| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.1 |
| 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 |
|
| 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 prophylactic BCX7353 at 3 doses over 28 days as measured by the frequency of attacks in subjects with hereditary angioedema (HAE) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of BCX7353 over 28 days in subjects with HAE
• To describe the pharmacokinetic (PK) profile of BCX7353 in subjects with HAE
• To characterize the anticipated pharmacodynamic (PD) effects of BCX7353 in subjects with HAE
• To evaluate effects of BCX7353 on quality of life
|
|
| E.2.3 | Trial contains a sub-study | No |
| 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 as
documented at any time in the medical records or at the screening visit
by:
a. A low C1 INH antigenic level OR
b. A low C1 INH functional level
4. All subjects must have:
a. An HAE attack rate of <<BLINDED>> prior to the screening visit as documented in acceptable source records.
AND
b. <<BLINDED>> with zero HAE attacks in the <<BLINDED>> prior to the screening visit as documented in acceptable source records.
5. Access to and ability to use 1 or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE
6. Female participants must meet at least 1 of the following requirements:
a. Be a woman of childbearing potential who agrees to use at least 1 highly effective contraceptive method during the study and for a
duration of 30 days after last dose of study drug. One or more of the following methods are acceptable:
§ surgical sterilization (ie, bilateral tubal occlusion or vasectomy of male partner)
§ placement of an intrauterine device (IUD) or intrauterine system (IUS) (implanted any time prior to or during screening)
§ progesterone-only (implantable or injectable only) hormonal contraception associated with inhibition of ovulation excluding
desogestrel initiated at least 60 days prior to the screening visit
Female subjects who report being postmenopausal for ≤ 2 years and have a screening follicle stimulating hormone (FSH) ≤ 40 mIU/mL must
agree to use at least 1 highly effective contraceptive method and (as proposed above) during study and for 30 days after dose of study drug.
b. Be a woman of nonchildbearing potential.
c. Be a woman declaring herself as either sexually abstinent or exclusively having female sexual partners.
7. Male subjects must comply with the following requirements for a duration of 90 days after last dose of study drug:
a. Subjects with female partners of childbearing potential must agree to utilize at least 1 highly effective contraceptive method. At least 1 or
more of the following methods are acceptable:
§ surgical sterilization (ie, vasectomy or bilateral occlusion of a female partner)
§ placement of an IUD or IUS
§ any form of hormonal contraception that is associated with inhibition of ovulation (oral, implantable, injectable, intravaginal, or transdermal)
b. Male subjects who declare themselves as sexually abstinent are acceptable for the purposes of this study.
c. Must abstain from sperm donation for a period of 90 days after last dose of study drug.
8. Any concomitant medication recorded at the screening visit and not stated as exclusionary 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.
9. In the opinion of the Investigator, the subject is expected to adequately comply with all required study procedures for the duration of
the study. The subject must demonstrate adequate compliance with all study procedures required from the screening visit through
randomization, including e-diary recording of HAE attacks beginning at the screening visit. |
|
| E.4 | Principal exclusion criteria |
1. 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.
2. Clinically significant abnormal ECG at the screening visit. This includes, but is not limited to, a QTcF > 470 msec, a PR > 220 msec, or
ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping.
3. Any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac arrhythmias, left ventricular
hypertrophy, cardiomyopathy, or any other cardiovascular abnormality.
4. Family history of sudden death from causes other than HAE.
5. History of or current implanted defibrillator or pacemaker.
6. Any abnormal laboratory or urinalysis 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
7. Concurrent use of angiotensin converting enzyme inhibitors from the screening visit or expected use at any time through the end of the study.
8. Use of a medication that is clinically known to induce or inhibit drug transporters at the screening visit or anticipated use through the followup
visit, including no use for a minimum of 7 days prior to Day 1.
9. Use of a medication that is clinically known or suspected to prolong the QT interval at the screening visit or anticipated use through the
follow-up visit, including no use for a minimum of 7 days prior to Day 1.
10. Use of a medication that primarily relies upon CYP2C9, CYP2C19, CYP2D6 and CYP3A4 for metabolism (eg, any P450 substrates listed on
the Indiana University Clinical Pharmacology website) at the screening visit or anticipated use through the follow-up visit, including no use for a
minimum of 7 days prior to Day 1.
11. Initiation of a progesterone contraceptive within 60 days of the screening visit (except subjects who switch from desogestrel).
12. Use of desogestrel (a progesterone contraceptive) is excluded; however, subjects who take a desogestrel-based contraceptive may
switch to an injectable or implantable progesterone-only contraceptive at any time prior to randomization.
13. Use of an estrogen-containing hormonal contraceptive within 60 days of the screening visit.
14. Use within the 7 days prior to the screening visit or expected use at any time through the end of the study of C1 INH, androgens or
tranexamic acid for prophylaxis of HAE attacks. Use of a C1 INH therapy for treatment of acute attacks is not excluded at any time.
15. Current participation in any other investigational drug study or received another investigational drug within 30 days of the screening
visit.
16. 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).
17. Positive serology for human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
18. Pregnant, planning to become pregnant within 30 days of the study, or nursing.
19. Positive drugs of abuse screen (unless as used as medical treatment, eg, with a prescription).
20. History of severe hypersensitivity to any medicinal product. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Weekly confirmed HAE attack rate
• Number of attack-free subjects
• Number of attack-free days
• Assessment of disease activity and attack severity, as measured by the AAS28
• Acute HAE attack medication administrations
• Duration of attacks
• Attack onset relative to the time of last dose of study drug
• Discontinuations due to lack of efficacy
• Symptoms and anatomical locations of attacks
• Number of emergency room visits and/or hospitalizations |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Post 28 days of treatment |
|
| E.5.2 | Secondary end point(s) |
Safety:
· The proportion of subjects who discontinue due to a treatment-emergent AE
· The proportion of subjects with treatment-emergent SAEs
· The proportion of subjects with treatment-emergent Grade 3 or 4 AEs
· The proportion of subjects with treatment-emergent Grade 3 or 4 laboratory abnormalities
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| throughout the study, post 28 days of treatment and post 2 weeks followup off treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| 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 | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Canada |
| Germany |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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