-0.870 to -0.247
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.775
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value 0.057
Confidence Interval (2-Sided) 95%
-0.339 to 0.454
Estimation Comments [Not Specified]
6.Secondary Outcome
Title HAE Disease Activity - Modified Angioedema Activity Score
Hide Description Activity of disease (i.e. disease severity) was assessed using a modified Angioedema Activity Score (AAS). The relevant endpoint for this study was the total modified AAS score, defined as the sum of the individual scores for 4 AAS domains (daily activities, appearance, physical discomfort, and overall severity) for all subject-reported attacks reported during the treatment period. Individual domain scores were based on answers to questions each of which had 4 possible responses scored 0-3 (0 - no impact; 1-3 - increasing levels of impact). The total modified AAS score per attack could range from 0 to 12; lower scores & higher scores represent lower & higher disease activities, respectively. However, the overall total modified AAS score reported for this study included the total scores for all subject-reported attacks, therefore the upper limit of the range was subject-specific. The statistical analysis of the total modified AAS scores for the treatment period is presented below.
Time Frame 28-day treatment period + 1 day
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post baseline HAE diary data recorded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 18 14 14 7 22
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
14.070  (2.610) 9.416  (2.952) 7.256  (2.954) 22.559  (4.200) 18.519  (2.356)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.209
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -4.449
Confidence Interval (2-Sided) 95%
-11.453 to 2.555
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.019
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -9.103
Confidence Interval (2-Sided) 95%
-16.639 to -1.567
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -11.263
Confidence Interval (2-Sided) 95%
-18.808 to -3.718
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.405
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value 4.040
Confidence Interval (2-Sided) 95%
-5.586 to 13.665
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Angioedema Quality of Life (AE-QoL)
Hide Description Quality of Life (QoL) specific to hereditary angioedema (HAE) was assessed at baseline and Day 29 by a questionnaire (i.e. AE-QoL) consisting of 17 questions that spanned 4 domains (functioning, fatigue/mood, fear/shame, and nutrition). Each AE-QoL question had 5 answer options (scored 1-5), with lower and higher scores indicting less and more adverse impact, respectively. Per-subject scores for each domain were computed using the appropriate scoring algorithm applied to the question response scores for each domain. Per-subject total scores (including all 4 domains) were similarly computed using the question response scores for all 17 questions. The outputs from the scoring algorithm were normalized on a scale ranging from 0 (less adverse impact) to 100 (most adverse impact). The statistical analysis of the AE-QoL total score change from baseline to Day 29 is presented below.
Time Frame The subject-completed AE-QoL was administered at baseline (Day 1) and at Day 29
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post baseline HAE diary data recorded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 17 14 14 7 22
Least Squares Mean (Standard Error)
Unit of Measure: AE-QoL score - change from baseline
-12.59  (4.04) -13.39  (4.44) -28.95  (4.44) -12.30  (6.32) -4.47  (3.54)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.135
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -8.12
Confidence Interval (2-Sided) 95%
-18.826 to 2.584
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.121
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -8.92
Confidence Interval (2-Sided) 95%
-20.260 to 2.410
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -24.49
Confidence Interval (2-Sided) 95%
-35.834 to -13.137
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.284
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -7.84
Confidence Interval (2-Sided) 95%
-22.316 to 6.640
Estimation Comments [Not Specified]
8.Secondary Outcome
Title DASS (Depression, Anxiety and Stress Scales)
Hide Description The Depression, Anxiety & Stress Scale (DASS) was used to measure the negative emotional states of depression, anxiety & stress. This assessment was based on a DASS questionnaire administered at baseline, Day 14 & Day 29. The questionnaire consisted of 3 DASS scales (depression, anxiety & stress) containing 14 items each on a scale of 0 to 3 (0, did not apply to me at all; 1, applied to me to some degree/some of the time; 2, applied to me to a considerable degree/a good part of the time; 3, applied to me very much or most of the time). Per-subject scores for the depression, anxiety & stress scales were obtained by summing the scores for the appropriate questionnaire items for the respective category. Total DASS scores were then derived as the sum of the 3 individual scales & ranged from 0 to 126. Higher & lower total scores are associated with more & less adverse impact, respectively. The statistical analysis of the total DASS score change from baseline to Day 29 is presented below.
Time Frame The DASS was administered at baseline (Day 1), Day 14, and Day 29.
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set population included all subjects who were randomized, received at least 1 dose of study drug, and had post baseline HAE diary data recorded. Only data from subjects who completed the DASS-42 questionnaire (i.e. 3 DASS scales each containing 14 items) were included in this analyses. Data collected on the DASS-21 questionnaire were excluded.
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Placebo
Hide Arm/Group Description:
Berotralstat capsules (350 mg) administered QD for 28 days
Berotralstat capsules (250 mg) administered QD for 28 days
Berotralstat capsules (125 mg) administered QD for 28 days
Berotralstat capsules (62.5 mg) administered QD for 28 days
Placebo capsules administered QD for 28 days
Overall Number of Participants Analyzed 16 13 14 6 19
Least Squares Mean (Standard Error)
Unit of Measure: DASS score - D29 change from baseline
-7.627  (3.275) -6.429  (3.609) -10.840  (3.477) -9.141  (5.336) 0.643  (2.984)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 350 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.067
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -8.270
Confidence Interval (2-Sided) 95%
-17.132 to 0.592
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 250 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.136
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -7.073
Confidence Interval (2-Sided) 95%
-16.432 to 2.287
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Berotralstat 125 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.015
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -11.484
Confidence Interval (2-Sided) 95%
-20.642 to -2.325
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Berotralstat 62.5 mg, Placebo
Comments The primary analysis of treatment-effect was performed using an ANCOVA with the terms of treatment and adjusted qualifying attack rate as the covariate.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.114
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -9.785
Confidence Interval (2-Sided) 95%
-22.001 to 2.431
Estimation Comments [Not Specified]
Time Frame Adverse event data were collected from Day 1 of the study treatment period until 30 days after the last dose of study drug. Last dose was on study day 28 except in the event of early termination.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Placebo
Hide Arm/Group Description Berotralstat capsules (350 mg) administered QD for 28 days Berotralstat capsules (250 mg) administered QD for 28 days Berotralstat capsules (125 mg) administered QD for 28 days Berotralstat capsules (62.5 mg) administered QD for 28 days Placebo capsules administered QD for 28 days
All-Cause Mortality
Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/18 (0.00%)      0/14 (0.00%)      0/14 (0.00%)      0/7 (0.00%)      0/22 (0.00%)    
Hide Serious Adverse Events
Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/18 (0.00%)      1/14 (7.14%)      0/14 (0.00%)      0/7 (0.00%)      0/22 (0.00%)    
Gastrointestinal disorders           
Gastrointestinal infection  1  0/18 (0.00%)  0 1/14 (7.14%)  1 0/14 (0.00%)  0 0/7 (0.00%)  0 0/22 (0.00%)  0
1
Term from vocabulary, MedDRA (18.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Berotralstat 350 mg Berotralstat 250 mg Berotralstat 125 mg Berotralstat 62.5 mg Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/18 (77.78%)      11/14 (78.57%)      7/14 (50.00%)      4/7 (57.14%)      15/22 (68.18%)    
Gastrointestinal disorders           
Abdominal pain  1  3/18 (16.67%)  3 1/14 (7.14%)  1 2/14 (14.29%)  2 0/7 (0.00%)  0 0/22 (0.00%)  0
Abdominal pain upper  1  1/18 (5.56%)  1 0/14 (0.00%)  0 1/14 (7.14%)  1 1/7 (14.29%)  1 0/22 (0.00%)  0
Diarrhoea  1  4/18 (22.22%)  4 2/14 (14.29%)  2 0/14 (0.00%)  0 0/7 (0.00%)  0 2/22 (9.09%)  2
Flatulence  1  2/18 (11.11%)  2 0/14 (0.00%)  0 0/14 (0.00%)  0 0/7 (0.00%)  0 0/22 (0.00%)  0
Nausea  1  3/18 (16.67%)  3 3/14 (21.43%)  3 0/14 (0.00%)  0 0/7 (0.00%)  0 0/22 (0.00%)  0
Vomiting  1  2/18 (11.11%)  2 0/14 (0.00%)  0 0/14 (0.00%)  0 0/7 (0.00%)  0 0/22 (0.00%)  0
Constipation  1  1/18 (5.56%)  1 0/14 (0.00%)  0 0/14 (0.00%)  0 0/7 (0.00%)  0 1/22 (4.55%)  1
Gastrooesophageal reflux disease  1  0/18 (0.00%)  0 0/14 (0.00%)  0 1/14 (7.14%)  1 0/7 (0.00%)  0 1/22 (4.55%)  1
General disorders           
Fatigue  1  2/18 (11.11%)  2 0/14 (0.00%)  0 0/14 (0.00%)  0 1/7 (14.29%)  1 1/22 (4.55%)  1
Influenza like illness  1  0/18 (0.00%)  0 1/14 (7.14%)  1 0/14 (0.00%)  0 0/7 (0.00%)  0 1/22 (4.55%)  1
Infections and infestations           
Nasopharyngitis  1  5/18 (27.78%)  5 1/14 (7.14%)  1 0/14 (0.00%)  0 2/7 (28.57%)  2 6/22 (27.27%)  6
Pharyngitis  1  1/18 (5.56%)  1 1/14 (7.14%)  1 0/14 (0.00%)  0 0/7 (0.00%)  0 0/22 (0.00%)  0
Gastrointestinal infection  1  1/18 (5.56%)  1 1/14 (7.14%)  1 0/14 (0.00%)  0 0/7 (0.00%)  0 0/22 (0.00%)  0
Upper respiratory tract infection  1  0/18 (0.00%)  0 1/14 (7.14%)  1 0/14 (0.00%)  0 0/7 (0.00%)  0 1/22 (4.55%)  1
Injury, poisoning and procedural complications           
Contusion  1  0/18 (0.00%)  0 1/14 (7.14%)  1 0/14 (0.00%)  0 0/7 (0.00%)  0 1/22 (4.55%)  1
Investigations           
Alanine aminotransferase increased  1  2/18 (11.11%)  2 0/14 (0.00%)  0 0/14 (0.00%)  0 0/7 (0.00%)  0 0/22 (0.00%)  0
Musculoskeletal and connective tissue disorders           
Arthralgia  1  1/18 (5.56%)  1 0/14 (0.00%)  0 0/14 (0.00%)  0 0/7 (0.00%)  0 1/22 (4.55%)  1
Nervous system disorders           
Headache  1  1/18 (5.56%)  1 1/14 (7.14%)  1 2/14 (14.29%)  2 2/7 (28.57%)  2 4/22 (18.18%)  4
Migraine  1  1/18 (5.56%)  1 0/14 (0.00%)  0 1/14 (7.14%)  1 0/7 (0.00%)  0 0/22 (0.00%)  0
Skin and subcutaneous tissue disorders           
Rash  1  0/18 (0.00%)  0 0/14 (0.00%)  0 0/14 (0.00%)  0 0/7 (0.00%)  0 2/22 (9.09%)  2
1
Term from vocabulary, MedDRA (18.1)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: BioCryst Pharmaceuticals Inc
Phone: +1 919-859-1302
EMail: clinicaltrials@biocryst.com
Layout table for additonal information
Responsible Party: BioCryst Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02870972    
Other Study ID Numbers: BCX7353-203
First Submitted: August 10, 2016
First Posted: August 18, 2016
Results First Submitted: November 17, 2020
Results First Posted: March 4, 2021
Last Update Posted: March 23, 2021