Efficacy and Safety of BCX7353 to Prevent Angioedema Attacks in Subjects With Hereditary Angioedema

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hereditary Angioedema (HAE)

Intervention / Treatment
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* Drug: BCX7353
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: BCX7353 350 mg once daily<br>BCX7353 capsules, 350 mg dose administered once per day for 28 days | Drug: BCX7353<br>* Plasma kallikrein inhibitor<br>|
| Experimental: Parts 2 and 3: BCX7353 250 mg once daily<br>BCX7353 capsules, 250 mg dose administered once per day for 28 days | Drug: BCX7353<br>* Plasma kallikrein inhibitor<br>|
| Experimental: Parts 2 and 3: BCX7353 125 mg once daily<br>BCX7353 capsules, 125 mg dose administered once per day for 28 days | Drug: BCX7353<br>* Plasma kallikrein inhibitor<br>|
| Placebo Comparator: Parts 1, 2 and 3: Placebo<br>Placebo capsules, administered once per day for 28 days | Drug: Placebo<br> <br> |
| Experimental: Part 3: BCX7353 62.5 mg once daily<br>BCX7353 capsules, 62.5 mg dose administered once per day for 28 days | Drug: BCX7353<br>* Plasma kallikrein inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Confirmed HAE Attacks | 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. | 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). | 
| Proportion of Subjects Who Were HAE Attack-free During the Entire Dosing Period | Assessment of the proportion of subjects who had no HAE attacks during the entire dosing period | 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). | 

Secondary Outcome Measures

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