E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cystic Fibrosis |
Fibrosis Quística |
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E.1.1.1 | Medical condition in easily understood language |
Cystic Fibrosis |
Fibrosis Quística |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
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 VX-661 in combination with ivacaftor through Week 12 in subjects with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy (F508del/not responsive [NR]) |
Evaluar la eficacia de VX-661 en combinación con ivacaftor hasta la semana 12 en sujetos con fibrosis quística (FQ) heterocigóticos para la mutación F508del en el gen regulador de la conductancia transmembrana de la FQ (CF transmembrane conductance regulator, CFTR) y en un segundo alelo con una mutación en el CFTR que no es probable que responda al tratamiento con VX-661 y/o ivacaftor (F508del/no respondedores [NR]). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of VX-661 in combination with ivacaftor and to investigate the pharmacokinetics (PK) of VX-661 and its metabolite M1-661, and ivacaftor and its metabolite M1-ivacaftor |
Evaluar la seguridad de VX-661 en combinación con ivacaftor y Investigar la farmacocinética (FC) de VX-661 y su metabolito M1-661, y de ivacaftor y su metabolito M1-ivacaftor. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Heterozygous for the F508del CFTR mutation and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy, genotype to be confirmed via assessment at the Screening Visit.
Confirmed diagnosis of CF defined as a sweat chloride value ?60 mmol/L by quantitative pilocarpine iontophoresis (as documented in the subject?s medical record OR from sweat chloride test result obtained at the Screening, if subject does not have a sweat chloride test result in the medical record).
FEV1 ?40% and ?90% of predicted normal for age, sex, and height at Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria for acceptability and repeatability.
Stable CF disease as judged by the investigator.
Willing to remain on a stable CF medication regimen through Week 12 or, if applicable, the Safety Follow-up Visit. |
Heterocigóticos para la mutación F508del-CFTR y con una segunda mutación de CFTR que no es probable que responda al tratamiento con VX-661 y/o ivacaftor el genotipo se debe confirmar mediante evaluación en la visita de selección.
Diagnóstico confirmado de FQ, definida como un valor de cloruro en sudor ? 60 mmol/l mediante iontoforesis cuantitativa con pilocarpina (como se documenta en la historia clínica del sujeto O a partir del resultado de la prueba de cloruro en el sudor obtenido durante la investigación si el sujeto no tiene un resultado de la prueba de cloruro en el sudor en la historia clínica).
VEF1 ? 40 % y ? 90 % de valor normal previsto para la edad, el sexo y la estatura durante la selección. Las mediciones de la espirometría deben cumplir los criterios de la Sociedad Torácica Americana/Sociedad Respiratoria Europea de aceptabilidad y repetibilidad.
Enfermedad de la FQ estable, a juzgar por el investigador.
Disponibilidad para permanecer en una pauta estable de medicación para la FQ hasta la semana 12 o, si corresponde, hasta la visita de seguimiento de la seguridad. |
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E.4 | Principal exclusion criteria |
History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at Screening and Day 1. |
Antecedentes de alguna comorbilidad que, en opinión del investigador, podría confundir los resultados del estudio o suponer un riesgo adicional en la administración del fármaco del estudio al sujeto.
Infección aguda del tracto respiratorio superior o inferior, exacerbación pulmonar o cambios en el tratamiento (incluidos los antibióticos) para la enfermedad pulmonar en los 28 días antes del día 1 (primera dosis del fármaco del estudio).
Mujeres embarazadas y lactantes: las mujeres en edad fértil deben presentar un test de embarazo negativo en el momento de la selección y el día 1. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Absolute change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline through Week 12. |
Cambio absoluto desde el inicio en el porcentaje del VEF1 previsto hasta la semana 12. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Relative change in percent predicted FEV1 from baseline through Week 12
Absolute change in sweat chloride from baseline through Week 12
Absolute change in body mass index (BMI) from baseline at Week 12
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline through Week 12
Number of pulmonary exacerbations through Week 12
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values (i.e., hematology, coagulation studies, serum chemistry, vitamin levels, lipid panel, and urinalysis), standard digital electrocardiograms (ECGs), vital signs, and pulse oximetry
Time-to-first pulmonary exacerbation through Week 12
Absolute change in BMI z-score from baseline at Week 12 (in subjects <20 years old at time of screening)
Absolute change in body weight from baseline at Week 12
PK parameters of VX-661, M1-661, ivacaftor, and M1 ivacaftor |
Tiempo hasta la primera exacerbación pulmonar hasta la semana 12.
Cambio absoluto en el cloruro del sudor desde el inicio hasta la semana 12
Cambio absoluto en la puntuación z del IMC desde el inicio en la semana 12
Cambio absoluto en la puntuación de gravedad del diario de síntomas respiratorios de la fibrosis quística (Cystic Fibrosis Respiratory Symptom Diary, CFRSD) desde el inicio hasta la semana 12.
Número de exacerbaciones pulmonares hasta la semana 12.
Evaluaciones de seguridad y tolerabilidad basadas en acontecimientos adversos (AA), valores analíticos clínicos (es decir, hematología, estudios de coagulación, bioquímica sérica, niveles de vitaminas, panel de lípidos y análisis de orina), electrocardiogramas (ECG) digitales estándar, constantes vitales, oximetría de pulso y espirometría.
Tiempo hasta la primera exacerbación pulmonar hasta la semana 12.
Cambio absoluto en la puntuación z del IMC desde el inicio en la semana 12 (en sujetos < 20 años de edad en el momento de la selección).
Cambio absoluto en el peso corporal desde el inicio en la semana 12.
Parámetros FC de VX-661, M1-661, ivacaftor y M1-ivacaftor. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | 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 | 2 |
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 | 19 |
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 |
Australia |
Austria |
Canada |
France |
Germany |
Israel |
Spain |
United States |
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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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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 | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |