E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cystic Fibrosis |
Fibrosis quistica |
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E.1.1.1 | Medical condition in easily understood language |
Cystic Fibrosis |
Fibrosis Quistica |
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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 | 19.0 |
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 effect of GS-5745 on pre-bronchodilator forced expiratory volume in 1 second (FEV1) in subjects with cystic fibrosis (CF) after 8 weeks of treatment |
Evaluar el efecto de GS-5745 sobre el volumen espiratorio máximo en el primer segundo (VEMS) prebroncodilatación en pacientes con fibrosis quística (FQ) tras 8 semanas de tratamiento. |
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E.2.2 | Secondary objectives of the trial |
To assess safety, tolerability, and pharmacokinetics (PK) of GS-5745 in subjects with CF To evaluate the effect of GS-5745 on post-bronchodilator forced expiratory volume in 1 second (FEV1) in subjects with CF after 8 weeks of treatment |
Evaluar la seguridad, tolerabilidad y farmacocinética (FC) de GS-5745 en pacientes con FQ. Evaluar el efecto de GS-5745 sobre el volumen espiratorio máximo en el primer segundo (VEMS) posbroncodilatación en pacientes con FQ tras 8 semanas de tratamiento. |
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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 |
There will be a FRI sub-study for both Part 1 and Part 2 which will require 2 FRI scans (at Baseline and at the Week 8 visit). A subset of study sites will be trained in FRI. Those sites will be asked to participate in the FRI sub-study until approximately 30 subjects in Part 1 and 45 subjects in Part 2 have enrolled into the sub-study and completed Week 8.
There will be a sputum cytology sub-study for both Part 1 and Part 2. A subset of select sites will perform sputum cytology slide preparation from induced sputum samples to investigate changes in total cell count and cell count differential in sputum. No additional procedures will be required of subjects participating in the sputum cytology sub-study.
An optional PK sub-study will be performed on a subset of subjects in Part 1 and in Part 2 who provide separate consent. It is anticipated that 30% of subjects will enroll, 20 in Part 1 and 30 in Part 2. In the PK sub-study, 2 additional plasma PK samples will be collected on Day 5 (± 1) and on Day 48 (± 1). |
Habrá un subestudio de FRI tanto en la parte 1 como en la 2, que requerirá 2 FRI (en la visita basal y en la visita de la semana 8). Se impartirá formación sobre la FRI en un subgrupo de centros del estudio.Todos los pacientes del estudio inscritos en dichos centros participarán en el subestudio, hasta que se hayan incluido en este aproximadamente 30 pacientes de la parte 1 y 45 de la parte 2 y estos hayan completado la semana 8. |
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E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study. 1) Male or female 18 years of age or older 2) Confirmed diagnosis of CF as determined by the 2008 Cystic Fibrosis Foundation Consensus Report [Farrell et al., J Pediatr 2998; 153:S4-14] criteria 3) Subjects must be able to perform acceptable and reproducible spirometry as per the American Thoracic Society (ATS) Guidelines 4) Must have a body weight of > 40 kg (88.2 lbs) at study Screening 5) Subjects must be a never-smoker or an ex-smoker with < 5 pack-year history of smoking and be smoke-free (including marijuana or e-cigarettes/vaping) for 12 months prior to Screening 6) Pre-bronchodilator FEV1 >= 40% and =< 80% of predicted at Screening 7) Two pre-bronchodilator spirometry measures taken at least 4 days apart (one during Screening, one at Baseline) using the sponsor provided central spirometry equipment must meet the following 2 criteria: - The relative difference of FEV1(L), calculated as the absolute value of [(first FEV1 ? second FEV1) / first FEV1 ] x 100 should be < 12% AND - The absolute difference in FEV1 should be < 200 ml 8) Negative Investigation/History of Important Bacteria Inclusions: Tuberculosis (TB): - A negative QuantiFERON-TB Gold test during Screening Non-Tuberculous Mycobacteria species (NTM): - All sputum cultures for ANY Mycobacterium spp. performed 24 months prior to Screening must be negative. If only 1 NTM culture was performed 24 months prior to Screening, that NTM culture and the most recent NTM culture obtained >24 months prior to Visit 1 must both be negative AND - A negative sputum culture < 12 months prior to Screening for any Mycobacterium spp. AND - No current treatment for active NTM during Screening Burkholderia spp. - All sputum/throat cultures for ANY Burkholderia spp. performed 24 months prior to Screening must be negative. If only 1 Burkholderia culture was performed 24 months prior to Screening, that Burkholderia spp. culture and the most recent Burkholderia spp. culture obtained >24 months prior to Screening were both negative AND - A negative culture for Burkholderia spp. during Screening AND - No current treatment for Burkholderia spp. during Screening 9) Clinically stable with no evidence of significant respiratory symptoms that would require administration of (IV) antibiotics, oxygen supplementation, or hospitalization within 30 days of Baseline. 10) A chest radiograph, computed tomography (CT) or magnetic resonance imaging (MRI) within 90 days of Baseline, interpreted as showing no acute findings such as infiltrates [lobar or diffuse interstitial], pleural effusion, or pneumothorax, and no significant intercurrent illness; chronic, stable findings (eg chronic scarring or atelectasis) are allowed. If not available then a chest radiograph at Screening will be obtained and should be interpreted as above. 11) On stable CF chronic medical regimen for at least 30 days prior to Baseline and expected to remain stable through the completion of the study. This includes but is not limited to: chronic azithromycin use, inhaled bronchodilators, inhaled corticosteroids, inhaled dornase alpha, inhaled hypertonic saline, inhaled mannitol, ivacaftor, and/or ivacaftor/lumacaftor. - Inhaled antibiotics (ie, tobramycin, aztreonam, colistin) should be stable for 2 on-treatment cycles to be considered a stable CF medication (ie, approximately 2 months if they are taken as continuous inhaled antibiotics or about 4 months if they are taken as an alternating inhaled antibiotic). 12) A negative serum pregnancy test is required for women of childbearing potential 13) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception 14) Lactating females must agree to discontinue nursing before administration of study drug and during the course of the study 15) Male subjects must agree to refrain from sperm donation for 90 days after the last dose of study drug is administered |
Los pacientes deben cumplir todos los criterios de inclusion para ser incluidos en este estudio: 1.Ambos sexos, de 18 años en adelante. 2.Diagnostico confirmado de Fibrosis Quistica según: 2008 Cystic Fibrosis Foundation Consensus Report [Farrell et al., J Pediatr 2998; 153:S4-14] criteria. 3.Pacientes con capacidad de realizar una espirometría reproducible y aceptable, de acuerdo con las directrices de la Sociedad Americana del Tórax (American Thoracic Society, ATS). 4.Peso corporal >40 kg en la selección del estudio. 5.Pacientes que nunca hayan fumado o pacientes exfumadores con menos de 5 años como fumadores y no haber fumado (incluyendo marihuana o cigarrillos electronicos)los ultimos 12 meses antes del la seleccion. 6.VEMS prebroncodilatación >=40 % y =<80 % del valor predicho en la selección. 7.Los valores de 2 espirometrías prebroncodilatación realizadas con un mínimo de 4 días de diferencia (una durante la selección, otra en la visita basal) con el equipo de espirometría central suministrado por el promotor deben cumplir los 2 criterios siguientes: -La diferencia relativa en el VEMS (l), calculado como el valor absoluto de [(primer VEMS 1 segundo VEMS)/primer VEMS] x 100 debe ser <12 % Y -La diferencia absoluta en el VEMS debe ser <200 ml. 8.Negativo en detección/antecedentes de infecciones bacterianas importantes: Tuberculosis (TB): -Resultado negativo en la prueba QuantiFERON-TB Gold durante la selección. Especies de micobacterias no tuberculosas (MNT): -Todos los cultivos de esputo para la detección de CUALQUIER Mycobacterium spp. realizados en los 24 meses previos a la selección deben ser negativos. Si solo se hizo 1 cultivo para la detección de MNT en los 24 meses previos a la selección, dicho cultivo y el más reciente obtenido más de 24 meses antes de la selección deben ser negativos. -Cultivo de esputo negativo en el período =<12 meses antes de la selección para cualquier Mycobacterium spp. Y -Sin tratamiento en curso para infección activa por MNT durante la selección. 9.Estabilidad clínica, sin síntomas respiratorios significativos que precisen la administración i.v. de antibióticos, el aporte suplementario de oxígeno o la hospitalización, en los 30 días previos a la visita basal. 10.Radiografía, tomografía axial computerizada (TAC) o resonancia magnética (RM) del tórax en los 90 días previos a la visita basal, en la que no se observen signos graves como infiltrados (lobulares o intersticiales difusos), derrame pleural o neumotórax; tampoco enfermedades intercurrentes significativas; se permiten signos irreversibles estables (p. ej., fibrosis crónica o atelectasia). Si no se dispone de esta, se obtendrá una radiografía de tórax en la selección que se debe interpretar conforme a los criterios anteriores. 11.En tratamiento médico prolongado y estable para la FQ durante un mínimo de 30 días antes de la visita basal y con expectativas de que se mantenga estable hasta la finalización del estudio. Dicho tratamiento puede comprender, entre otros: broncodilatadores, corticoesteroides, dornasa alfa, solución salina hipertónica, manitol, ivacaftor y/o ivacaftor/lumacaftor, todos ellos por vía inhalatoria, o el uso prolongado de azitromicina. -A fin de considerarse un medicamento estable para la FQ, los antibióticos inhalados (tobramicina, aztreonam, colistina) deben ser estables durante 2 ciclos de tratamiento (es decir, aproximadamente 2 meses si se toman como antibióticos inhalados continuos, o aproximadamente 4 meses si se toman como antibióticos inhalados alternos). 12. test negativo de embarazo en mujeres potencialmente fertiles. 13.Hombres y mujeres fértiles que mantengan relaciones heterosexuales deben estar de acuerdo con los metodos anticonceptivos descritos en el protocolo. 14. Mujeres lactantes deberina discontinuar la lactancia antes de la administracion del farmaco y durante el estudio. 15.Pacientes masculinos deberan estar de acuerdo con abstenerse a la donacion de esperma durante los 90 dias despues de la ultima dosis del farmaco del estudio. |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 1) Concurrent use of oral antibiotics (excluding chronic azithromycin use) or IV antibiotics within 30 days of Baseline 2) Hospitalization for a respiratory event within 30 days of Baseline 3) Active allergic bronchopulmonary aspergillosis (ABPA) requiring treatment; previous history of ABPA without current ABPA anti-fungal prophylaxis is acceptable 4) Any acute non-CF related illness within 2 weeks prior to Baseline (eg, gastroenteritis) 5) Current use of systemic immunosuppressive drugs including oral corticosteroids within 30 days of Baseline 6) Current requirement for daily continuous oxygen supplementation or requirement (medically necessary) of more than 2 L/minute at night (subject would not meet this exclusion criterion if supplemental oxygen is used for comfort only) 7) History of anaphylaxis requiring the use of epinephrine 8) History of solid organ (including lung) or hematologic transplant, or currently on a transplant waiting list. 9) History of lung resection 10) History of HIV, hepatitis B, or hepatitis C 11) History of malignancy in the last 5 years except for subjects who have been successfully treated for non-melanoma skin cancer or cervical cancer 12) History of alcohol or drug abuse in the past year, including but not limited to cannabis, cocaine, opiates, as determined by the investigator 13) Laboratory parameters at screening: - Abnormal liver function tests defined as > 3 times the upper limit of normal (ULN) of any of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpetidase (GGT) and serum alkaline phosphatase, or total bilirubin - Total Bilirubin > 2 times the ULN - Hemoglobin < 10 g/dL for females and < 11.5 g/dL for males at screening - Serum creatinine > 2 times the ULN 14) Clinically significant abnormal ECG at screening; abnormalities considered not clinically significant, per investigator, are not exclusionary 15) Known hypersensitivity to the investigational medicinal product or formulation excipient 16) Presence of any condition or abnormality that would compromise subject safety or the quality of data, or any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol 17) Receipt of any investigational non-biological drug therapy within 30 days of enrollment OR receipt of any marketed or investigational biologic within 4 months prior to enrollment |
Pacientes que cumplan alguno de los siguientes criterios de exclusion no seran incluidos en el estudio. 1.Uso simultáneo de antibióticos orales (salvo el uso prolongado de azitromicina) o antibióticos i.v. en los 30 días previos a la visita basal. 2.Hospitalización por un episodio respiratorio en los 30 días previos a la visita basal. 3. con Aspergilosis alérgica broncopulmonar (ABAP) que requiera tratamiento; Historia previa de ABPA sin profilaxis ABAP anti-fungica actual es aceptable. 4. Cualquier enfermedad aguda no relaionada con Fibrosis Quistica 2 semanas antes de la visita Basal (ej, gastroenteritis) 5.Uso de inmunosupresores sistémicos, incluidos corticoesteroides orales, en los 30 días previos a la visita basal. 6.Necesidad de aporte suplementario de oxígeno continuo a diario, o necesidad (médica) de más de 2 litros/minuto durante la noche (el paciente no cumpliría este criterio de exclusión si el oxígeno suplementario se utilizase solamente para su bienestar). 7.Antecedentes de anafilaxis con eparina 8.Antecedentes de trasplante de organo solido (incluido de pulmón) o trasplante hematológico, o actualmente en lista de espera para trasplante. 9.Antecedentes de extirpacion de pulmon 10. Antecedentes de VIH, hepatitis B o hepatitis C. 11. Antecedentes de malginidad en los 5 ultimos años excepto pacientes que hayan superado satisfactoriamente cancer de piel, no melanoma o cancer cervical. 12.Antecedente de alcoholismo, consumo de drogas incluynedo, pero no limitado a cáñamo, cocaina, opiaceos,segun determine el investigador. 13) parámetros De laboratorio en selección: - el hígado Anormal funciona pruebas definidas como> 3 veces el límite superior de normal (ULN) de cualquiera de lo siguiente: suero aspartate transaminase (AST), suero alanine transaminase (ALT), gama-glutamyl transpetidase (GGT) y suero phosphatase alcalino, total bilirubina >2 veces el ULN, Hemoglobina <10 g/dL para hembras y <11.5 g/dL para machos en selección - Suero creatinine> 2 veces el ULN 14) ECG Clínicamente significativo anormal en el screening; las anormalidades consideradas no clínicamente significativas, por el investigador, no son excluyentes 15) la hipersensibilidad conocida al producto en investigacion o al excipiente de formulación 16) La presencia de cualquier condición o anormalidad que comprometería la seguridad del paciente o la calidad de datos, o cualquier enfermedad seria o activa médica o psiquiátrica, que en la opinión del investigador, interferiría con el tratamiento, la evaluación, o el cumplimiento con el protocolo. 17) Recibir cualquier terapia de producto en investigacion no biológico 30 días antes de la inscripción o el recibo de cualquier comercializado o producto en investigacion biológico dentro de 4 meses antes de la inscripción. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The absolute change in pre-bronchodilator FEV1 percent predicted from Baseline to Week 8 |
El criterio de valoración principal, el cambio absoluto porcentual predicho en el VEMS prebroncodilatación desde la visita basal hasta la semana 8. |
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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) |
- The safety evaluation will be assessed by AEs, concomitant medications, clinical laboratory tests, vital signs and ADA data. - Primary PK parameters will include Cmax, Tmax, Clast, Tlast, and AUClast (as applicable) - The absolute change in post-bronchodilator FEV1 percent predicted from Baseline to Week 8 - The relative change in pre-bronchodilator FEV1 percent predicted from Baseline to Week 8 - The relative change in post-bronchodilator FEV1 percent predicted from Baseline to Week 8 |
-La seguridad se evaluará por los acontecimientos adversos (AA), medicamentos concomitantes, análisis clínicos, constantes vitales, datos del ECG y datos de AAF. - Parametros PK primarios incluiran Cmax, Clast, T last y AUClast (segun aplique) - Cambio absoluto en el porcentaje de post-broncodilatador FEV1 predicho desde visita basal a la semana 8. -Cambio relativo en el porcentaje predicho en prebroncodilatador desde visita basal a semana 8 -Cambio relativo en el porcentaje predicho en postbroncodilatador FEV1 desde visita basal a la semana 8. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | 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 |
Belgium |
Canada |
France |
Germany |
Ireland |
Spain |
United Kingdom |
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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LVLS |
Ultima visita del ultimo paciente |
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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 | 7 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 10 |