| 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 | 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 |
|
| 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 |
Part 1 - To determine the efficacy of prophylactic BCX7353 110 mg and 150 mg administered once daily (QD) for 24 weeks compared to placebo in subjects with hereditary angioedema (HAE)
Part 2 - To evaluate the long-term safety and tolerability of BCX7353 110 mg and 150 mg administered QD over a 24- to 48-week administration period in subjects with HAE
Part 3 - To evaluate the long-term safety and tolerability of BCX7353 administered QD over a 48 - up to 240-week administration period in subjects with HAE |
|
| E.2.2 | Secondary objectives of the trial |
Part 1 - To assess the safety and tolerability of BCX7353 110 mg and 150 mg administered once daily for 24 weeks
To assess the effects of BCX7353 on HAE disease activity and HAE attack characteristics
To evaluate the effects of BCX7353 on quality of life
To characterize the pharmacodynamic effects of BCX7353
Part 2 - To assess the effectiveness (i.e., HAE attack frequency over time) of BCX7353 over a 24- to 48-week administration period
To evaluate quality of life and HAE disease activity of BCX7353 over a 24- to 48-week administration period
To evaluate subject’s satisfaction with BCX7353 over a 24- to 48-week administration period
Part 3 - To assess the effectiveness (i.e., HAE attack frequency over time) of BCX7353 over a 48 to up to 240-week administration period
To evaluate quality of life and HAE disease activity of BCX7353 over a 48 to 240-week administration period
To evaluate subject’s satisfaction with BCX7353 over a 48-240-week administration period |
|
| 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 |
this Sub Study is NOT done in Europe.
it is for adolescents |
|
| E.3 | Principal inclusion criteria |
1. Males and non-pregnant, non-lactating females ≥ 18 years of age (main study) .
2. Able to provide written, informed consent. Subjects aged 12 to 17 years who are screening for the substudy must be able to read, understand, and be willing to sign an assent form in addition to a caregiver providing informed consent.
3. Subject weight of ≥ 40 kg.
4. A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined as having a C1-INH functional level below 50% and a C4 level below the lower limit of the normal (LLN) reference range, as assessed during the Screening period. In the absence of a low C4 value drawn during the intercritical period (ie, subject is not having an HAE attack), one of the following is acceptable to confirm the diagnosis of HAE: 1) a SERPING-1 gene mutation known or likely to be associated with HAE Type 1 or 2 assessed during the screening period; 2) a confirmed family history of C1-INH deficiency; 3) a C4 redrawn and retested during an attack in the screening period with the results below the LLN reference range .
For subjects with C1-INH function ≥ 50% but less than the assay LLN, a SERPING-1 gene mutation known or likely to be associated with HAE Type I or II, as assessed during the screening period OR a repeat C1-INH functional level < 50% will be considered acceptable for enrollment
5. 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 (icatibant, plasma-derived C1 INH, ecallantide, or recombinant C1 INH). Cinryze used for acute treatment of HAE attacks is an acceptable medication for this purpose.
6. Subjects must be medically appropriate for on-demand treatment as the sole medicinal management for their HAE during the study.
7. The subject must have at least <<blinded>> HAE attacks which meet all of the requirements below during the run-in period of a maximum of 56 days from the screening visit.
8. Female and male subjects must agree to the contraception requirements (defined as acceptable effective) and must meet the inclusion criteria regarding contraception, and contraception of female partners (as applicable). Contraception is no longer required for male subjects and their female partners under protocol V3
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 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 increases the risk to the subject by participating in the study.
2. 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.
3. Anticipated use of short-term prophylaxis of angioedema attacks for a pre-planned procedure during the screening or study periods (part 1 and 2 only).
4. Concurrent diagnosis of any other type of recurrent angioedema.
5. 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, 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.
6. 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.
7. Known family history of sudden cardiac death. Family history of sudden death from HAE is not exclusionary.
8. History of or current implanted defibrillator or pacemaker.
9. 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 CLcr of ≤ 30 mL/min or AST or ALT value ≥ 3 times the upper limit of the normal reference range value obtained during screening is exclusionary.
10. Prior enrollment in a BCX7353 study.
11. Suspected C1-INH resistance in the opinion of the Investigator or Sponsor.
12. 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 alcohol intake > 3 drinks/day).
13. Positive serology for human immunodeficiency virus (HIV) or current infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
14. Pregnant, planning to become pregnant during the study, or nursing.
15. Positive drugs of abuse screen (unless drug is used as medical treatment with a prescription).
16. History of severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis with unclear etiology.
17. Use of androgens or tranexamic acid for prophylaxis of HAE attacks within the 28 days prior to the Screening visit or initiation during the study.
18. Use of C1-INH for prophylaxis of HAE attacks within the 14 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 preprocedure prophylaxis for an unplanned/unforeseen procedure.
19. 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.
20. 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 the baseline visit or planned initiation during the study.
21. Use of a medication that is transported by P-gp and has a narrow therapeutic range, within 7 days of the baseline visit or planned initiation during the study.
22. Use of an angiotensin-converting enzyme inhibitor within 7 days of the baseline visit or planned initiation during the study.
23. Initiation of an estrogen-containing hormonal contraceptive within 56 days of the screening visit or planned initiation during the study (part 1 and 2 only)
24. Current participation in any other investigational drug study or received another investigational drug within 30 days of the Screening visit.
25. An immediate family relationship to either Sponsor employees, the Investigator or employees of the study site named on the delegation log.
26. Held in an institution by a government or judicial order. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 - The rate of investigator-confirmed HAE attacks during dosing in the entire 24-week treatment period
Part 2 - Number and proportion of subjects with a TEAE
Number and proportion of subjects who discontinue due to a TEAE
Number and proportion of subjects who experience a TESAE
Number and proportion of subjects who experience a Grade 3 or 4 TEAE
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 laboratory abnormality
The proportion of subjects with a treatment-emergent, treatment related AE consistent with a drug rash
Part 2 - Number and proportion of subjects with a TEAE
Number and proportion of subjects who discontinue due to a TEAE
Number and proportion of subjects who experience a TESAE
Number and proportion of subjects who experience a Grade 3 or 4 TEAE
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 laboratory abnormality
The proportion of subjects with a treatment-emergent, treatment related AE consistent with a drug rash
Part 2 - Number and proportion of subjects with a TEAE
Number and proportion of subjects who discontinue due to a TEAE
Number and proportion of subjects who experience a TESAE
Number and proportion of subjects who experience a Grade 3 or 4 TEAE
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 laboratory abnormality
The proportion of subjects with a treatment-emergent, treatment related AE consistent with a drug rash
Part 3 - Number and proportion of subjects with a TEAE
Number and proportion of subjects who discontinue due to a TEAE
Number and proportion of subjects who experience a TESAE
Number and proportion of subjects who experience a Grade 3 or 4 TEAE
Number and proportion of subjects who experience a treatment-emergent Grade 3 or 4 laboratory abnormality
The proportion of subjects with a treatment-emergent, treatment related AE consistent with a drug rash |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1 - end of 24 weeks treatment
Part 2 - end of 48 weeks treatment
Part 3 - end of 240 weeks treatment |
|
| E.5.2 | Secondary end point(s) |
Part 1 Change from baseline in Angioedema Quality of Life questionnaire at Week 24 (AE-QoL; total score)
Number and proportion of days with angioedema symptoms through 24 weeks
Rate of investigator-confirmed HAE attacks during dosing in the effective treatment period (beginning on Day 8 through 24 weeks)
Part 2 Number and rate of HAE attacks
Durability of response (attack rate trend over time)
Number and proportion of days with angioedema symptoms
Use of HAE attack medications
Discontinuations due to lack of efficacy
Durability in Angioedema Quality of Life questionnaire scores
Durability in EQ-5D-5L scores
Durability in TSQM scores
Durability in WPAI scores
Part 3 Number and rate of HAE attacks
Durability of response (attack rate trend over time)
Number and proportion of days with angioedema symptoms
Use of HAE attack medications
Durability in Angioedema Quality of Life questionnaire scores
Durability in EQ-5D-5L scores
Durability in TSQM scores
Durability in WPAI scores
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1 - end of 24 weeks treatment
Part 2 - end of 48 weeks treatment
Part 3 - end of 240 weeks 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 | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| European Union |
| Macedonia, the former Yugoslav Republic of |
| United States |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
Print
