Efficacy and Safety Study of BCX7353 as an Oral Treatment for the Prevention of Attacks in HAE (APeX-2)
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| ClinicalTrials.gov Identifier: NCT03485911 |
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Recruitment Status :
Completed
First Posted : April 3, 2018
Results First Posted : March 2, 2021
Last Update Posted : June 26, 2023
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Sponsor:
BioCryst Pharmaceuticals
Information provided by (Responsible Party):
BioCryst Pharmaceuticals
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Brief Summary:
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral BCX7353 in preventing acute angioedema attacks in patients with Type I and Type II HAE.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Hereditary Angioedema HAE | Drug: BCX7353 capsules Drug: Placebo oral capsule | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 121 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Masking Description: | Only Part 1 and Part 2 were blinded. As part 3 was open-label, no blinding was used |
| Primary Purpose: | Prevention |
| Official Title: | A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Two Dose Levels of BCX7353 as an Oral Treatment for the Prevention of Attacks in Subjects With Hereditary Angioedema |
| Actual Study Start Date : | February 6, 2018 |
| Actual Primary Completion Date : | April 10, 2019 |
| Actual Study Completion Date : | April 6, 2022 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Hereditary angioedema
MedlinePlus related topics:
Safety
| Arm | Intervention/treatment |
|---|---|
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Experimental: BCX7353 110 mg once daily
BCX7353 administered as oral capsules once daily
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Drug: BCX7353 capsules
BCX7353 oral capsules administered once daily
Other Name: Berotralstat |
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Experimental: BCX7353 150 mg once daily
BCX7353 administered as oral capsules once daily
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Drug: BCX7353 capsules
BCX7353 oral capsules administered once daily
Other Name: Berotralstat |
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Placebo Comparator: Placebo
Matching placebo administered as oral capsules once daily
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Drug: Placebo oral capsule
Matching oral capsules administered once daily |
Primary Outcome Measures :
- Part 1: The Rate of Investigator-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168) [ Time Frame: 24 weeks ]Treatment comparisons between each berotralstat dose and placebo in the rate of investigator-confirmed HAE attacks during the Part 1 dosing period were analyzed using a negative binomial model. The number of investigator-confirmed attacks was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline attack rate) was included as a covariate, and the logarithm of duration on treatment was included as an offset variable. The estimated attack rate for each treatment group, the treatment differences expressed as the attack rate ratio (berotralstat over placebo rate ratio), and the associated 95% confidence intervals (CIs) were provided from the negative binomial model.
- Part 2 & 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE [ Time Frame: Part 2: 24 weeks (Days 169 to 337). Part 3: 48 weeks (Days 338 to 674). ]The safety data was assessed for the safety population, for subjects who entered Part 2 and Part 3, and includes TEAEs that began in Part 2 or 3, respectively, for these subjects. Safety data for Part 2 and Part 3 is combined to clearly show TEAEs occurring in subjects as the proceeded through the 2 study parts. TEAEs are defined as AEs that occurred on or after first dose of study treatment, whether in Part 1 or 2, and were assigned to the relevant treatment depending on when the TEAE began (Part 2 or Part 3 treatment). No statistical analysis was performed on this safety data.
Secondary Outcome Measures :
- Part 1: Change From Baseline in Angioedema Quality of Life Questionnaire at Week 24 (Total Score) [ Time Frame: Baseline and 24 weeks ]Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL is only validated for adults; however, data were collected on all adult and adolescent study subjects.
- Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks [ Time Frame: 24 weeks ]Assessment of proportion of days subjects had angioedema symptoms from expert-confirmed HAE attacks during Part 1.
- Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period [ Time Frame: Day 8 through to 24 weeks (or or the last dose date/time in Part 1 + 24 hours for subjects who discontinued drug in Part 1) ]The rate of expert-confirmed HAE attacks for the effective treatment period gives an analysis of the efficacy of active treatment after berotralstat had reached steady-state concentrations, given the effective half-life of 150 mg berotralstat in Study BCX7353-106 (Study 106) of 89 hours.
- Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 48 Week Period [ Time Frame: 24 weeks (Days 169 to 337) ]
Monthly Attack Rate was defined as the total number of investigator-confirmed HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the subject was on treatment during that month. The end of Month 6 was defined as the start of Part 2 treatment.
Baseline investigator-confirmed attack rate was defined as the total number of investigator-confirmed HAE attacks experienced in the period between screening and first dose of study drug adjusted for the length of a month (defined as 28 days) and the number of days during that period.
- To Evaluate Angioedema Quality of Life Questionnaire (Total Score) Following Berotralstat Administration for up to 144 Weeks [ Time Frame: Up to 144 weeks ]Angioedema-specific QoL was assessed by the AE-QoL, consisting of 4 domains (i.e., functioning, fatigue/mood, fears/shame, and nutrition) and a total score. The AE-QoL scores range from 0 points (best QoL) to 100 points (worst QoL). A decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL was completed by the subjects at each visit starting at baseline, and questions were answered with regard to the previous 28 days. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.
- To Evaluate Treatment Satisfaction Questionnaire for Medication (TSQM) Following Berotralstat Administration for up to 144 Weeks [ Time Frame: Up to 144 weeks ]The Treatment Satisfaction Questionnaire for Medication (TSQM) was completed by subjects at baseline and at each study visit until the end of the study. TSQM scores consisted of 14 items of which 13 items were made up of 3 specific scales (Effectiveness, Side Effects, and Convenience) and 1 global satisfaction scale (Global Satisfaction). At baseline, TSQM questionnaires were completed based on subject's satisfaction with usual medications. At all other time points for collection of TSQM, subjects were asked about their level of satisfaction or dissatisfaction with the study drug. Scales scores were calculated for each scale and were transformed into scores ranging from 0 to 100, with higher scores indicating higher satisfaction. TSQM score and corresponding change from baseline values were calculated at each visit. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.
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| Ages Eligible for Study: | 12 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Gender Based Eligibility: | Yes |
| Accepts Healthy Volunteers: | No |
Criteria
Key Inclusion Criteria:
- A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined as having a C1-INH functional level and a C4 level below the lower limit of the normal (LLN) reference range, as assessed during the Screening period.
- Subject weight of ≥ 40 kg
- Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE
- Subjects must be medically appropriate for on-demand treatment as the sole medicinal management for their HAE during the study.
- Subjects must have a specified number of investigator-confirmed attacks during the run-in period of a maximum of 56 days from the Screening visit.
- Acceptable effective contraception
- Written informed consent
Key Exclusion Criteria:
- Pregnancy or breast-feeding
- Any clinically significant medical condition or medical history that, in the opinion of the Investigator or Sponsor, would interfere with the subject's safety or ability to participate in the study
- Any laboratory parameter abnormality that, in the opinion of the Investigator, is clinically significant and relevant for this study
- Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/ anaphylaxis with unclear etiology
- Use of C1-INH within 14 days or use of androgens or tranexamic acid within 28 days prior to the Screening visit for prophylaxis of HAE attacks, or initiation of these drugs during the study
- Current participation in any other investigational drug study or received another investigational drug within 30 days of the Screening visit
- Prior enrollment in a BCX7353 study
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03485911
Locations
Show 47 study locations
Sponsors and Collaborators
BioCryst Pharmaceuticals
Investigators
| Principal Investigator: | Bruce Zuraw, MD | UC San Diego School of Medicine, US HAE Angioedema Center |
Study Documents (Full-Text)
Documents provided by BioCryst Pharmaceuticals:
Documents provided by BioCryst Pharmaceuticals:
Study Protocol [PDF] February 10, 2020
Statistical Analysis Plan [PDF] January 29, 2019
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | BioCryst Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT03485911 |
| Other Study ID Numbers: |
BCX7353-302 |
| First Posted: | April 3, 2018 Key Record Dates |
| Results First Posted: | March 2, 2021 |
| Last Update Posted: | June 26, 2023 |
| Last Verified: | May 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by BioCryst Pharmaceuticals:
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BCX7353 Berotralstat |
Additional relevant MeSH terms:
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Angioedema Angioedemas, Hereditary Vascular Diseases Cardiovascular Diseases Urticaria Skin Diseases, Vascular Skin Diseases Hypersensitivity, Immediate Hypersensitivity Immune System Diseases |
Hereditary Complement Deficiency Diseases Primary Immunodeficiency Diseases Genetic Diseases, Inborn Immunologic Deficiency Syndromes Berotralstat Serine Proteinase Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |