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

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

This is a phase 3, multi-center, 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 who live in Japan.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema, HAE
• Intervention / Treatment: Drug: BCX7353 capsules; Drug: Placebo oral capsule

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan
    • Study Site
  • Gunma, Japan
    • Study Site
  • Hokkaido, Japan
    • Study Site
  • Nagoya, Japan
    • Study Site
  • Osaka, Japan
    • Study Site
  • Saga, Japan
    • Study Center
  • Saitama, Japan
    • Study Site
  • Shimane, Japan
    • Study Site
  • Shizuoka, Japan
    • Study Site
  • Tokyo, Japan
    • Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• A clinical diagnosis of hereditary angioedema (HAE) 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.
• 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 expert-confirmed attacks during the run-in period 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BCX7353 110mg once daily; BCX7353 capsules administered orally once daily	Drug: BCX7353 capsules; BCX7353 capsules administered orally once daily
Experimental: BCX7353 150mg once daily; BCX7353 capsules administered orally once daily	Drug: BCX7353 capsules; BCX7353 capsules administered orally once daily
Placebo Comparator: Placebo; Matching placebo oral capsules administered orally once daily	Drug: Placebo oral capsule; Matching placebo capsules administered orally once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: The Rate of Expert-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168)	The angioedema event rate and the treatment comparisons between each berotralstat dose and placebo in the rate of expert-confirmed angioedema events during the entire dosing period was analyzed using a negative binomial regression model. The number of expert-confirmed angioedema events was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline monthly angioedema event rate) and study (for the combined study analysis) were included as covariates, and the logarithm of duration on treatment was included as an offset variable. The estimated rate of angioedema events for each treatment group, the treatment differences expressed as the angioedema event rate ratio (berotralstat) over placebo rate ratio), and their associated 95% confidence intervals (CIs) were provided from the negative binomial regression model.	24 weeks
Part 2: 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 includes TEAEs that occurred in Part 1 and Part 2 for these subjects with a data cut-off date of 10-April-2020. TEAEs are defined as AEs that occurred on or after first dose of study treatment, whether in Part 1 or 2, and were assigned to the relevant treatment depending on when the TEAE began (Part 1 or Part 2 treatment). TEAEs were assessed for severity (graded) using the Division of Microbiology and Infectious Disease (DMID) criteria for grading AEs. TEAEs not covered by the DMID criteria were assessed as Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3) or Life-threatening (Grade 4).	Part 1: 24 weeks (Week 0 to 24 to 52), Part 2: 28 weeks (Week 24 to 52)
Part 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat Administered QD Over a 52- to up to 104-week Administration Period in Subjects With HAE.	The safety data was assessed for the safety population for subjects who entered Part 3, and includes TEAEs that occurred in Part 3 for these subjects.	Part 3: Week 52 to up to Week 104.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks.	Assessment of number and proportion of days subjects had angioedema symptoms from expert-confirmed angioedema events during Part 1.	24 weeks
Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period	The rate of expert-confirmed angioedema events for the effective treatment period gives an analysis of the efficacy of active treatment after berotralstat had reached steady-state concentrations, given the effective half-life of 150 mg berotralstat in Study BCX7353-106 (Study 106) of 89 hours.	Day 8 through to 24 weeks
Part 1: Change From Baseline in Angioedema Quality of Life (AE-QoL) 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).	Baseline and 24 weeks
Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 52-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. For crossover subjects receiving active treatment following placebo, months were adjusted according to the date of the first dose of active treatment. Baseline investigator-confirmed attack rate was defined as the total number of investigator-confirmed HAE attacks experienced in the period between screening and first dose of study drug adjusted for the length of a month (defined as 28 days) and the number of days during that period.	28 weeks (Week 24 to 52)
Part 2: To Evaluate QoL Following Berotralstat Administration Over a 24- to 52-week Period.	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.	28 Weeks (Week 24 to 52)
Part 3: To Assess the Effectiveness of Berotralstat Over a 52- to up to 104-week Administration Period	Adjusted subject-reported event rate was defined as (total number of adjusted subject-reported HAE events experienced in the period between the Week 52 visit and end of study [or the last dose date/time in Part 3 + 24 hours for subjects who discontinued drug in Part 3]) * 28/(date of last dose in Part 3 - date of Week 52 visit + 1).	52 weeks (Week 52 to 104)
Part 3: To Evaluate QoL Following Berotralstat Administration Over a 52- to up to 104-week Period	Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.	52 Weeks (Week 52 to 104)
Part 3: To Evaluate Subject's Satisfaction With Berotralstat During 52- to 104-week Administration Period	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.	52 Weeks (Week 52 to 104)

Collaborators and Investigators

• Sponsor: BioCryst Pharmaceuticals
• Investigators: Principal Investigator: Isao Ohsawa, Saiyu Soka Hospital

Publications and helpful links

General Publications

• 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.
• Ohsawa I, Honda D, Suzuki Y, Fukuda T, Kohga K, Morita E, Moriwaki S, Ishikawa O, Sasaki Y, Tago M, Chittick G, Cornpropst M, Murray SC, Dobo SM, Nagy E, Van Dyke S, Reese L, Best JM, Iocca H, Collis P, Sheridan WP, Hide M. Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial. Allergy. 2021 Jun;76(6):1789-1799. doi: 10.1111/all.14670. Epub 2020 Dec 23.

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2018
• Primary Completion (Actual): July 8, 2021
• Study Completion (Actual): July 8, 2021

Study Registration Dates

• First Submitted: March 11, 2019
• First Submitted That Met QC Criteria: March 11, 2019
• First Posted (Actual): March 13, 2019

Study Record Updates

• Last Update Posted (Actual): July 19, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: BCX7353
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Berotralstat
• Other Study ID Numbers: BCX7353-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No