| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019860 |
| E.1.2 | Term | Hereditary angioedema |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of single oral doses of BCX7353 in treating acute attacks in subjects with hereditary angioedema |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of single oral doses of BCX7353 in subjects with HAE
To evaluate the relationship of BCX7353 dose with clinical responses
To evaluate subject satisfaction with BCX7353 treatment
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title, date and version - all identical to main study
Objective - to describe the natural history and temporal pattern of symptoms of untreated attacks and those treated with commercially available attack medications |
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| E.3 | Principal inclusion criteria |
1. Able to provide written, informed consent
2. Males and non-pregnant, non-lactating females age 18 to 70 years
3. A clinical diagnosis of hereditary angioedema Type 1 or Type 2 defined having a C1INH functional level below 50% of normal and a C4 level below the lower limit of normal reference range, as assessed at the Screening visit
4. Access to and ability to use standard of care acute attack treatment. Standard of care acute attack treatment is defined as a medication approved by the relevant competent authority for the treatment of attacks of HAE (e.g., icatibant, ecallantide, plasma-derived C1INH, recombinant C1INH).
5. Female participants must meet at least 1 of the following requirements:
a. Be a woman of childbearing potential (defined as a nonmenopausal female who has not had a hysterectomy, bilateral oophorectomy, or documented ovarian failure) who agrees to use an acceptable effective contraceptive method during the study and for a duration of 30 days after last dose of study drug.
Female subjects who report being postmenopausal for ≤ 2 years and have a screening follicle stimulating hormone (FSH) ≤ 40 mIU/mL must agree to use an acceptable effective contraceptive method during study and for 30 days after the last dose of study drug.
b. Be a woman of nonchildbearing potential (defined as postmenopausal for > 2 years or a screening FSH > 40 mIU/mL if postmenopausal ≤ 2 years or have had a hysterectomy, bilateral oophorectomy, or documented ovarian failure).
c. Be a woman declaring herself as either sexually abstinent or exclusively having female sexual partners. Abstinence in this study is defined as "true abstinence: when this is in line with the preferred and usual lifestyle of the subject."
6. Male participants must comply with the following requirements through to the end of the study:
a. Subjects with female partners of childbearing potential (defined as postmenopausal ≤ 2 years or a nonmenopausal female who has not had a hysterectomy, bilateral oophorectomy, or documented ovarian failure) must agree to utilize an acceptable effective contraceptive method.
b. Male subjects who declare themselves as sexually abstinent or exclusively having male sexual partners are acceptable for the purposes of this study. Abstinence in this study is defined as “true abstinence: when this is in line with the preferred and usual lifestyle of the subject.”
7. Any regularly administered concomitant medication recorded at the Screening visit and not stated as prohibited must be anticipated to be continued through the entire study and be of a stable dose and regimen for the duration of the entire study.
8. In the opinion of the Investigator, the subject is expected to adequately comply with all required study procedures for the duration of the study. To be dispensed study drug at baseline, the subject must demonstrate adequate compliance with all study procedures required from the Screening visit through randomization, including phoning the investigator and diary recording of at least one HAE attack during the screening period.
9. Must have an HAE attack rate of at least 1 unique attack per month for 3 months (up to 93 days) within the 4 months prior to the Screening visit.
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| E.4 | Principal exclusion criteria |
1. No HAE attack reported to the on-call Investigator (or designee) during the 35-day screening period.
2. Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the Investigator or Sponsor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject.
3. Dementia, altered mental status, or any psychiatric condition, or stay in an institution further to an official or court order that would prohibit the understanding or rendering of informed consent or participation in the study.
4. Clinically significant abnormal ECG at the Screening visit. This includes, but is not limited to, a QTcF > 470 msec for women, a QTcF > 450 msec for men, a PR > 220 msec (both sexes), or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping.
5. Any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other clinically significant cardiovascular abnormality such as poorly controlled hypertension.
6. Known family history of sudden cardiac death from causes other than HAE. Family history of sudden death from HAE is not exclusionary.
7. History of or current implanted defibrillator or pacemaker.
8. Any laboratory parameter at screening that, in the opinion of the Investigator, is clinically significant and relevant for this study. A calculated creatinine clearance of ≤ 60 mL/min or AST or ALT value ≥ 2 times the upper limit of the normal reference range value obtained during screening is exclusionary.
9. Suspected C1 INH resistance in the opinion of the Investigator and Sponsor.
10. History of alcohol or drug abuse within the previous year prior to the screening visit, or current evidence of substance dependence or abuse (self-reported alcoholic intake > 3 drinks/day).
11. Positive serology for human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
12. Pregnant, planning to become pregnant within 30 days of the study, or nursing.
13. Positive drugs of abuse screen (unless as used as medical treatment, e.g., with a prescription).
14. History of severe hypersensitivity to any medicinal product, which was associated with swelling, a severe rash requiring treatment / hospitalization, or anaphylaxis.
15. Hypersensitivity reaction to BCX7353.
16. Use of tranexamic acid, androgens or C1 INH for prophylaxis of HAE attacks within the 7 days prior to the Screening visit or initiation during the study. Use of a C1 INH therapy for treatment of attacks is not excluded at any time, nor is C1 INH for pre-procedure prophylaxis.
17. Use of concomitant medications that are metabolized by CYP2D6, CYP2C9, CYP2C19, and CYP3A4 and have a narrow therapeutic range, within 7 days of the baseline visit or planned initiation during the study. For the purpose of this protocol, these include, but are not limited to the following: warfarin, phenytoin, s-mephenytoin, thioridazine, pimodizine, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine and desogestrel.
18. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or planned initiation during the study.
19. Use of a medication that is clinically known to prolong the QT interval and is metabolized by CYP2D6, CYP2C9, CYP2C19, and/or CYP3A4 7 days prior to baseline or initiation during the study.
20. Current participation in any other investigational drug study or received another investigational drug within 30 days of the Screening visit.
21. An immediate family relationship to either Sponsor employees, the Investigator or employees of the study site named on the delegation log |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. The 3-symptom composite VAS score at 4 hours post-dose
2. Patient global assessment at 4 hours post-dose
3. Subject attacks with no symptoms or mild symptoms of an HAE attack at 4 hours post-dose
4. Use of standard of care attack treatment through 24 hours post-dose
5. Time to use of standard of care acute attack treatment through 24 hours post-dose
6. Time to stable or improved symptoms by composite VAS score through 24 hours post-dose
7. Time to symptom relief |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 4hours post dose and 24 hours post dose |
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| E.5.2 | Secondary end point(s) |
Safety - discontinuations due to a treatment-emergent AE; experience a treatment-emergent SAE; experience a Grade 3 or 4 treatment-emergent AE; and experience a treatment emergent Grade 3 or 4 laboratory abnormality.
Efficacy - treatment satisfaction score. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety - throughout the study
Efficacy - each study visit post dose. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| European Union |
| Israel |
| Macedonia, the former Yugoslav Republic of |
| Switzerland |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The last subject completes the Post Attack 3 visit.
The sub-study, for patients who are willing to enter, commences after the Post Attack 3 visit, however it is non-interventional in nature, and does not involve any treatment with IMPs. The sub-study is anticipated to complete approximately 12 weeks after the End of Trial as defined above. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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