Clinical Trial Results:
A Phase 2a double-blind placebo-controlled 2-period crossover study to evaluate the safety and efficacy of BCX4161 as a prophylactic treatment to reduce the frequency of attacks in subjects with hereditary angioedema
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Summary
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EudraCT number |
2013-002319-82 |
Trial protocol |
DE GB |
Global end of trial date |
13 May 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Mar 2021
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First version publication date |
11 Mar 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BCX4161-203
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01984788 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
BioCryst Pharmaceuticals Inc
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Sponsor organisation address |
4505 Emperor Blvd, Durham, United States, NC 27703
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Public contact |
Study Director, BioCryst Pharmaceuticals Inc, 001 919 859 1302, clinicaltrials@biocryst.com
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Scientific contact |
Study Director, BioCryst Pharmaceuticals Inc, 001 919 859 1302, clinicaltrials@biocryst.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 May 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
13 May 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
13 May 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the effect of prophylactic Avoralstat (BCX4161) as measured by the frequency of attacks in subjects with hereditary angioedema (HAE)
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Protection of trial subjects |
This trial was conducted in compliance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines for conducting, recording, and reporting trials, and in accordance with the Declaration of Helsinki. The informed consent form (ICF), protocol and amendments for this trial were submitted to and approved by an appropriate Independent Ethics Committee (IEC). Routine monitoring was performed to verify that rights and well-being of subjects were protected. Emergency equipment and medications were available within the clinical unit as per current standard procedures. Any medication considered necessary for the subject’s safety and well-being was given at the discretion of the Investigator. A signed informed consent form (ICF) was obtained from each subject prior to performing any study-related procedures. The informed consent process took place under conditions where the subject had adequate time to consider the risks and benefits associated with his/her participation in the study. The Investigator explained to potential subjects the aims, methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it may entail.
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Background therapy |
Subjects used their prescribed standard of care medication to treat any breakthrough HAE attacks on study | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Oct 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
Germany: 20
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Worldwide total number of subjects |
24
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EEA total number of subjects |
24
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
24
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||
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Pre-assignment
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Screening details |
Subjects attended a Screening Visit up to 14 days before dosing for assessment of eligibility to participate in the study. Healthy male and healthy non-pregnant, non lactating female subjects aged 18 to 65 years who had a clinical diagnosis of hereditary angioedema with an average of 1 attack per week over at least a 3 month period were eligible. | |||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Investigator, Monitor, Data analyst, Subject, Carer, Assessor | |||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Avoralstat | |||||||||
Arm description |
Subjects who met all eligibility criteria were randomized to 1 of 2 treatment sequences. Treatment Sequence 1: Subjects received 28 days of Avoralstat at a dose of 400 mg administered 3 times per day, followed by 28 days of placebo treatment administered 3 times per day. Treatment Sequence 2: Subjects received 28 days of placebo treatment administered 3 times per day, followed by 28 days of Avoralstat at a dose of 400 mg administered 3 times per day. A washout period of at least 7 days was imposed between administration of each 28-day regimen of study drug (Avoralstat or placebo). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Avoralstat
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Investigational medicinal product code |
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Other name |
BCX4161
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received 28 days of Avoralstat 4× 100-mg capsules for oral administration 3 times per day (total daily dose of 1200 mg)
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Arm title
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Placebo | |||||||||
Arm description |
Subjects who met all eligibility criteria were randomized to 1 of 2 treatment sequences. Treatment Sequence 1: Subjects received 28 days of Avoralstat at a dose of 400 mg administered 3 times per day, followed by 28 days of placebo treatment administered 3 times per day. Treatment Sequence 2: Subjects received 28 days of placebo treatment administered 3 times per day, followed by 28 days of Avoralstat at a dose of 400 mg administered 3 times per day. A washout period of at least 7 days was imposed between administration of each 28-day regimen of study drug (Avoralstat or placebo). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received 28 days of matching placebo capsules administered as 4 capsules 3 times per day.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Avoralstat
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Reporting group description |
Subjects who met all eligibility criteria were randomized to 1 of 2 treatment sequences. Treatment Sequence 1: Subjects received 28 days of Avoralstat at a dose of 400 mg administered 3 times per day, followed by 28 days of placebo treatment administered 3 times per day. Treatment Sequence 2: Subjects received 28 days of placebo treatment administered 3 times per day, followed by 28 days of Avoralstat at a dose of 400 mg administered 3 times per day. A washout period of at least 7 days was imposed between administration of each 28-day regimen of study drug (Avoralstat or placebo). | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects who met all eligibility criteria were randomized to 1 of 2 treatment sequences. Treatment Sequence 1: Subjects received 28 days of Avoralstat at a dose of 400 mg administered 3 times per day, followed by 28 days of placebo treatment administered 3 times per day. Treatment Sequence 2: Subjects received 28 days of placebo treatment administered 3 times per day, followed by 28 days of Avoralstat at a dose of 400 mg administered 3 times per day. A washout period of at least 7 days was imposed between administration of each 28-day regimen of study drug (Avoralstat or placebo). | ||
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End point title |
Rate of Confirmed Acute Attacks | ||||||||||||
End point description |
Efficacy was evaluated by the rate of acute HAE 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.
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End point type |
Primary
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End point timeframe |
Investigators collected data from patient diaries from the first day of dosing through to Day 28 of each dosing period.
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Statistical analysis title |
Difference in HAE attack rates | ||||||||||||
Comparison groups |
Avoralstat v Placebo
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Number of subjects included in analysis |
48
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Fixed Effect | ||||||||||||
Parameter type |
Difference Least Mean Square | ||||||||||||
Point estimate |
-0.453
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.679 | ||||||||||||
upper limit |
-0.227 | ||||||||||||
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End point title |
Number of Attack Free Days | ||||||||||||
End point description |
Assessment of the number of days each subject experienced no HAE attacks during each treatment period with Avoralstat or Placebo
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End point type |
Secondary
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End point timeframe |
Investigators collected data on HAE attacks from patient diaries from the first day of dosing through to Day 28 of each dosing period.
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Statistical analysis title |
Difference in HAE attack-free Days | ||||||||||||
Comparison groups |
Avoralstat v Placebo
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Number of subjects included in analysis |
48
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.008 | ||||||||||||
Method |
Fixed Effect | ||||||||||||
Parameter type |
Difference Least Mean Square | ||||||||||||
Point estimate |
3.083
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.888 | ||||||||||||
upper limit |
5.279 | ||||||||||||
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End point title |
Angioedema Quality of Life (AE-QoL) | ||||||||||||
End point description |
Quality of Life (QoL) specific to hereditary angioedema (HAE) was assessed at baseline and Day 29 of each treatment period 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.
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End point type |
Secondary
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End point timeframe |
Day 1 & 29 of each treatment period
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Statistical analysis title |
Total AE-QoL Change from Baseline Score | ||||||||||||
Comparison groups |
Avoralstat v Placebo
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Number of subjects included in analysis |
48
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.004 | ||||||||||||
Method |
Fixed Effect | ||||||||||||
Parameter type |
Difference Least Mean Square | ||||||||||||
Point estimate |
-7.904
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-12.981 | ||||||||||||
upper limit |
-2.827 | ||||||||||||
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End point title |
Pharmacokinetics - Avoralstat Day 14 AUC(0-3) [1] | ||||||||
End point description |
Avoralstat plasma concentrations were evaluated in all 24 subjects during both treatment periods on Days 1 and 14 at pre-dose, 0.5, 1, 2 and 3 hours post morning dose and on Day 7 at pre-morning dose and also on Day 29. For 15 subjects who consented for the PK sub-study, Avoralstat plasma concentrations were also evaluated during both treatment periods on Day 14 at 4, 6, and 8 hours post-morning dose. Mean Avoralstat plasma concentration versus time profile after oral administration of multiple doses of Avoralstat was used to determine AUC(0-3) at Day 14.
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End point type |
Secondary
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End point timeframe |
Both treatment periods: Day 1 & 14 pre-dose, 0.5, 1, 2 & 3 hrs post-morning dose; Day 7 pre-morning dose; Day 29. Optional - Both treatment periods: Day 14 at 4, 6 & 8 hrs post-morning dose
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| Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Avoralstat PK parameters only reported for Avoralstat treatment periods; not applicable for placebo treatment periods. |
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| Notes [2] - PK parameter cannot be estimated in 1 subject due to insufficient data. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Plasma Kallikrein Inhibition - Day 29 | ||||||||||||
End point description |
Kallikrein activity was evaluated in all 24 subjects during Avoralstat treatment and in 22 subjects during placebo treatment on Days 1 & 14 at pre-dose, 0.5, 1, 2 and 3 hrs after the morning dose, on Day 7 prior to dosing and on Day 29. In addition, kallikrein activity was evaluated over the 8-hr dosing interval in a subset of 15 subjects on Day 14. Mean kallikrein inhibition was determined after oral administration of multiple doses of Avoralstat and placebo. Mean kallikrein inhibition at the end of each treatment period (Avoralstat or placebo) is presented below.
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End point type |
Secondary
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End point timeframe |
Both treatment periods: Day 1 & 14 pre-dose, 0.5, 1, 2 & 3 hrs post-morning dose; Day 7 pre-morning dose; Day 29. Optional - Both treatment periods: Day 14 at 4, 6 & 8 hrs post-morning dose
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| No statistical analyses for this end point | |||||||||||||
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End point title |
C1 Esterase Inhibitor (C1 INH) Levels - Day 29 | ||||||||||||
End point description |
C1 INH antigen levels were evaluated in 23 subjects during Avoralstat or placebo treatment on Days 1, 29, and 36. Mean C1 INH antigen level change from baseline on Day 29 of each treatment period (Avoralstat or placebo) is presented below.
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End point type |
Secondary
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End point timeframe |
Days 1, 29 and 36.
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse Events (AEs) reported from informed consent signature until the follow-up visit (8 days +/-2 days after last dose IMP) or until the AE is resolved or the subject is in a clinically stable condition with regards to the AE.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16
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Reporting groups
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Reporting group title |
Avoralstat
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Reporting group description |
Subjects who met all eligibility criteria were randomized to 1 of 2 treatment sequences. Treatment Sequence 1: Subjects received 28 days of Avoralstat at a dose of 400 mg administered 3 times per day, followed by 28 days of placebo treatment administered 3 times per day. Treatment Sequence 2: Subjects received 28 days of placebo treatment administered 3 times per day, followed by 28 days of Avoralstat at a dose of 400 mg administered 3 times per day. A washout period of at least 7 days was imposed between administration of each 28-day regimen of study drug (Avoralstat or placebo). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects who met all eligibility criteria were randomized to 1 of 2 treatment sequences. Treatment Sequence 1: Subjects received 28 days of Avoralstat at a dose of 400 mg administered 3 times per day, followed by 28 days of placebo treatment administered 3 times per day. Treatment Sequence 2: Subjects received 28 days of placebo treatment administered 3 times per day, followed by 28 days of Avoralstat at a dose of 400 mg administered 3 times per day. A washout period of at least 7 days was imposed between administration of each 28-day regimen of study drug (Avoralstat or placebo). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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09 Sep 2013 |
An independent Data Monitoring Committee (DMC) was added to periodically review safety data in accordance with a separate DMC Charter.
Inclusion criterion number 5a was modified to indicate that estrogen-containing hormonal contraception was only permitted if it had been used for at least 60 days prior to screening.
The washout period between Periods 1 and 2 was expanded to indicate a minimum of 7 days and a maximum of 14 days to allow for flexibility. |
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01 Nov 2013 |
an intravenous or subcutaneous treatment indicated for treatment of acute attacks to treat symptoms.
The ITT population was modified to include all subjects who were randomized and received at least 1 dose of study drug in both study periods. |
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11 Feb 2014 |
A Clinical Endpoint Adjudication Panel (CEAP) was implemented to review and confirm subject-reported attacks for inclusion in all efficacy analyses. The CEAP was defined in a separate charter that delineated membership, roles, and processes.
Inclusion criterion number 5a was modified to indicate that progestin-containing hormonal contraception was only permitted if it had been used for at least 60 days prior to screening although IUDs with progestin would be permitted to be placed any time prior to or during screening.
Temporary treatment interruptions were made permissible |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
