Back to resultsEfficacy and Safety Study of BCX7353 as an Oral Treatment for the Prevention of Attacks in HAE (APeX-2)
Primary Purpose
Hereditary Angioedema, HAE
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
BCX7353 capsules
Placebo oral capsule
Sponsored by
About this trial
This is an interventional prevention trial for Hereditary Angioedema focused on measuring BCX7353, Berotralstat
Eligibility Criteria
Key Inclusion Criteria:
- A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined as having a C1-INH functional level and a C4 level below the lower limit of the normal (LLN) reference range, as assessed during the Screening period.
- Subject weight of ≥ 40 kg
- Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE
- Subjects must be medically appropriate for on-demand treatment as the sole medicinal management for their HAE during the study.
- Subjects must have a specified number of investigator-confirmed attacks during the run-in period of a maximum of 56 days from the Screening visit.
- Acceptable effective contraception
- Written informed consent
Key Exclusion Criteria:
- Pregnancy or breast-feeding
- Any clinically significant medical condition or medical history that, in the opinion of the Investigator or Sponsor, would interfere with the subject's safety or ability to participate in the study
- Any laboratory parameter abnormality that, in the opinion of the Investigator, is clinically significant and relevant for this study
- Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/ anaphylaxis with unclear etiology
- Use of C1-INH within 14 days or use of androgens or tranexamic acid within 28 days prior to the Screening visit for prophylaxis of HAE attacks, or initiation of these drugs during the study
- Current participation in any other investigational drug study or received another investigational drug within 30 days of the Screening visit
- Prior enrollment in a BCX7353 study
Sites / Locations
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Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
BCX7353 110 mg once daily
BCX7353 150 mg once daily
Placebo
Arm Description
BCX7353 administered as oral capsules once daily
BCX7353 administered as oral capsules once daily
Matching placebo administered as oral capsules once daily
Outcomes
Primary Outcome Measures
Part 1: The Rate of Investigator-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168)
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.
Part 2 & 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE
The safety data was assessed for the safety population, for subjects who entered Part 2 and Part 3, and includes TEAEs that began in Part 2 or 3, respectively, for these subjects. Safety data for Part 2 and Part 3 is combined to clearly show TEAEs occurring in subjects as the proceeded through the 2 study parts. 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 2 or Part 3 treatment). No statistical analysis was performed on this safety data.
Secondary Outcome Measures
Part 1: Change From Baseline in Angioedema Quality of Life Questionnaire at Week 24 (Total Score)
Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL is only validated for adults; however, data were collected on all adult and adolescent study subjects.
Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks
Assessment of proportion of days subjects had angioedema symptoms from expert-confirmed HAE attacks during Part 1.
Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period
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.
Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 48 Week Period
Monthly Attack Rate was defined as the total number of investigator-confirmed HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the subject was on treatment during that month. The end of Month 6 was defined as the start of Part 2 treatment.
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.
To Evaluate Angioedema Quality of Life Questionnaire (Total Score) Following Berotralstat Administration for up to 144 Weeks
Angioedema-specific QoL was assessed by the AE-QoL, consisting of 4 domains (i.e., functioning, fatigue/mood, fears/shame, and nutrition) and a total score. The AE-QoL scores range from 0 points (best QoL) to 100 points (worst QoL). 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 was completed by the subjects at each visit starting at baseline, and questions were answered with regard to the previous 28 days. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.
To Evaluate Treatment Satisfaction Questionnaire for Medication (TSQM) Following Berotralstat Administration for up to 144 Weeks
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03485911
Brief Title
Efficacy and Safety Study of BCX7353 as an Oral Treatment for the Prevention of Attacks in HAE
Acronym
APeX-2
Official Title
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Two Dose Levels of BCX7353 as an Oral Treatment for the Prevention of Attacks in Subjects With Hereditary Angioedema
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
February 6, 2018 (Actual)
Primary Completion Date
April 10, 2019 (Actual)
Study Completion Date
April 6, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
BioCryst Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral BCX7353 in preventing acute angioedema attacks in patients with Type I and Type II HAE.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hereditary Angioedema, HAE
Keywords
BCX7353, Berotralstat
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
Only Part 1 and Part 2 were blinded. As part 3 was open-label, no blinding was used
Allocation
Randomized
Enrollment
121 (Actual)
8. Arms, Groups, and Interventions
Arm Title
BCX7353 110 mg once daily
Arm Type
Experimental
Arm Description
BCX7353 administered as oral capsules once daily
Arm Title
BCX7353 150 mg once daily
Arm Type
Experimental
Arm Description
BCX7353 administered as oral capsules once daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo administered as oral capsules once daily
Intervention Type
Drug
Intervention Name(s)
BCX7353 capsules
Other Intervention Name(s)
Berotralstat
Intervention Description
BCX7353 oral capsules administered once daily
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Intervention Description
Matching oral capsules administered once daily
Primary Outcome Measure Information:
Title
Part 1: The Rate of Investigator-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168)
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
Title
Part 2 & 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE
Description
The safety data was assessed for the safety population, for subjects who entered Part 2 and Part 3, and includes TEAEs that began in Part 2 or 3, respectively, for these subjects. Safety data for Part 2 and Part 3 is combined to clearly show TEAEs occurring in subjects as the proceeded through the 2 study parts. 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 2 or Part 3 treatment). No statistical analysis was performed on this safety data.
Time Frame
Part 2: 24 weeks (Days 169 to 337). Part 3: 48 weeks (Days 338 to 674).
Secondary Outcome Measure Information:
Title
Part 1: Change From Baseline in Angioedema Quality of Life Questionnaire at Week 24 (Total Score)
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
Title
Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks
Description
Assessment of proportion of days subjects had angioedema symptoms from expert-confirmed HAE attacks during Part 1.
Time Frame
24 weeks
Title
Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period
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)
Title
Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 48 Week Period
Description
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.
Baseline investigator-confirmed attack rate was defined as the total number of investigator-confirmed HAE attacks experienced in the period between screening and first dose of study drug adjusted for the length of a month (defined as 28 days) and the number of days during that period.
Time Frame
24 weeks (Days 169 to 337)
Title
To Evaluate Angioedema Quality of Life Questionnaire (Total Score) Following Berotralstat Administration for up to 144 Weeks
Description
Angioedema-specific QoL was assessed by the AE-QoL, consisting of 4 domains (i.e., functioning, fatigue/mood, fears/shame, and nutrition) and a total score. The AE-QoL scores range from 0 points (best QoL) to 100 points (worst QoL). 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 was completed by the subjects at each visit starting at baseline, and questions were answered with regard to the previous 28 days. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.
Time Frame
Up to 144 weeks
Title
To Evaluate Treatment Satisfaction Questionnaire for Medication (TSQM) Following Berotralstat Administration for up to 144 Weeks
Description
The Treatment Satisfaction Questionnaire for Medication (TSQM) was completed by subjects at baseline and at each study visit until the end of the study. TSQM scores consisted of 14 items of which 13 items were made up of 3 specific scales (Effectiveness, Side Effects, and Convenience) and 1 global satisfaction scale (Global Satisfaction). At baseline, TSQM questionnaires were completed based on subject's satisfaction with usual medications. At all other time points for collection of TSQM, subjects were asked about their level of satisfaction or dissatisfaction with the study drug. Scales scores were calculated for each scale and were transformed into scores ranging from 0 to 100, with higher scores indicating higher satisfaction. TSQM score and corresponding change from baseline values were calculated at each visit. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.
Time Frame
Up to 144 weeks
10. Eligibility
Sex
All
Gender Based
Yes
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined as having a C1-INH functional level and a C4 level below the lower limit of the normal (LLN) reference range, as assessed during the Screening period.
Subject weight of ≥ 40 kg
Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE
Subjects must be medically appropriate for on-demand treatment as the sole medicinal management for their HAE during the study.
Subjects must have a specified number of investigator-confirmed attacks during the run-in period of a maximum of 56 days from the Screening visit.
Acceptable effective contraception
Written informed consent
Key Exclusion Criteria:
Pregnancy or breast-feeding
Any clinically significant medical condition or medical history that, in the opinion of the Investigator or Sponsor, would interfere with the subject's safety or ability to participate in the study
Any laboratory parameter abnormality that, in the opinion of the Investigator, is clinically significant and relevant for this study
Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/ anaphylaxis with unclear etiology
Use of C1-INH within 14 days or use of androgens or tranexamic acid within 28 days prior to the Screening visit for prophylaxis of HAE attacks, or initiation of these drugs during the study
Current participation in any other investigational drug study or received another investigational drug within 30 days of the Screening visit
Prior enrollment in a BCX7353 study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruce Zuraw, MD
Organizational Affiliation
UC San Diego School of Medicine, US HAE Angioedema Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Study center
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35209
Country
United States
Facility Name
Study center
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85251
Country
United States
Facility Name
Study center
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
Study Center
City
San Diego
State/Province
California
ZIP/Postal Code
92122
Country
United States
Facility Name
Study center
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
Study Center
City
Walnut Creek
State/Province
California
ZIP/Postal Code
94598
Country
United States
Facility Name
Study center
City
Colorado Springs
State/Province
Colorado
ZIP/Postal Code
80907
Country
United States
Facility Name
Study Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33613
Country
United States
Facility Name
Study center
City
Chevy Chase
State/Province
Maryland
ZIP/Postal Code
20815
Country
United States
Facility Name
Study Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Study Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48106
Country
United States
Facility Name
Study center
City
Plymouth
State/Province
Minnesota
ZIP/Postal Code
55446
Country
United States
Facility Name
Study Center
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63141
Country
United States
Facility Name
Study center
City
Belleville
State/Province
New Jersey
ZIP/Postal Code
07109
Country
United States
Facility Name
Study Center
City
Fair Lawn
State/Province
New Jersey
ZIP/Postal Code
07410
Country
United States
Facility Name
Study center
City
Piscataway
State/Province
New Jersey
ZIP/Postal Code
08854
Country
United States
Facility Name
Study Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Study Site
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28277
Country
United States
Facility Name
Study Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Study Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45231
Country
United States
Facility Name
Study center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43235
Country
United States
Facility Name
Study center
City
Clackamas
State/Province
Oregon
ZIP/Postal Code
97015
Country
United States
Facility Name
Study Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
Study center
City
Austin
State/Province
Texas
ZIP/Postal Code
78731
Country
United States
Facility Name
Study center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75231
Country
United States
Facility Name
Study Center
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Study Center
City
Spokane
State/Province
Washington
ZIP/Postal Code
99202
Country
United States
Facility Name
Study Center
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
Study Center
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1G 6C6
Country
Canada
Facility Name
Study Center
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4V 1R2
Country
Canada
Facility Name
Study Center
City
Québec
ZIP/Postal Code
G1V 4W2
Country
Canada
Facility Name
Study Center
City
Brno
ZIP/Postal Code
656 91
Country
Czechia
Facility Name
Study Center
City
Plzen
ZIP/Postal Code
30460
Country
Czechia
Facility Name
Study Center
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
Study Center
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Study Center
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
Study Center
City
Frankfurt
ZIP/Postal Code
D-60590
Country
Germany
Facility Name
Study Center
City
Budapest
ZIP/Postal Code
H-1225
Country
Hungary
Facility Name
Study Center
City
Skopje
ZIP/Postal Code
1000
Country
North Macedonia
Facility Name
Study Center
City
Sângeorgiu de Mureș
State/Province
Jud. Mureș
ZIP/Postal Code
547530
Country
Romania
Facility Name
Study Center
City
Barcelona
ZIP/Postal Code
08907
Country
Spain
Facility Name
Study Center
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Study Center
City
Seville
ZIP/Postal Code
41013
Country
Spain
Facility Name
Study Center
City
Cambridge
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
Facility Name
Study Center
City
Frimley
ZIP/Postal Code
GU16 7UJ
Country
United Kingdom
Facility Name
Study Center
City
London
ZIP/Postal Code
E1 2ES
Country
United Kingdom
Facility Name
Study Center
City
Plymouth
ZIP/Postal Code
PL6 8DH
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
36326435
Citation
Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database Syst Rev. 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2.
Results Reference
derived
PubMed Identifier
33866032
Citation
Wedner HJ, Aygoren-Pursun E, Bernstein J, Craig T, Gower R, Jacobs JS, Johnston DT, Lumry WR, Zuraw BL, Best JM, Iocca HA, Murray SC, Desai B, Nagy E, Sheridan WP, Kiani-Alikhan S. Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2). J Allergy Clin Immunol Pract. 2021 Jun;9(6):2305-2314.e4. doi: 10.1016/j.jaip.2021.03.057. Epub 2021 Apr 15.
Results Reference
derived
PubMed Identifier
33098856
Citation
Zuraw B, Lumry WR, Johnston DT, Aygoren-Pursun E, Banerji A, Bernstein JA, Christiansen SC, Jacobs JS, Sitz KV, Gower RG, Gagnon R, Wedner HJ, Kinaciyan T, Hakl R, Hanzlikova J, Anderson JT, McNeil DL, Fritz SB, Yang WH, Tachdjian R, Busse PJ, Craig TJ, Li HH, Farkas H, Best JM, Clemons D, Cornpropst M, Dobo SM, Iocca HA, Kargl D, Nagy E, Murray SC, Collis P, Sheridan WP, Maurer M, Riedl MA. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol. 2021 Jul;148(1):164-172.e9. doi: 10.1016/j.jaci.2020.10.015. Epub 2020 Oct 21.
Results Reference
derived
Learn more about this trial
Efficacy and Safety Study of BCX7353 as an Oral Treatment for the Prevention of Attacks in HAE
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