| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hereditary angioedema |
| angioedema hereditario |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hereditary Angioedema |
| angioedema hereditario |
|
| 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 |
Parte 1. Determinar la eficacia de la profilaxis de BCX7353 110 mg y 150 mg administrado una vez al día durante 24 semanas, en comparación con el placebo, en sujetos con angioedema hereditario (AEH)
Parte 2. · Evaluar la seguridad y la tolerabilidad a largo plazo de BCX7353 110 mg y 150 mg administrados una vez al día durante un periodo de 24 a 48 semanas a sujetos con AEH |
|
| 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 |
|
| 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, protocol date and version - identical to main study
Objectives - to assess the same Part 1 and Part 2 objectives of the main study, in adolescent subjects ≥ 12 to 17 years of age |
|
| E.3 | Principal inclusion criteria |
1. Males and non-pregnant, non-lactating females ≥ 18 years of age (main study) or ≥ 12 to 17 years of age (substudy).
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 .
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 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)
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. |
1. Varones y mujeres no embarazadas, no lactantes, de ≥ 18 años de edad (estudio principal) o de ≥ 12 a 17 años de edad (subestudio).
2. Ser capaz de proporcionar consentimiento informado por escrito. Los sujetos de 12 a 17 años que sean seleccionados deben ser capaces de leer, comprender y estar dispuestos a firmar un formulario de consentimiento, siendo necesario además un documento de consentimiento informado proporcionado por un tutor.
3. Peso del sujeto ≥ 40 kg.
4. Diagnóstico clínico de angioedema hereditario Tipo 1 o 2, definido por presentar un nivel funcional de C1-INH inferior al 50% y un C4 menor que el límite inferior normal en el rango de referencia, según lo evaluado durante el periodo de screening. En ausencia de un valor bajo de C4 obtenido durante el periodo intercrítico (cuando el sujeto no está teniendo un ataque de AEH), se acepta uno de los siguientes para confirmar el diagnóstico de AEH: 1) mutación del gen SERPING-1 conocido por asociarse (o probablemente se asocie) al Tipo 1 o 2 de AEH, evaluada durante el periodo de screening; 2) historia familiar confirmada de déficit de C1-INH: 3) un nivel de C4 obtenido y probado de nuevo durante un ataque en el periodo de screening con resultados por debajo del límite inferior normal en el rango de referencia.
5. Acceso y capacidad de tomar una o más medicaciones para tratar los brotes agudos que fueran autorizadas por el responsable médico competente para el tratamiento de ataques agudos de AEH (icatibant, plasma como fuente de C1inhibidor, ecallantide o C1inhibidor recombinante). El Cinryze empleado como tratamiento para los ataques agudos de AEH es una medicación aceptable para este fin.
6. Los sujetos deben reunir las condiciones médicas adecuadas para recibir tratamiento a demanda como única forma de gestionar el AEH durante el estudio.
7. El sujeto debe experimentar al menos << >> ataques de AEH que reúnan los requisitos siguientes durante el periodo de adaptación, con un máximo de 56 días desde la consulta de screening.
8. Los sujetos mujeres y varones deben aceptar los requisitos de anticoncepción (Acceptable effective), y cumplir los criterios de inclusión, y la de sus parejas mujeres (según corresponda).
9. A consideración del Investigador, el sujeto deberá cumplir adecuadamente todos los procedimientos necesarios durante el periodo del estudio. El sujeto debe demostrar un cumplimiento adecuado desde el screening, hasta la aleatorización, incluido el registro diario de los ataques de AEH, comenzando en la consulta de screening. |
|
| 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.
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.
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. |
1. Toda enfermedad médica o psiquiátrica con relevancia clínica o historia médica que, en opinión del Investigador o Promotor, pudiera interferir con la capacidad del sujeto para participar en el estudio o aumentar los riesgos derivados de su participación.
2. Demencia, estado mental alterado o cualquier enfermedad psiquiátrica, o estancia en una institución en virtud de una sentencia judicial o una ley que impidiera comprender u otorgar el consentimiento para participar en el estudio.
3. Uso anticipado de profilaxis a corto plazo de ataques de angioedema para un procedimiento planificado previamente durante los periodos de screening o del estudio.
4. Diagnóstico concurrente con cualquier otro tipo de angioedema recurrente.
5. Electrocardiograma con anomalías clínicamente relevantes en el screening. Esto incluye, pero no se limita a: QTcF> 470 msec en mujeres, QTcF> 450 msec en hombres, PR > 220 msec (ambos sexos), o contracciones ventriculares y/o atriales prematuras más frecuentes de las ocasionales, y/o agrupadas en dos o más.
6. Cualquier historia de relevancia médica de angina de pecho, infarto de miocardio, desmayo, arritmias cardiacas de relevancia médica, hipertrofia ventricular izquierda, miocardiopatía, o cualquier otra anomalía cardiovascular de relevancia médica, como la hipertensión deficientemente controlada.
7. Historia familiar conocida de muerte súbita cardiaca. La historia familiar de muerte súbita por AEH no es excluyente.
8. Historia, o implantación actual, de desfibrilador o marcapasos.
9. Cualquier hallazgo anormal de laboratorio o parámetro anormal en análisis de orina en el screening que, a consideración del Investigador, resulte clínicamente relevante para este ensayo. Es excluyente una depuración de la creatinina CLcr estimada de ≤ 30 mL/min o valor AST o ALT ≥ 3 veces del límite máximo normal en el rango de referencia que hubiera sido obtenida durante el screening.
10. Anterior participación en un estudio de BCX7353.
11. Sospecha de resistencia a C1-INH a consideración del Investigador o Promotor.
12. Historia de abuso de alcohol o drogas durante el año anterior al screening, o evidencia de dependencia o abuso actual de sustancias (ingesta auto-informada de bebidas alcohólicas > 3 bebidas/día).
13. Serología positiva para el virus de inmunodeficiencia humana (VIH) o infección actual por el virus de la hepatitis B (VHB) o el virus de la hepatitis C (VHC).
14. Embarazo, planear embarazo dentro de los 30 días siguientes al comienzo del estudio, o lactancia.
15. Positivo en examen médico de abuso de drogas (salvo utilizadas como tratamiento médico, por ejemplo, con receta).
16. Historia de hipersensibilidad grave a múltiples productos médicos o hipersensibilidad/anafilaxia severa con etiología poco clara.
17. Uso de andrógenos o ácido tranexámico para profilaxis de ataques de AEH en los 28 días anteriores al screening o inicio de empleo de tales sustancias durante el estudio.
18. Uso de C1-INH para profilaxis de ataques de AEH en los 14 días anteriores al screening o inicio de empleo de tales sustancias durante el estudio. El empleo de una terapia con C1 INH para el tratamiento de los ataques no se excluye en un momento dado, como tampoco se excluye el uso de C1-INH para profilaxis previa al procedimiento en caso de procedimiento no planeado/no previsto.
19. Uso de medicaciones concomitantes que se metabolicen mediante CYP2D6, CYP2C9, CYP2C19 y CYP3A4, con rango terapéutico limitado, dentro de los 7 días de la consulta inicial (de referencia), o en caso de planear iniciarlo durante el estudio.
20. Uso de medicación conocida clínicamente como causante de prolongar el intervalo QT y se metabolice mediante CYP2D6, CYP2C9, CYP2C19, y/o CYP3A4, en los 7 días anteriores a la consulta inicial, o en caso de planear iniciarlo durante el estudio.
21. Empleo de medicación transportada mediante la P-gp con rango terapéutico limitado, dentro de los 7 días desde la consulta inicial o se planee iniciarla durante el estudio.
22. Empleo de un inhibidor de la enzima convertidora de angiotensina dentro de los 7 días siguientes a la consulta inicial, o planear iniciarlo durante el estudio
23. Iniciación de método anticonceptivo hormonal que contenga estrógenos en los 56 días siguientes al screening o planear iniciarlo durante el estudio.
24. Participación actual en cualquier otro estudio de medicamentos en investigación o haber recibido otro medicamento en investigación dentro de los 30 días siguientes a la consulta de screening.
25. Relación familiar inmediata a cualesquiera empleados del Promotor, Investigador o personal del lugar del estudio cuyo nombre conste en la relación de puestos de trabajo del estudio.
26. Hallarse en situación de permanencia en institución por ley o sentencia judicial. |
|
| 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 |
|
| 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 |
Parte 1 - 24 semanas
Parte 2 - 48 semanas |
|
| 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 |
|
| 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 |
Parte 1 - 24 semanas
Parte 2 - 48 semanas |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 | 2 |
| 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 | 2 |
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