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

Hereditary Angioedema Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03485911
• Other study ID #: BCX7353-302
• Status: Completed
• Phase: Phase 3
• Start date: February 6, 2018
• Est. completion date: April 6, 2022

Study information

• Verified date: May 2023
• Source: BioCryst Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: April 6, 2022
• Est. primary completion date: April 10, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Angioedema
• HAE
• Hereditary Angioedema

Intervention

Drug:
• BCX7353 capsules
BCX7353 oral capsules administered once daily
• Placebo oral capsule
Matching oral capsules administered once daily

Locations

Country	Name	City	State
Austria	Study Center	Vienna
Canada	Study Center	Ottawa	Ontario
Canada	Study Center	Québec
Canada	Study Center	Toronto	Ontario
Czechia	Study Center	Brno
Czechia	Study Center	Plzen
France	Study Center	Grenoble
France	Study Center	Paris
Germany	Study Center	Berlin
Germany	Study Center	Frankfurt
Hungary	Study Center	Budapest
North Macedonia	Study Center	Skopje
Romania	Study Center	Sângeorgiu de Mure?	Jud. Mure?
Spain	Study Center	Barcelona
Spain	Study Center	Madrid
Spain	Study Center	Seville
United Kingdom	Study Center	Cambridge
United Kingdom	Study Center	Frimley
United Kingdom	Study Center	London
United Kingdom	Study Center	Plymouth
United States	Study Center	Ann Arbor	Michigan
United States	Study center	Austin	Texas
United States	Study center	Belleville	New Jersey
United States	Study center	Birmingham	Alabama
United States	Study Center	Boston	Massachusetts
United States	Study Site	Charlotte	North Carolina
United States	Study center	Chevy Chase	Maryland
United States	Study Center	Cincinnati	Ohio
United States	Study center	Clackamas	Oregon
United States	Study center	Colorado Springs	Colorado
United States	Study center	Columbus	Ohio
United States	Study center	Dallas	Texas
United States	Study Center	Durham	North Carolina
United States	Study Center	Fair Lawn	New Jersey
United States	Study Center	Hershey	Pennsylvania
United States	Study center	Little Rock	Arkansas
United States	Study Center	New York	New York
United States	Study center	Piscataway	New Jersey
United States	Study center	Plymouth	Minnesota
United States	Study Center	Saint Louis	Missouri
United States	Study Center	San Antonio	Texas
United States	Study Center	San Diego	California
United States	Study center	Santa Monica	California
United States	Study center	Scottsdale	Arizona
United States	Study Center	Spokane	Washington
United States	Study Center	Tampa	Florida
United States	Study Center	Walnut Creek	California

Sponsors (1)

Lead Sponsor	Collaborator
BioCryst Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Czechia,  France,  Germany,  Hungary,  North Macedonia,  Romania,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	24 weeks
Primary	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.	Part 2: 24 weeks (Days 169 to 337). Part 3: 48 weeks (Days 338 to 674).
Secondary	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.	Baseline and 24 weeks
Secondary	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.	24 weeks
Secondary	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.	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)
Secondary	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.	24 weeks (Days 169 to 337)
Secondary	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.	Up to 144 weeks
Secondary	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.	Up to 144 weeks