HAE, Hereditary Angioedema
Conditions
Keywords
BCX4161, Prophylaxis, Prevention, HAE, Hereditary Angioedema
Brief summary
This study will evaluate the safety and efficacy of an oral treatment, BCX4161, in preventing acute attacks in participants with hereditary angioedema (HAE). Eligible participants will be randomized to receive one of two doses of BCX4161 or placebo for 12 weeks. The study will compare the number of acute attacks in each treatment group, as well as a number of other clinical outcomes, and the safety and tolerability of each dose of BCX4161 compared to placebo.
Interventions
DRUGBCX4161
DRUGPlacebo
Sponsors
BioCryst Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. A clinical diagnosis of HAE type I or II 2. Documented HAE attacks within a defined calendar period; in the absence of documented HAE attacks, participants will be required to enter a run-in period to document attacks 3. Access to acute attack medications 4. Sexually active women of child-bearing potential and sexually active men must utilize highly effective contraception Key
Exclusion criteria
1. Women who are pregnant or breast-feeding 2. Any clinical condition or medical history that would interfere with the subject's safety or ability to participate in the study 3. Use of C1INH or tranexamic acid for prophylaxis of HAE attacks 4. Current participation in any other investigational drug study or within the last 30 days 5. History of or current alcohol or drug abuse 6. Infection with hepatitis B, hepatitis C or HIV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Mean Acute Angioedema Attack Rate | 12 weeks | An angioedema attack was defined as swelling at any location reported by participant, which had no swelling earlier. Total number of confirmed attacks during the treatment period standardized to a weekly attack-rate to adjust for the total duration of treatment. The attack rate was derived for each participant by treatment period. The weekly attack rate was equal to the total number of confirmed attacks during a treatment period divided by the duration of the treatment (in days) times 7 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Are Attack-free | 12 weeks | The number of participants who reported no attacks during the 12-week treatment period. |
| Disease Activity, as Measured by the 84-day Angioedema Activity Score | 12 weeks | Angioedema Activity Score (AAS) consists of 5 questions (period in which swelling occurred, physical discomfort, daily activity restriction, cosmetic disfigurement, and overall severity) to be answered for each day during which a subject experiences an HAE attack. A score between 0 (no symptoms) and 3 (Severe symptoms) was assigned to the responses for each question and the total daily score will be derived as the sum of the 5 question scores for each day during which the subject experiences a confirmed attack. Daily AAS ranged from 0 to 15 with higher scores indicating the greater disease severity. For participants who completed the study, the 84-day AAS was obtained by sum of AAS score during the treatment period and ranged from 0 (best) to 1,260 (worst).For participants who discontinued the study prematurely the 84-day AAS was obtained using the formula: Sum of AAS score of each day on treatment ∗ 84/Number of days on treatment. |
| Number of Attack-free Days | 12 weeks | The number of attack free days was the sum of the days during the treatment period for which participants reported no attacks. |
| Number of Participants With Treatment Emergent Adverse Events | From first dose up to 14 weeks | An adverse event (AE) is any untoward medical occurrence in a clinical study participant. No causal relationship with study drug or with the clinical study itself is implied. An AE could be an unfavorable and unintended sign, symptom (including an abnormal laboratory finding), syndrome, or illness that developed or worsened during the clinical study. A serious adverse event (SAE) is any untoward medical occurrence resulting in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or other medically important event. Any graded abnormality that occurred following the initiation of study drug and up to 30 days after the last dose of study drug, and represented at least a 1-grade increase from the baseline assessment, was defined as treatment emergent. |
| Change From Baseline at Week 12 in Quality of Life, as Measured by the EuroQoL Five-dimensional, 5-level Questionnaire | Baseline (Day 1) and Week 12 | The EuroQoL five-dimensional, 5-level (EQ-5D-5L) was used to assess overall wellbeing and comprised the following five domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain has 5 response levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. It included the EQ Visual Analogue scale (EQ VAS) to rate overall health on a scale of 0 (worst health) to 100 (best health). |
| Change From Baseline at Week 12, in Quality of Life as Measured by the Angioedema Quality of Life Questionnaire | Baseline (Day 1) and Week 12 | Angioedema Quality of Life questionnaire (AE-QoL) consisted of 4 domains (i.e., functioning, fatigue/mood, fear/shame, and nutrition) and a total score based on a total of 17 possible responses. The results of all the responses are summed up and transformed to a scale ranging from 0 (best) to 100 (worst). |
Countries
Belgium, Canada, France, Germany, Hungary, Italy, United Kingdom, United States
Participant flow
Recruitment details
Participants were recruited from study sites in Belgium, Canada, France, Germany, Hungary, Italy, the United Kingdom and the United States, between December 2014 and October 2015
Participants by arm
| Arm | Count |
|---|---|
| BCX4161 300 mg Three Times Daily Three BCX4161 capsules (100 mg) and two placebo capsules to be taken three times daily by mouth
BCX4161
Placebo | 36 |
| BCX4161 500 mg Three Times Daily Five BCX4161 capsules (100 mg) to be taken three times daily by mouth
BCX4161 | 38 |
| Placebo Three Times Daily Five placebo capsules to be taken three times daily by mouth
Placebo | 36 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 1 |
| Overall Study | Pregnancy | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Subject Non-Compliance | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | BCX4161 500 mg Three Times Daily | Total | Placebo Three Times Daily | BCX4161 300 mg Three Times Daily |
|---|---|---|---|---|
| Age, Continuous | 41.1 years STANDARD_DEVIATION 15.1 | 41.2 years STANDARD_DEVIATION 13.3 | 42.1 years STANDARD_DEVIATION 12.5 | 40.4 years STANDARD_DEVIATION 12.4 |
| Qualifying attack rate | 0.95 Attacks/ week STANDARD_DEVIATION 0.39 | 0.93 Attacks/ week STANDARD_DEVIATION 0.37 | 0.92 Attacks/ week STANDARD_DEVIATION 0.34 | 0.93 Attacks/ week STANDARD_DEVIATION 0.39 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 36 Participants | 102 Participants | 34 Participants | 32 Participants |
| Region of Enrollment Belgium | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Canada | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Region of Enrollment France | 1 Participants | 6 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Germany | 6 Participants | 17 Participants | 8 Participants | 3 Participants |
| Region of Enrollment Hungary | 1 Participants | 6 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Italy | 4 Participants | 5 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 14 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 19 Participants | 55 Participants | 17 Participants | 19 Participants |
| Sex: Female, Male Female | 30 Participants | 85 Participants | 26 Participants | 29 Participants |
| Sex: Female, Male Male | 8 Participants | 25 Participants | 10 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 38 | 0 / 36 |
| other Total, other adverse events | 31 / 36 | 35 / 38 | 32 / 36 |
| serious Total, serious adverse events | 2 / 36 | 3 / 38 | 3 / 36 |
Outcome results
Primary
The Mean Acute Angioedema Attack Rate
An angioedema attack was defined as swelling at any location reported by participant, which had no swelling earlier. Total number of confirmed attacks during the treatment period standardized to a weekly attack-rate to adjust for the total duration of treatment. The attack rate was derived for each participant by treatment period. The weekly attack rate was equal to the total number of confirmed attacks during a treatment period divided by the duration of the treatment (in days) times 7 days.
Time frame: 12 weeks
Population: The intent-to-treat (ITT) population included all participants who were randomized and received at least 1 dose of study intervention.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BCX4161 300 mg three times daily | The Mean Acute Angioedema Attack Rate | 0.675 Confirmed attacks per week | Standard Error 0.089 |
| BCX4161 500 mg three times daily | The Mean Acute Angioedema Attack Rate | 0.589 Confirmed attacks per week | Standard Error 0.086 |
| Placebo three times daily | The Mean Acute Angioedema Attack Rate | 0.593 Confirmed attacks per week | Standard Error 0.088 |
Secondary
Change From Baseline at Week 12, in Quality of Life as Measured by the Angioedema Quality of Life Questionnaire
Angioedema Quality of Life questionnaire (AE-QoL) consisted of 4 domains (i.e., functioning, fatigue/mood, fear/shame, and nutrition) and a total score based on a total of 17 possible responses. The results of all the responses are summed up and transformed to a scale ranging from 0 (best) to 100 (worst).
Time frame: Baseline (Day 1) and Week 12
Population: The ITT population included all participants who were randomized and received at least 1 dose of study intervention. Here 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BCX4161 300 mg three times daily | Change From Baseline at Week 12, in Quality of Life as Measured by the Angioedema Quality of Life Questionnaire | -9.89 score on a scale | Standard Error 3.11 |
| BCX4161 500 mg three times daily | Change From Baseline at Week 12, in Quality of Life as Measured by the Angioedema Quality of Life Questionnaire | -17.45 score on a scale | Standard Error 2.66 |
| Placebo three times daily | Change From Baseline at Week 12, in Quality of Life as Measured by the Angioedema Quality of Life Questionnaire | -12.14 score on a scale | Standard Error 2.64 |
Secondary
Change From Baseline at Week 12 in Quality of Life, as Measured by the EuroQoL Five-dimensional, 5-level Questionnaire
The EuroQoL five-dimensional, 5-level (EQ-5D-5L) was used to assess overall wellbeing and comprised the following five domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain has 5 response levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. It included the EQ Visual Analogue scale (EQ VAS) to rate overall health on a scale of 0 (worst health) to 100 (best health).
Time frame: Baseline (Day 1) and Week 12
Population: The ITT population included all participants who were randomized and received at least 1 dose of study intervention. Here 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BCX4161 300 mg three times daily | Change From Baseline at Week 12 in Quality of Life, as Measured by the EuroQoL Five-dimensional, 5-level Questionnaire | 3.26 score on a scale | Standard Error 2.38 |
| BCX4161 500 mg three times daily | Change From Baseline at Week 12 in Quality of Life, as Measured by the EuroQoL Five-dimensional, 5-level Questionnaire | 2.41 score on a scale | Standard Error 3.13 |
| Placebo three times daily | Change From Baseline at Week 12 in Quality of Life, as Measured by the EuroQoL Five-dimensional, 5-level Questionnaire | 9.92 score on a scale | Standard Error 1.72 |
Secondary
Disease Activity, as Measured by the 84-day Angioedema Activity Score
Angioedema Activity Score (AAS) consists of 5 questions (period in which swelling occurred, physical discomfort, daily activity restriction, cosmetic disfigurement, and overall severity) to be answered for each day during which a subject experiences an HAE attack. A score between 0 (no symptoms) and 3 (Severe symptoms) was assigned to the responses for each question and the total daily score will be derived as the sum of the 5 question scores for each day during which the subject experiences a confirmed attack. Daily AAS ranged from 0 to 15 with higher scores indicating the greater disease severity. For participants who completed the study, the 84-day AAS was obtained by sum of AAS score during the treatment period and ranged from 0 (best) to 1,260 (worst).For participants who discontinued the study prematurely the 84-day AAS was obtained using the formula: Sum of AAS score of each day on treatment ∗ 84/Number of days on treatment.
Time frame: 12 weeks
Population: The ITT population included all participants who were randomized and received at least 1 dose of study intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCX4161 300 mg three times daily | Disease Activity, as Measured by the 84-day Angioedema Activity Score | 113.9 score on a scale | Standard Deviation 101.9 |
| BCX4161 500 mg three times daily | Disease Activity, as Measured by the 84-day Angioedema Activity Score | 88.5 score on a scale | Standard Deviation 85.1 |
| Placebo three times daily | Disease Activity, as Measured by the 84-day Angioedema Activity Score | 97.2 score on a scale | Standard Deviation 77.3 |
Secondary
Number of Attack-free Days
The number of attack free days was the sum of the days during the treatment period for which participants reported no attacks.
Time frame: 12 weeks
Population: The ITT population included all participants who were randomized and received at least 1 dose of study intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCX4161 300 mg three times daily | Number of Attack-free Days | 62.8 Number of attack-free days | Standard Deviation 18.2 |
| BCX4161 500 mg three times daily | Number of Attack-free Days | 66.0 Number of attack-free days | Standard Deviation 17.9 |
| Placebo three times daily | Number of Attack-free Days | 63.6 Number of attack-free days | Standard Deviation 14.9 |
Secondary
Number of Participants Who Are Attack-free
The number of participants who reported no attacks during the 12-week treatment period.
Time frame: 12 weeks
Population: The ITT population included all participants who were randomized and received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCX4161 300 mg three times daily | Number of Participants Who Are Attack-free | 1 Participants |
| BCX4161 500 mg three times daily | Number of Participants Who Are Attack-free | 1 Participants |
| Placebo three times daily | Number of Participants Who Are Attack-free | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study participant. No causal relationship with study drug or with the clinical study itself is implied. An AE could be an unfavorable and unintended sign, symptom (including an abnormal laboratory finding), syndrome, or illness that developed or worsened during the clinical study. A serious adverse event (SAE) is any untoward medical occurrence resulting in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or other medically important event. Any graded abnormality that occurred following the initiation of study drug and up to 30 days after the last dose of study drug, and represented at least a 1-grade increase from the baseline assessment, was defined as treatment emergent.
Time frame: From first dose up to 14 weeks
Population: The safety population included all randomized participants who received at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCX4161 300 mg three times daily | Number of Participants With Treatment Emergent Adverse Events | 31 Participants |
| BCX4161 500 mg three times daily | Number of Participants With Treatment Emergent Adverse Events | 35 Participants |
| Placebo three times daily | Number of Participants With Treatment Emergent Adverse Events | 32 Participants |