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

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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:
Information provided by (Responsible Party):
BioCryst Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE August 10, 2016
First Posted Date  ICMJE August 18, 2016
Results First Submitted Date  ICMJE November 17, 2020
Results First Posted Date  ICMJE March 4, 2021
Last Update Posted Date March 23, 2021
Actual Study Start Date  ICMJE August 2016
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 11, 2021)
  • 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.
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: August 17, 2016)
Number of confirmed HAE attacks [ Time Frame: 28 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 3, 2021)
  • 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)
  • 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).
  • 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)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 17, 2016)
  • Incidence and severity of adverse events and laboratory abnormalities [ Time Frame: 28 days ]
  • Quality of Life, as measured by the Angioedema Quality of Life Questionnaire [ Time Frame: 28 days ]
  • Quality of Life, as measured by the Depression, Anxiety, Stress Scales (DASS) questionnaire [ Time Frame: 28 days ]
  • Plasma concentrations of BCX7353 at steady state [ Time Frame: 28 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of BCX7353 to Prevent Angioedema Attacks in Subjects With Hereditary Angioedema
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Hereditary Angioedema (HAE)
Intervention  ICMJE
  • Drug: BCX7353
    Plasma kallikrein inhibitor
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Part 1: BCX7353 350 mg once daily
    BCX7353 capsules, 350 mg dose administered once per day for 28 days
    Intervention: Drug: BCX7353
  • Experimental: Parts 2 and 3: BCX7353 250 mg once daily
    BCX7353 capsules, 250 mg dose administered once per day for 28 days
    Intervention: Drug: BCX7353
  • Experimental: Parts 2 and 3: BCX7353 125 mg once daily
    BCX7353 capsules, 125 mg dose administered once per day for 28 days
    Intervention: Drug: BCX7353
  • Placebo Comparator: Parts 1, 2 and 3: Placebo
    Placebo capsules, administered once per day for 28 days
    Intervention: Drug: Placebo
  • Experimental: Part 3: BCX7353 62.5 mg once daily
    BCX7353 capsules, 62.5 mg dose administered once per day for 28 days
    Intervention: Drug: BCX7353
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 24, 2017)
75
Original Estimated Enrollment  ICMJE
 (submitted: August 17, 2016)
50
Actual Study Completion Date  ICMJE August 2017
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Canada,   Denmark,   Germany,   Hungary,   Italy,   North Macedonia,   Spain,   Switzerland,   United Kingdom
Removed Location Countries Macedonia, The Former Yugoslav Republic of
 
Administrative Information
NCT Number  ICMJE NCT02870972
Other Study ID Numbers  ICMJE BCX7353-203
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party BioCryst Pharmaceuticals
Study Sponsor  ICMJE BioCryst Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Emel Aygören-Pürsün, MD University Hospital Frankfurt Goethe University
PRS Account BioCryst Pharmaceuticals
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP