Hereditary Angioedema (HAE)
Conditions
Keywords
HAE, hereditary angioedema, kallikrein inhibitor, plasma kallikrein
Brief summary
This 3-part study will evaluate the efficacy and safety of an oral kallikrein inhibitor, BCX7353, in the treatment angioedema attacks in subjects with Type I or II hereditary angioedema (HAE). In each study part, subjects will treat 3 attacks with BCX7353 (2 attacks) or placebo (1 attack), in a randomly allocated order. In Part 1, the dose of 750mg will be assessed relative to placebo in up to 36 patients. If this is shown to be effective, then a further 12 patients will be enrolled at a 500mg dose (Part 1), followed by a further 12 (if efficacy still shown) at a dose of 250mg (Part 3) to determine the minimum effective dose of BCX7353 compared to placebo for treating HAE attacks. Efficacy will be determined by subject diary entries completed at pre-defined times post-dose.
Interventions
DRUGBCX7353
oral liquid formulation
DRUGPlacebo
oral liquid formulation to match BCX7353
Sponsors
BioCryst Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Able to provide written, informed consent. 2. A clinical diagnosis of hereditary angioedema Type 1 or Type 2 as documented at any time in the medical records or at the screening visit. 3. Access to and ability to use standard of care acute attack treatment for attacks of HAE. 4. Sexually active women of child-bearing potential and sexually active men must utilize effective contraception.
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, androgens or tranexamic acid for prophylaxis of HAE attacks. 4. History of or current alcohol or drug abuse. 5. Infection with hepatitis B, hepatitis C or HIV. 6. Participation in any other investigational drug study currently or within the last 30 days. 7. Positive drugs of abuse screen (unless as used as medical treatment, e.g., with a prescription). 8. An immediate family relationship to either Sponsor employees, the Investigator or employees of the study site.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose | Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0. |
| Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours | 24 hours | The proportion of attacks for which subjects took SOC-Rx in the 24 hours following treatment with study drug. HAE Rescue Medications included C1-INH (Berinert, Cinryze, Ruconest) and Firazyr/Icatibant. |
Countries
Austria, Denmark, France, Germany, Hungary, Israel, Italy, North Macedonia, Poland, Romania, Switzerland, United Kingdom
Participant flow
Pre-assignment details
HAE subjects attended a Screening Visit up to 35 days before the baseline visit, for assessment of eligibility to participate in the study.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Berotralstat (750 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 750 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization. | 33 |
| Part 2: Berotralstat (500 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 500 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization. | 14 |
| Part 3: Berotralstat (250 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 250 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization. | 11 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Intercurrent illness. | 0 | 1 | 0 |
| Overall Study | Rash | 1 | 0 | 0 |
| Overall Study | sponsor closure/completion of Part 1 of the study | 1 | 0 | 0 |
| Overall Study | Sponsor/competent authority/IRB/IEC discontinuation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 2: Berotralstat (500 mg) & Placebo Treated HAE Attacks | Part 1: Berotralstat (750 mg) & Placebo Treated HAE Attacks | Total | Part 3: Berotralstat (250 mg) & Placebo Treated HAE Attacks |
|---|---|---|---|---|
| Adjusted qualifying HAE attack rate | 3.03 HAE attacks/month STANDARD_DEVIATION 1.23 | 3.08 HAE attacks/month STANDARD_DEVIATION 1.4 | 3.09 HAE attacks/month STANDARD_DEVIATION 1.42 | 3.23 HAE attacks/month STANDARD_DEVIATION 1.82 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 32 Participants | 57 Participants | 11 Participants |
| Age, Continuous | 42.1 years STANDARD_DEVIATION 10.5 | 43.7 years STANDARD_DEVIATION 12.5 | 41.6 years STANDARD_DEVIATION 12 | 34.9 years STANDARD_DEVIATION 10.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 33 Participants | 58 Participants | 11 Participants |
| Region of Enrollment Austria | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Denmark | 0 participants | 3 participants | 3 participants | 0 participants |
| Region of Enrollment France | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Germany | 2 participants | 3 participants | 9 participants | 4 participants |
| Region of Enrollment Hungary | 0 participants | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Israel | 2 participants | 4 participants | 6 participants | 0 participants |
| Region of Enrollment Italy | 4 participants | 3 participants | 9 participants | 2 participants |
| Region of Enrollment North Macedonia | 0 participants | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Poland | 1 participants | 2 participants | 6 participants | 3 participants |
| Region of Enrollment Romania | 0 participants | 4 participants | 4 participants | 0 participants |
| Region of Enrollment Switzerland | 0 participants | 2 participants | 2 participants | 0 participants |
| Region of Enrollment United Kingdom | 5 participants | 6 participants | 13 participants | 2 participants |
| Sex: Female, Male Female | 11 Participants | 17 Participants | 35 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 16 Participants | 23 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 14 | 0 / 11 | 0 / 53 |
| other Total, other adverse events | 12 / 33 | 8 / 14 | 7 / 11 | 17 / 53 |
| serious Total, serious adverse events | 0 / 33 | 1 / 14 | 0 / 11 | 1 / 53 |
Outcome results
Primary
Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours
The proportion of attacks for which subjects took SOC-Rx in the 24 hours following treatment with study drug. HAE Rescue Medications included C1-INH (Berinert, Cinryze, Ruconest) and Firazyr/Icatibant.
Time frame: 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Berotralstat 750 mg - Predose | Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours | 29.7 Percentage attacks treated with SOC-Rx |
| Part 1: Placebo - Pre-dose | Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours | 61.3 Percentage attacks treated with SOC-Rx |
| Part 1: Berotralstat 750 mg - 4hr Post-dose | Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours | 32.0 Percentage attacks treated with SOC-Rx |
| Part 1: Placebo - 4hr Post-dose | Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours | 45.5 Percentage attacks treated with SOC-Rx |
| Part 2: Berotralstat 500 mg - Predose | Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours | 38.1 Percentage attacks treated with SOC-Rx |
| Part 2: Placebo - Pre-dose | Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours | 45.5 Percentage attacks treated with SOC-Rx |
Comparison: Analyses were performed using a generalized logistic model including treatment, period and sequence as fixed effects, and subject within sequence as a random effect. The odds of a berotralstat 750 mg-treated-attack requiring SOC-Rx was 0.196 that of a placebo attack.p-value: 0.002995% CI: [0.069, 0.559]logistic mixed effect model
Comparison: Analyses were performed using a generalized logistic model including treatment, period and sequence as fixed effects, and subject within sequence as a random effect. The odds of a berotralstat 500 mg-treated-attack requiring SOC-Rx was 0.472 that of a placebo attack.p-value: 0.404895% CI: [0.074, 2.988]logistic mixed effect model
Comparison: Analyses were performed using a generalized logistic model including treatment, period and sequence as fixed effects, and subject within sequence as a random effect. The odds of a berotralstat 250 mg-treated-attack requiring SOC-Rx was 0.587 that of a placebo attack.p-value: 0.598495% CI: [0.073, 4.733]logistic mixed effect model
Primary
Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score
Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0.
Time frame: Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose
Population: The number of participants analyzed in each analysis set corresponds to number of HAE attacks treated with placebo or berotralstat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Berotralstat 750 mg - Predose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 13.96 VAS score - millimeters | Standard Deviation 9.84 |
| Part 1: Placebo - Pre-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 15.04 VAS score - millimeters | Standard Deviation 11.9 |
| Part 1: Berotralstat 750 mg - 4hr Post-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 10.54 VAS score - millimeters | Standard Deviation 11.39 |
| Part 1: Placebo - 4hr Post-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 18.42 VAS score - millimeters | Standard Deviation 14.19 |
| Part 2: Berotralstat 500 mg - Predose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 17.69 VAS score - millimeters | Standard Deviation 15.25 |
| Part 2: Placebo - Pre-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 13.48 VAS score - millimeters | Standard Deviation 16.11 |
| Part 2: Berotralstat 500 mg - 4hr Post-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 11.31 VAS score - millimeters | Standard Deviation 15.75 |
| Part 2: Placebo - 4hr Post-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 9.26 VAS score - millimeters | Standard Deviation 11.53 |
| Part 3: Berotralstat 250 mg - Predose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 14.57 VAS score - millimeters | Standard Deviation 11.78 |
| Part 3: Placebo - Pre-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 11.33 VAS score - millimeters | Standard Deviation 10.17 |
| Part 3: Berotralstat 250 mg - 4hr Post-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 10.92 VAS score - millimeters | Standard Deviation 10.31 |
| Part 3: Placebo - 4hr Post-dose | Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score | 9.21 VAS score - millimeters | Standard Deviation 9.67 |
Comparison: Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 750mg berotralstat or placebo.p-value: 0.002495% CI: [-11.37, -2.6]Mixed effect linear model
Comparison: Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 500mg berotralstat or placebo.p-value: 0.642495% CI: [-11.49, 7.29]Mixed effect linear model
Comparison: Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 250mg berotralstat or placebo.p-value: 0.828395% CI: [-4.9, 6.03]Mixed effect linear model