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Efficacy and Safety Study of BCX7353 as an Oral Treatment for the Prevention of Attacks in HAE (APeX-2)

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ClinicalTrials.gov Identifier: NCT03485911
Recruitment Status : Active, not recruiting
First Posted : April 3, 2018
Results First Posted : March 2, 2021
Last Update Posted : March 2, 2021
Sponsor:
Information provided by (Responsible Party):
BioCryst Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Prevention
Conditions Hereditary Angioedema
HAE
Interventions Drug: BCX7353 capsules
Drug: Placebo oral capsule
Enrollment 121
Recruitment Details  
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 HAE attacks documented during a prospective run-in period of 14 to 56 days from the date of the screening visit. Randomization was stratified by the HAE attack rate over the period between screening and randomization (≥ 2 attacks per month vs. < 2 attacks per month).
Arm/Group Title Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Hide Arm/Group Description Berotralstat administered as two 55mg capsules, orally QD for 24 weeks. Berotralstat administered as two 75mg capsules, orally QD for 24 weeks. Placebo administered as two 2 matching capsules, orally QD for 24 weeks.
Period Title: Overall Study
Started 41 40 40
Completed 40 38 36
Not Completed 1 2 4
Reason Not Completed
Withdrawal by Subject             0             2             2
Adverse Event             1             0             1
High frequency of HAE attacks             0             0             1
Arm/Group Title Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo Total
Hide Arm/Group Description Berotralstat administered as two 55mg capsules, orally QD for 24 weeks. Berotralstat administered as two 75mg capsules, orally QD for 24 weeks. Placebo administered as two 2 matching capsules, orally QD for 24 weeks. Total of all reporting groups
Overall Number of Baseline Participants 41 40 40 121
Hide Baseline Analysis Population Description
Intent to treat population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 41 participants 40 participants 40 participants 121 participants
40.4  (17.51) 40.0  (13.98) 44.5  (14.12) 41.6  (15.32)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 40 participants 40 participants 121 participants
Female
30
  73.2%
23
  57.5%
27
  67.5%
80
  66.1%
Male
11
  26.8%
17
  42.5%
13
  32.5%
41
  33.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 40 participants 40 participants 121 participants
Hispanic or Latino
0
   0.0%
2
   5.0%
1
   2.5%
3
   2.5%
Not Hispanic or Latino
39
  95.1%
38
  95.0%
38
  95.0%
115
  95.0%
Unknown or Not Reported
2
   4.9%
0
   0.0%
1
   2.5%
3
   2.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 40 participants 40 participants 121 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   2.4%
0
   0.0%
0
   0.0%
1
   0.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
2
   4.9%
1
   2.5%
2
   5.0%
5
   4.1%
White
38
  92.7%
38
  95.0%
37
  92.5%
113
  93.4%
More than one race
0
   0.0%
1
   2.5%
1
   2.5%
2
   1.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Canada Number Analyzed 41 participants 40 participants 40 participants 121 participants
4 3 3 10
Austria Number Analyzed 41 participants 40 participants 40 participants 121 participants
1 2 1 4
Romania Number Analyzed 41 participants 40 participants 40 participants 121 participants
0 1 0 1
Hungary Number Analyzed 41 participants 40 participants 40 participants 121 participants
2 0 0 2
United States Number Analyzed 41 participants 40 participants 40 participants 121 participants
28 24 25 77
Czechia Number Analyzed 41 participants 40 participants 40 participants 121 participants
2 3 3 8
North Macedonia Number Analyzed 41 participants 40 participants 40 participants 121 participants
0 1 1 2
United Kingdom Number Analyzed 41 participants 40 participants 40 participants 121 participants
1 4 2 7
France Number Analyzed 41 participants 40 participants 40 participants 121 participants
2 0 1 3
Germany Number Analyzed 41 participants 40 participants 40 participants 121 participants
1 2 2 5
Spain Number Analyzed 41 participants 40 participants 40 participants 121 participants
0 0 2 2
Baseline Investigator-confirmed attack rate   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
≥ 2 HAE attacks/month Number Analyzed 41 participants 40 participants 39 participants 120 participants
28
  68.3%
30
  75.0%
27
  69.2%
85
  70.8%
< 2 HAE attacks/month Number Analyzed 41 participants 40 participants 39 participants 120 participants
13
  31.7%
10
  25.0%
12
  30.8%
35
  29.2%
[1]
Measure Analysis Population Description: Safety Population. One subject from ITT population, randomised to the placebo group, was not dosed
1.Primary Outcome
Title Part 1: The Rate of Investigator-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168)
Hide Description Treatment comparisons between each berotralstat dose and placebo in the rate of investigator confirmed HAE attacks during the Part 1 dosing period were analyzed using a negative binomial model. The number of investigator-confirmed attacks was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline attack rate) was included as a covariate, and the logarithm of duration on treatment was included as an offset variable. The estimated attack rate for each treatment group, the treatment differences expressed as the attack rate ratio (berotralstat over placebo rate ratio), and the associated 95% confidence intervals (CIs) were provided from the negative binomial model.
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Hide Arm/Group Description:
Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.
Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.
Placebo administered as two 2 matching capsules, orally QD for 24 weeks.
Overall Number of Participants Analyzed 41 40 40
Measure Type: Number
Unit of Measure: HAE attack rate per 28 days
1.65 1.31 2.35
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 110 mg Once Daily, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.024
Comments [Not Specified]
Method negative binomial regression model
Comments [Not Specified]
Method of Estimation Estimation Parameter negative binomial regression model
Estimated Value -30.0
Confidence Interval (2-Sided) 95%
-48.7 to -4.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 150 mg Once Daily, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method negative binomial regression model
Comments [Not Specified]
Method of Estimation Estimation Parameter negative binomial regression model
Estimated Value -44.2
Confidence Interval (2-Sided) 95%
-59.5 to -23.0
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Part 1: Change From Baseline in Angioedema Quality of Life Questionnaire at Week 24 (Total Score)
Hide Description 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 Baseline and 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Hide Arm/Group Description:
Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.
Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.
Placebo administered as two 2 matching capsules, orally QD for 24 weeks.
Overall Number of Participants Analyzed 40 38 36
Least Squares Mean (Standard Error)
Unit of Measure: AE-QoL Total Score Change from baseline
-12.46  (2.530) -14.59  (2.592) -9.69  (2.643)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 110 mg Once Daily, Placebo
Comments Numerical difference in change from baseline of AE-QoL total score between treatment groups.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.453
Comments [Not Specified]
Method mixed-model repeated measures analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.77
Confidence Interval (2-Sided) 95%
-10.08 to 4.53
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 150 mg Once Daily, Placebo
Comments Numerical difference in change from baseline of AE-QoL total score between treatment groups.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.188
Comments [Not Specified]
Method mixed-model repeated measures analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.90
Confidence Interval (2-Sided) 95%
-12.23 to 2.43
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks
Hide Description Assessment of proportion of days subjects had angioedema symptoms from expert-confirmed HAE attacks during Part 1.
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Hide Arm/Group Description:
Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.
Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.
Placebo administered as two 2 matching capsules, orally QD for 24 weeks.
Overall Number of Participants Analyzed 41 40 40
Least Squares Mean (Standard Error)
Unit of Measure: Proportion days with angioedema symptoms
0.134  (0.0191) 0.119  (0.0194) 0.197  (0.0196)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 110 mg Once Daily, Placebo
Comments Numerical differences from the placebo treatment in the LSM proportion of the 169 days of treatment with angioedema symptoms. 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 proportion of days with angioedema symptoms through 24 weeks for statistical significance would not be completed. P-values that are reported are nominal.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.025
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Least Square Means
Estimated Value -0.062
Confidence Interval (2-Sided) 95%
-0.117 to -0.008
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 150 mg Once Daily, Placebo
Comments Numerical differences from the placebo treatment in the LSM proportion of the 169 days of treatment with angioedema symptoms. 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 number and proportion of days with angioedema symptoms through 24 weeks for statistical significance would not be completed. P-values that are reported are nominal.
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 -0.078
Confidence Interval (2-Sided) 95%
-0.133 to -0.023
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period
Hide Description The rate of expert-confirmed HAE attacks 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 (or or the last dose date/time in Part 1 + 24 hours for subjects who discontinued drug in Part 1)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Hide Arm/Group Description:
Berotralstat administered as two 55mg capsules, orally QD for 24 weeks.
Berotralstat administered as two 75mg capsules, orally QD for 24 weeks.
Placebo administered as two 2 matching capsules, orally QD for 24 weeks.
Overall Number of Participants Analyzed 41 40 40
Mean (Standard Deviation)
Unit of Measure: HAE attack rate per 28 days
1.918  (1.7345) 1.552  (1.6390) 2.490  (1.6135)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Berotralstat 110 mg Once Daily, Placebo
Comments 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 rate of expert-confirmed HAE attacks during dosing in the effective treatment period for statistical significance would not be completed. P-values reported are nominal.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.026
Comments [Not Specified]
Method negative binomial regression model
Comments [Not Specified]
Method of Estimation Estimation Parameter negative binomial regression model
Estimated Value 30.4
Confidence Interval (2-Sided) 95%
4.3 to 49.3
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Berotralstat 150 mg Once Daily, Placebo
Comments 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 rate of expert-confirmed HAE attacks during dosing in the effective treatment period for statistical significance would not be completed. P-values reported are nominal.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method negative binomial regression model
Comments [Not Specified]
Method of Estimation Estimation Parameter negative binomial regression model
Estimated Value 46.5
Confidence Interval (2-Sided) 95%
25.6 to 61.5
Estimation Comments [Not Specified]
Time Frame Adverse Events (AEs) were assessed and recorded from the time that the Informed consent form was signed through 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 regards to the AE.
Adverse Event Reporting Description AE data is presented for patients from the Safety Population; i.e. those who received at least one dose of study drug
 
Arm/Group Title Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Hide Arm/Group Description Berotralstat administered as two 55mg capsules, orally QD for 24 weeks. Berotralstat administered as two 75mg capsules, orally QD for 24 weeks. Placebo administered as two 2 matching capsules, orally QD for 24 weeks.
All-Cause Mortality
Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/41 (0.00%)      0/40 (0.00%)      0/39 (0.00%)    
Hide Serious Adverse Events
Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/41 (2.44%)      0/40 (0.00%)      3/39 (7.69%)    
Gastrointestinal disorders       
Diverticulum intestinal haemorrhagic  1  0/41 (0.00%)  0 0/40 (0.00%)  0 1/39 (2.56%)  1
Infections and infestations       
Pneumonia  1  0/41 (0.00%)  0 0/40 (0.00%)  0 1/39 (2.56%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Plasma cell myeloma  1  1/41 (2.44%)  1 0/40 (0.00%)  0 0/39 (0.00%)  0
Uterine leiomyoma  1  0/41 (0.00%)  0 0/40 (0.00%)  0 1/39 (2.56%)  1
Nervous system disorders       
Transient ischaemic attack  1  0/41 (0.00%)  0 0/40 (0.00%)  0 1/39 (2.56%)  1
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Berotralstat 110 mg Once Daily Berotralstat 150 mg Once Daily Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   34/41 (82.93%)      34/40 (85.00%)      30/39 (76.92%)    
Gastrointestinal disorders       
Nausea  1  6/41 (14.63%)  7 6/40 (15.00%)  9 7/39 (17.95%)  8
Vomiting  1  4/41 (9.76%)  6 6/40 (15.00%)  7 1/39 (2.56%)  2
Dyspepsia  1  4/41 (9.76%)  4 3/40 (7.50%)  3 3/39 (7.69%)  6
Diarrhoea  1  4/41 (9.76%)  4 5/40 (12.50%)  6 0/39 (0.00%)  0
Abdominal pain  1  2/41 (4.88%)  5 4/40 (10.00%)  5 2/39 (5.13%)  2
Abdominal discomfort  1  1/41 (2.44%)  1 3/40 (7.50%)  4 3/39 (7.69%)  3
Flatulence  1  2/41 (4.88%)  2 3/40 (7.50%)  3 1/39 (2.56%)  1
Gastroesophageal reflux disease  1  4/41 (9.76%)  4 2/40 (5.00%)  2 0/39 (0.00%)  0
Abdominal pain upper  1  1/41 (2.44%)  1 2/40 (5.00%)  2 1/39 (2.56%)  1
General disorders       
Fatigue  1  3/41 (7.32%)  3 2/40 (5.00%)  2 1/39 (2.56%)  1
Infections and infestations       
Nasopharyngitis  1  6/41 (14.63%)  10 9/40 (22.50%)  17 9/39 (23.08%)  15
Upper respiratory tract infection  1  6/41 (14.63%)  7 3/40 (7.50%)  3 1/39 (2.56%)  1
Gastroenteritis  1  0/41 (0.00%)  0 2/40 (5.00%)  2 2/39 (5.13%)  2
Oral herpes  1  0/41 (0.00%)  0 2/40 (5.00%)  2 1/39 (2.56%)  1
Hordeolum  1  0/41 (0.00%)  0 2/40 (5.00%)  2 0/39 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  1  1/41 (2.44%)  1 4/40 (10.00%)  4 1/39 (2.56%)  1
Nervous system disorders       
Headache  1  3/41 (7.32%)  3 4/40 (10.00%)  4 2/39 (5.13%)  2
Reproductive system and breast disorders       
Polymenorrhoea  1  0/41 (0.00%)  0 2/40 (5.00%)  2 0/39 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Oropharyngeal pain  1  3/41 (7.32%)  3 0/40 (0.00%)  0 3/39 (7.69%)  3
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
These are results from the primary analysis completed at the end of Part 1 only. Results for Part 2 and Part 3 will be available in the final analysis.
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: NCT03485911    
Other Study ID Numbers: BCX7353-302
First Submitted: March 15, 2018
First Posted: April 3, 2018
Results First Submitted: November 17, 2020
Results First Posted: March 2, 2021
Last Update Posted: March 2, 2021