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

• 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: BioCryst Pharmaceuticals
• Information provided by (Responsible Party): BioCryst Pharmaceuticals

Study Description

Brief Summary:

This 3-part study will evaluate the safety and efficacy of an oral treatment, BCX7353, in preventing angioedema attacks in subjects with hereditary angioedema (HAE). In Part 1 of the study, eligible subjects will be randomized to receive oral BCX7353 or placebo for 4 weeks. Assuming successful completion of Part 1, additional subjects will be randomized in Part 2 to one of 2 lower doses of BCX7353 or placebo. Part 3 will enroll additional subjects into one of three doses of BCX7353 or placebo. The study will compare the number of acute attacks in each treatment group, as well as a number of other clinical and pharmacologic outcomes, and the safety and tolerability of each dose of BCX7353 compared to placebo.

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema (HAE)	Drug: BCX7353; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Parallel-group Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BCX7353 as a Preventative Treatment to Reduce the Frequency of Attacks in Subjects With Hereditary Angioedema
• Actual Study Start Date: August 2016
• Actual Primary Completion Date: August 2017
• Actual Study Completion Date: August 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: BCX7353 350 mg once daily; BCX7353 capsules, 350 mg dose administered once per day for 28 days	Drug: BCX7353; Plasma kallikrein inhibitor
Experimental: Parts 2 and 3: BCX7353 250 mg once daily; BCX7353 capsules, 250 mg dose administered once per day for 28 days	Drug: BCX7353; Plasma kallikrein inhibitor
Experimental: Parts 2 and 3: BCX7353 125 mg once daily; BCX7353 capsules, 125 mg dose administered once per day for 28 days	Drug: BCX7353; Plasma kallikrein inhibitor
Placebo Comparator: Parts 1, 2 and 3: Placebo; Placebo capsules, administered once per day for 28 days	Drug: Placebo
Experimental: Part 3: BCX7353 62.5 mg once daily; BCX7353 capsules, 62.5 mg dose administered once per day for 28 days	Drug: BCX7353; Plasma kallikrein inhibitor

Outcome Measures

Primary Outcome Measures :

1. Number of Confirmed HAE Attacks [ 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). ]
   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.
2. Proportion of Subjects Who Were HAE Attack-free 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). ]
   Assessment of the proportion of subjects who had no HAE attacks during the entire dosing period

Secondary Outcome Measures :

1. Number of Confirmed Abdominal HAE Attacks [ 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). ]
   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)
2. Number of Confirmed Peripheral HAE Attacks [ 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). ]
   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).
3. HAE Attacks Requiring Treatment [ 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). ]
   A prespecified secondary endpoint analyzed the number of attacks requiring treatment with acute HAE medication (Berinert, Firazyr, Cinryze or Ruconest)
4. HAE Disease Activity - Modified Angioedema Activity Score [ Time Frame: 28-day treatment period + 1 day ]
   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.
5. Angioedema Quality of Life (AE-QoL) [ Time Frame: The subject-completed AE-QoL was administered at baseline (Day 1) and at Day 29 ]
   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.
6. DASS (Depression, Anxiety and Stress Scales) [ Time Frame: The DASS was administered at baseline (Day 1), Day 14, and Day 29. ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• A clinical diagnosis of HAE type I or II
• Documented HAE attacks within a defined calendar period
• Access to acute attack medications
• Sexually active women of child-bearing potential and sexually active men must utilize effective contraception

Key Exclusion Criteria:

• Women who are pregnant or breast-feeding
• Any clinical condition or medical history that would interfere with the subject's safety or ability to participate in the study
• Use of C1INH, androgens or tranexamic acid for prophylaxis of HAE attacks
• History of or current alcohol or drug abuse
• Infection with hepatitis B, hepatitis C or HIV
• Participation in any other investigational drug study currently or within the last 30 days

Contacts and Locations

Locations

Australia

Adelaide, Australia

Campbelltown, Australia

Austria

Graz, Austria

Vienna, Austria

Canada

Quebec City, Canada

Toronto, Canada

Denmark

Odense, Denmark

Germany

Berlin, Germany

Frankfurt, Germany

Ulm, Germany

Hungary

Budapest, Hungary

Italy

Milano, Italy

Padova, Italy

Salerno, Italy

North Macedonia

Skopje, North Macedonia

Spain

Barcelona, Spain

Madrid, Spain

Sevilla, Spain

Switzerland

Zürich, Switzerland

United Kingdom

Brimingham, United Kingdom

Bristol, United Kingdom

London, United Kingdom

Oxford, United Kingdom

Southampton, United Kingdom

Sponsors and Collaborators

BioCryst Pharmaceuticals

Investigators

• Principal Investigator: Emel Aygören-Pürsün, MD; University Hospital Frankfurt Goethe University

  Study Documents (Full-Text)

Documents provided by BioCryst Pharmaceuticals:

Study Protocol  [PDF] July 5, 2017

Statistical Analysis Plan  [PDF] February 7, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Aygören-Pürsün E, Bygum A, Grivcheva-Panovska V, Magerl M, Graff J, Steiner UC, Fain O, Huissoon A, Kinaciyan T, Farkas H, Lleonart R, Longhurst HJ, Rae W, Triggiani M, Aberer W, Cancian M, Zanichelli A, Smith WB, Baeza ML, Du-Thanh A, Gompels M, Gonzalez-Quevedo T, Greve J, Guilarte M, Katelaris C, Dobo S, Cornpropst M, Clemons D, Fang L, Collis P, Sheridan W, Maurer M, Cicardi M. Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema. N Engl J Med. 2018 Jul 26;379(4):352-362. doi: 10.1056/NEJMoa1716995.

• Responsible Party: BioCryst Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02870972
• Other Study ID Numbers: BCX7353-203
• First Posted: August 18, 2016
• Results First Posted: March 4, 2021
• Last Update Posted: March 23, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Additional relevant MeSH terms:

Angioedema; Angioedemas, Hereditary; Vascular Diseases; Cardiovascular Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Immunologic Deficiency Syndromes; Berotralstat; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action