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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part1: BCX7353 750 mg | Experimental |
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| Part 2: BCX7353 500 mg | Experimental |
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| Part 3: BCX7353 250 mg | Experimental |
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| Parts 1, 2 and 3: placebo | Placebo Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BCX7353 | Drug | oral liquid formulation |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose |
| 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. | 24 hours |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hilary Longhurst, MBBS, PhD | Barts & The London NHS Trust | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Study Center | Graz | Austria | ||||
| Study Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36408587 | Derived | Farkas H, Balla Z. A review of berotralstat for the treatment of hereditary angioedema. Expert Rev Clin Immunol. 2023 Feb;19(2):145-153. doi: 10.1080/1744666X.2023.2150611. Epub 2022 Nov 29. |
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HAE subjects attended a Screening Visit up to 35 days before the baseline visit, for assessment of eligibility to participate in the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Part 2: Berotralstat (500 mg) & Placebo Treated HAE Attacks |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 29, 2019 | Oct 23, 2020 |
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| Placebo | Drug | oral liquid formulation to match BCX7353 |
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| Odense |
| Denmark |
| Study Center | Grenoble | France |
| Study Center | Lille | France |
| Study Center | Berlin | Germany |
| Study Center | Frankfurt | Germany |
| Study Center | Budapest | Hungary |
| Study Center | Ashkelon | Israel |
| Study Center | Tel Aviv | Israel |
| Study Center | Tel Litwinsky | Israel |
| Study Center | Milan | Italy |
| Study center | Padova | Italy |
| Study Center | Salerno | Italy |
| Study Center | Skopje | North Macedonia |
| Study Center | Krakow | Poland |
| Study Center | Târgu Mureş | Romania |
| Study Center | Zurich | Switzerland |
| Study Center | Birmingham | United Kingdom |
| Study Center | Bristol | United Kingdom |
| Study Center | Cambridge | United Kingdom |
| Study Center | London | United Kingdom |
| Study Center | Manchester | United Kingdom |
| Study Center | Plymouth | United Kingdom |
| Study Center | Southampton | United Kingdom |
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. |
| FG002 | 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. |
| Completed Period 1 |
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| Completed Period 2 |
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| Completed Period 3 |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Adjusted qualifying HAE attack rate | Mean | Standard Deviation | HAE attacks/month |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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. | The number of participants analyzed in each analysis set corresponds to number of HAE attacks treated with placebo or berotralstat. | Posted | Mean | Standard Deviation | VAS score - millimeters | Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose | HAE Attacks | HAE Attacks |
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| 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. | Posted | Number | Percentage attacks treated with SOC-Rx | 24 hours | HAE Attacks | HAE Attacks |
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Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days.
AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part1: Berotralstat 750 mg | Berotralstat : oral liquid formulation | 0 | 33 | 0 | 33 | 12 | 33 |
| EG001 | Part 2: Berotralstat 500 mg | Berotralstat: oral liquid formulation | 0 | 14 | 1 | 14 | 8 | 14 |
| EG002 | Part 3: Berotralstat 250 mg | Berotralstat: oral liquid formulation | 0 | 11 | 0 | 11 | 7 | 11 |
| EG003 | Parts 1, 2 and 3: Placebo | Placebo: oral liquid formulation to match Berotralstat | 0 | 53 | 1 | 53 | 17 | 53 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| kidney contusion | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
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| Ankle fracture | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
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| Ligament sprain | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Arthropod bite | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
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| Limb injury | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
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| Dysplastic naevus | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.0) | Systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA (19.0) | Systematic Assessment |
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| Vessel puncture site reaction | General disorders | MedDRA (19.0) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (19.0) | Systematic Assessment |
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| Abdominal discomfort | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Faeces discoloured | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Epigastric discomfort | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Rhinitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Contusion | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Muscle contusion | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
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| Blood creatine phosphokinase increased | Investigations | MedDRA (19.0) | Systematic Assessment |
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| Cholelithiasis | Hepatobiliary disorders | MedDRA (19.0) | Systematic Assessment |
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| Infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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In this interim clinical study report (CSR), the VAS change from pre-dose at 4 hours and the proportion of attacks requiring SOC-Rx through the 24 hour post dose were discussed. Assessment of other efficacy endpoints were to be discussed in a final CSR, but this is no longer planned due to a decision to not proceed further with trials of acute treatment of HAE attacks with berotralstat.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | BioCryst Pharmaceuticals Inc | +1 919-859-1302 | clinicaltrials@biocryst.com |
| SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Mar 16, 2018 | Feb 10, 2021 | Prot_001.pdf |
| ID | Term |
|---|---|
| D054179 | Angioedemas, Hereditary |
| ID | Term |
|---|---|
| D000799 | Angioedema |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000081208 | Hereditary Complement Deficiency Diseases |
| D000081207 | Primary Immunodeficiency Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D014581 | Urticaria |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D007153 | Immunologic Deficiency Syndromes |
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| ID | Term |
|---|---|
| C000706836 | berotralstat |
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| Between 18 and 65 years |
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| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Romania |
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| Hungary |
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| Denmark |
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| North Macedonia |
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| Poland |
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| Italy |
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| United Kingdom |
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| Israel |
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| France |
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| Switzerland |
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| Germany |
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| Part 3: Placebo - Pre-dose |
HAE attack prior to dosing with placebo |
| OG010 | Part 3: Berotralstat 250 mg - 4hr Post-dose | HAE attack 4 hr post dosing with 250mg berotralstat |
| OG011 | Part 3: Placebo - 4hr Post-dose | HAE attack 4 hr post dosing with placebo |
| HAE Attacks |
|
| Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 500mg berotralstat or placebo. | Mixed effect linear model | 0.6424 | Difference in Least Square Means | -2.1 | 2-Sided | 95 | -11.49 | 7.29 | Superiority | Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and predose 3-symptom composite VAS score as a covariate. |
| Change in HAE attack symptoms from pre-dose to 4 hours post-dose was assessed following treatment with either 250mg berotralstat or placebo. | Mixed effect linear model | 0.8283 | Difference in Least Square Means | 0.57 | 2-Sided | 95 | -4.9 | 6.03 | Superiority | Comparisons were performed separately at each time point using a mixed effect linear model including treatment, period and sequence as fixed effects, subject within sequence as a random effect, and predose 3-symptom composite VAS score as a covariate. |
| OG005 | Part 3: Placebo | HAE attack treated with placebo |
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