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    Summary
    EudraCT Number:2016-000454-36
    Sponsor's Protocol Code Number:VX15-440-101
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-10-26
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-000454-36
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis
    Estudio en fase II, aleatorizado, doble ciego y controlado para evaluar la seguridad y eficacia de VX-440 en politerapia en pacientes de al menos 12 años de edad con fibrosis quística
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis
    Estudio para evaluar la seguridad y eficacia de VX 440 en politerapia en pacientes con fibrosis quística
    A.4.1Sponsor's protocol code numberVX15-440-101
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorVertex Pharmaceuticals Incorporated
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportVertex Pharmaceuticals Incorporated
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVertex Pharmaceuticals Incorporated
    B.5.2Functional name of contact pointClinical Trials and Medical Info
    B.5.3 Address:
    B.5.3.1Street Address50 Northern Avenue
    B.5.3.2Town/ cityBoston, MA
    B.5.3.3Post code02210
    B.5.3.4CountryUnited States
    B.5.4Telephone number-
    B.5.5Fax number001 510 595 8183
    B.5.6E-mailmedicalinfo@vrtx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVX-440
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVX-440
    D.3.9.3Other descriptive nameVX-440
    D.3.9.4EV Substance CodeSUB180062
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1281
    D.3 Description of the IMP
    D.3.1Product nametezacaftor/ivacaftor 100mg/150mg
    D.3.2Product code VX-661/VX-770
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtezacaftor
    D.3.9.2Current sponsor codeVX-661
    D.3.9.3Other descriptive nameVX-661
    D.3.9.4EV Substance CodeSUB33135
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIVACAFTOR
    D.3.9.1CAS number 873054-44-5
    D.3.9.4EV Substance CodeSUB33103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTezacaftor
    D.3.2Product code VX-661
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTezacaftor (TEZ)
    D.3.9.3Other descriptive nameVX-661
    D.3.9.4EV Substance CodeSUB33135
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Kalydeco 150 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderVertex Pharmaceuticals (Europe) Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/008/556
    D.3 Description of the IMP
    D.3.1Product nameIvacaftor
    D.3.2Product code VX-770
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIVACAFTOR
    D.3.9.1CAS number 873054-44-5
    D.3.9.2Current sponsor codeVX-770
    D.3.9.4EV Substance CodeSUB33103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cystic fibrosis
    Fibrosis quística
    E.1.1.1Medical condition in easily understood language
    Cystic fibrosis
    Fibrosis quística
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10011762
    E.1.2Term Cystic fibrosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the safety and tolerability of VX-440 in dual and triple combination with tezacaftor (TEZ) and ivacaftor (IVA)
    • To evaluate the efficacy of VX-440 in dual and triple combination with TEZ and IVA
    - Evaluar la seguridad y tolerabilidad de VX 440 en bi- o triterapia con tezacaftor (TEZ) e ivacaftor (IVA).
    - Evaluar la eficacia de VX-440 en bi- o triterapia con TEZ e IVA.
    E.2.2Secondary objectives of the trial
    • To evaluate the pharmacodynamic (PD) effect of VX-440 in dual and triple combination with TEZ and IVA on sweat chloride concentrations
    • To evaluate the pharmacokinetics (PK) of VX-440 when administered in dual and triple combination with TEZ and IVA
    • To evaluate the PK of TEZ, IVA, and their respective metabolites when administered with VX-440
    • Evaluar el efecto farmacodinámico (FD) de VX-440 en bi- o triterapia con TEZ e IVA en las concentraciones de cloruro en el sudor.
    • Evaluar la farmacocinética (FC) de VX-440 cuando se administra en bi- o triterapia con TEZ e IVA.
    • Evaluar la FC de TEZ, IVA y sus metabolitos correspondientes cuando se administran con VX-440.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject (or subject’s legally appointed and authorized representative) will sign and date an informed consent form (ICF), and, when appropriate, an assent form.
    2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
    3. Subjects will be aged 18 years or older for Parts 1 and 2, and aged 12 years or older for Part 4, on the date of informed consent and, when appropriate, date of assent.
    4. Body weight ≥35 kg.
    5. Sweat chloride value ≥60 mmol/L from test results obtained during screening. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s medical record may be used to establish eligibility. (It is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator).
    6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before randomization (Parts 1 and 4) or before Day -28 (Part 2), a previous CFTR genotype laboratory report may be used to establish eligibility. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.5).
    -Part 1 and Part 4: Heterozygous for F508del with a second CFTR allele carrying an MF mutation that is not likely to respond to TEZ and/or IVA therapy (Appendix A)
    -Part 2: Homozygous for F508del
    7. Parts 1, 2, and 4 subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height (equations of the Global Lung Function Initiative [GLI]) at the Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria for acceptability and repeatability.
    8. Stable CF disease as judged by the investigator.
    9. Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow-up Visit.
    1. El paciente (o su representante legal autorizado) firmará y fechará un formulario de consentimiento informado (FCI) y, cuando proceda, un formulario de asentimiento.
    2. El paciente debe estar dispuesto a, y ser capaz de cumplir con, las visitas programadas, el plan de tratamiento, las restricciones del estudio, los análisis clínicos, las directrices sobre anticonceptivos y otros procedimientos del estudio.
    3. Los pacientes tendrán al menos 18 años de edad para las partes 1, y 2, y al menos 12 años para la parte 4, en la fecha del consentimiento informado y, cuando proceda, del asentimiento.
    4. Peso corporal ≥ 35 kg.
    5. Cloruro en sudor ≥ 60 mmol/l en los resultados de los análisis efectuados durante selección. Si el valor no puede determinarse a partir del análisis de selección, para establecer la idoneidad puede usarse un valor de cloruro en sudor recogido en la historia clínica del paciente. (Es aceptable usar un valor de cloruro en sudor obtenido antes del tratamiento anterior con IVA, LUM/IVA o un modulador del CFTR en investigación).
    6. Los pacientes deben tener un genotipo de CFTR idóneo, según se indica a continuación. Si el resultado del genotipo de CFTR de selección no se recibe antes de la aleatorización (partes 1 y 4) o antes del día -28 (parte 2), para establecer la idoneidad puede usarse un informe de un análisis anterior del genotipo de CFTR. Nota: los pacientes a los que se haya aleatorizado y cuyo genotipo de selección no confirme la idoneidad para el estudio debe retirarse de él (sección 9..5).
    7. Los pacientes de las partes 1, 2 y 4 deben tener un VEMS ≥ 40 % y ≤ 90 % del valor normal previsto para edad, sexo y estatura (ecuaciones de la Global Lung Function Initiative [GLI]) en visita de selección. Las espirometrías deben cumplir los criterios de la American Thoracic Society/European Respiratory Society de idoneidad y repetibilidad.
    8. FQ estable, a criterio del investigador
    9. Dispuesto a mantenerse con una pauta farmacológica estable para la FQ hasta el final de tratamiento programado o, si procede, la visita de seguimiento de seguridad.
    E.4Principal exclusion criteria
    1. History of any comorbidity that might confound the results of the study or pose an additional risk in administering study drug to the subject.
    2. History of cirrhosis with portal hypertension.
    3. Risk factors for Torsade de Pointes, including but not limited to, history of any of the following: familial long QT syndrome, chronic hypokalemia, heart failure, left ventricular hypertrophy, chronic bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia , obesity, acute neurologic events (subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or autonomic neuropathy.
    4. History of hemolysis.
    5. G6PD deficiency, defined as G6PD activity less than the lower limit of normal (LLN) or 70% of the mean of the LLN and the ULN.
    6. Any of the following abnormal laboratory values at screening:
    -Hemoglobin <10 g/dL
    -Total bilirubin ≥2 × ULN
    -Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), or alkaline phosphatase (ALP) ≥3 × ULN
    -Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 for subjects ≥18 years of age and ≤45 mL/min/1.73 m2 for subjects aged 12 to 17 years
    7. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before the first dose of study drug (Day 1 for Parts 1 and 4, Day -28 for Part 2).
    8. Lung infection with organisms associated with a more rapid decline in pulmonary status. For subjects who have had a history of a positive culture in the past, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms:
    -The subject has had 2 respiratory tract cultures negative for these organisms within the past 12 months, with no subsequent positive cultures.
    -These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was obtained within the past 6 months.
    9. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug (Day 1 for Parts 1 and 4, Day -28 for Part 2).
    10. A standard digital ECG demonstrating QTc >450 msec at screening.
    11. History of solid organ or hematological transplantation.
    12. History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period.
    13. History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
    14. Ongoing or prior participation in an investigational drug study with the exception of the following:
    -Ongoing or prior participation in an investigational study of TEZ/IVA, IVA, LUM/IVA, or other CFTR modulator. For Parts 1 and 4, a washout period of 28 days must elapse before Day 1. Subjects participating in Study 661-110 may have the Part 1 or Part 4 Screening Period extended by 4 weeks (Section 8.1.1.3). For Part 2, a washout period before Day -28 is not required, and subjects participating in Study 661-110 will transition directly from their prior treatment to the TEZ/IVA Run-in Period providing that they meet eligibility criteria. For all parts, subjects participating in Study 661-110 may have their screening assessments performed while continuing to participate in Study 661-110.
    -For prospective subjects with ongoing or prior participation in all other interventional studies, a washout period of 28 days or 5 terminal half-lives, whichever is longer, must elapse before screening. The duration of the elapsed time may be longer if required by local regulations.
    -Ongoing participation in a noninterventional study (including observational studies and studies requiring assessments without administration of study drug or assignment to other interventions) is permitted.
    15. Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days before screening (Parts 1 and 4 only).
    16. Use of restricted medications as defined in Table 9-1, within the specified window before the first dose of study drug (Day 1 in Parts 1 and 4, Day -28 in Part 2).
    17. Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.
    18. The subject or a close relative of the subject is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study. An adult who is a relative of a study staff member may be randomized in the study provided that
    -the adult lives independently of and does not reside with the study staff member, and
    -the adult participates in the study at a site other than the site at which the family member is employed.
    1.Antecedentes enfermedad asociada que podría confundir resultados del estudio o suponer riesgo adicional al administrar el fármaco del estudio
    2.Antecedentes de cirrosis con hipertensión portal
    3.Factores riesgo torsade de pointes, como antecedentes síndrome de QT largo familiar, hipopotasiemia crónica, insuficiencia cardíaca, hipertrofia ventricular izqda, bradicardia crónica, infarto de miocardio, miocardiopatía, arritmia, obesidad, episodios neurológicos agudos o neuropatía autónoma
    4.Antecedentes de hemólisis
    5.Deficiencia de G6PD, definida como actividad de G6PD inferior al LIN o del 70 % d media del LIN y del LSN, el mayor
    6.Alguna de siguientes anomalías en selección:
    -Hemoglobina < 10 g/dl
    -Bilirrubina total ≥ 2 veces LSN
    -AST, ALT, GGT o FA ≥ 3 veces LSN
    -Función renal anómala, definida como filtración glomerular ≤ 50 ml/min/1,73 m2 (según ecuación Modification of Diet in Renal Disease Study Equation) para pacientes ≥ 18 años de edad y ≤ 45 ml/min/1,73 m2 (según ecuación de Counahan-Barratt) para pacientes de entre 12 y 17 años (incl)
    7.Infección aguda vías respiratorias altas o bajas, reagudización pulmonar o cambios en tto, inclu antibióticos, por neumopatía en 28 días antes a primera dosis fármaco del estudio (D1 partes 1 y 4, D-28 parte 2)
    8.Infección pulmonar por microorganismo asociado a deterioro más rápido del estado pulmonar (p. ej., Burkholderia cenocepacia, Burkholderia dolosa y Mycobacterium abscessus). En ptes con antecedentes de cultivo positivo en pasado, el investigador aplicará criterios siguientes para establecer q no presentan infección por esos microorganismos:
    -El Pte ha tenido 2 resultados negativos en cultivos de vías respiratorias para esos microorganismos en últimos 12 meses, sin cultivos positivos posteriores
    -Estos 2 cultivos se obtuvieron con intervalo de al menos 3 meses, 1 se obtuvo en últimos 6 meses
    9.Enfermedad aguda no relacionada con FQ (p. ej., gastroenteritis) en 14 días antes a administración de primera dosis del fármaco del estudio (D1 partes 1 y 4, D-28 parte 2)
    10.ECG digital estándar que demuestra QTc > 450 ms en selección. Si QTc > de 450 ms en ECG de selección, repetir en 2 ocasiones más durante selección, y se excluirá al pte si el promedio de los 3 valores del QTc es > 450 ms
    11.Antecedentes de trasplante de órgano sólido o hematológico
    12.Antecedentes o indicios de cataratas u opacidad del cristalino consideradas clínicamente significativas por oftalmólogo u optometrista basándose en exploración oftalmológica durante selección. Si documentada exploración que cumpla criterios del protocolo en 3 meses antes a fecha del consentimiento informado (o asentimiento), no es necesario repetir exploración oftalmológica durante selección. Este criterio no se aplica si documentada extracción bilateral de cataratas. La exploración oftalmológica no necesaria en estos ptes en selección
    13.Antecedentes de alcoholismo o toxicomanía en último año, inclu cannabis, cocaína y opiáceos, según investigador
    14.Participación anterior o en curso en estudio de fármaco en investigación, excepto:
    -Estudios TEZ/IVA, IVA, LUM/IVA u otro modulador del CFTR. En partes 1 y 4, requiere período de lavado de 28 días antes de D1. El período de selección puede ampliarse en 4 semanas en ptes que participan en parte 1 4 del estudio -661-110 (sección 8.1.1.3). En parte 2 no necesario período de lavado y los ptes que participen en estudio -661- 110 pasarán directamente de su tto anterior al período de preinclusión con TEZ/IVA, siempre que cumplan criterios de idoneidad. En todas las partes, los ptes que participen en el estudio -661-110 pueden realizar sus evaluaciones de selección mientras siguen participando en el estudio -661-110
    - los posibles ptes que hayan participado o estén participando en todos los demás estudios de intervención, antes de selección requieren período de lavado de 28 días o 5 semividas terminales, el más largo. La duración puede ser mayor si lo exige la normativa local
    - Se permite participación en curso en estudio no intervencionista (inclu estudios observación y los que requieran evaluaciones sin administración de fármaco del estudio ni asignación a otras intervenciones)
    15.Uso modulador del CFTR comercializado (ej., Kalydeco u Orkambi) en 14 días antes a selección (solo partes 1 y 4)
    16.Uso medicamentos restringidos según Tabla 9-1, en margen de tiempo especificado antes de primera dosis del fármaco del estudio (D1 partes 1 y 4, D-28 parte 2).
    17.Mujeres embarazadas o en lactancia: mujeres fértiles requieren resultado negativo en prueba de embarazo en selección y D1.
    18.Paciente o familiar cercano es investigador o invest asociado, ayudante investigación, farmacéutico, coordinador del estudio u otro personal que participa directamente en realización del mismo. Puede aleatorizarse a un adulto (al menos 18 años) familiar del personal, si vive independientemente, no reside con él, y participa en un centro distinto del que trabaja su familiar
    E.5 End points
    E.5.1Primary end point(s)
    • Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry
    • Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
    • Evaluaciones de seguridad y tolerabilidad basadas en los acontecimientos adversos (AA), valores de los análisis clínicos, electrocardiogramas estándar de 12 derivaciones (ECG), constantes vitales y pulsioximetría.
    • Variación absoluta del volumen espiratorio máximo en el primer segundo porcentual previsto (VEMSpp) con respecto al valor inicial hasta el día 29 (partes 1 y 2) y hasta la semana 12 (parte 4).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
    Hasta el día 29 (partes 1 y 2) y hasta la semana 12 (parte 4).
    E.5.2Secondary end point(s)
    1. Absolute change in sweat chloride concentrations from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
    2. Relative change in ppFEV1 from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
    3. Number of pulmonary exacerbations through Week 12 (Part 4)
    4. Time-to-first pulmonary exacerbation through Week 12 (Part 4)
    5. Absolute change in body mass index (BMI) from baseline at Week 12 (Part 4)
    6. Absolute change in BMI z-score from baseline at Week 12 (Part 4)
    7. Absolute change in weight from baseline at Week 12 (Part 4)
    8. Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
    9. PK parameters of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA
    1. Variación absoluta de las concentraciones de cloruro en el sudor con respecto al valor inicial hasta el día 29 (partes 1 y 2) y hasta la semana 12 (parte 4).
    2. Variación relativa del VEMSpp con respecto al valor inicial hasta el día 29 (partes 1 y 2) y hasta la semana 12 (parte 4).
    3. Número de reagudizaciones pulmonares hasta la semana 12 (parte 4).
    4. Tiempo transcurrido hasta la primera reagudización pulmonar hasta la semana 12 (parte 4).
    5. Variación absoluta del índice de masa corporal (IMC) con respecto al valor inicial en la semana 12 (parte 4).
    6. Variación absoluta de la puntuación z del IMC con respecto al valor inicial en la semana 12 (parte 4).
    7. Variación absoluta del peso con respecto al valor inicial en la semana 12 (parte 4).
    8. Variación absoluta de la puntuación del dominio respiratorio del cuestionario de fibrosis quística revisado (Cystic Fibrosis Questionnaire-Revised, CFQ-R) con respecto al valor inicial en el día 29 (partes 1 y 2) y en la semana 12 (parte 4).
    9. Parámetros farmacocinéticos de VX-440, TEZ, M1-TEZ, IVA y M1 IVA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
    2. through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
    3. through Week 12 (Part 4)
    4. through Week 12 (Part 4)
    5.Week 12 (Part 4)
    6. Week 12 (Part 4)
    7. Week 12 (Part 4)
    8. at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
    9. Day 1, 8, 15, 29, 43 and ETT vist (part 1 Cohort A); Day 1, 15, 29, 43 , ETT visit (Part 1 Cohort B); Day1, 15, 29, 43, ETT vist (Part 2); Day 1, 15, Week 4, Week 8, Week 12, ETT visit (part 4)
    1. Hasta el día 29 (partes 1 y 2) y hasta la semana 12 (parte 4).
    2. Hasta el día 29 (partes 1 y 2) y hasta la semana 12 (parte 4).
    3. Hasta semana 12 (parte 4).
    4. Hasta semana 12 (parte 4).
    5. Semana 12 (parte 4).
    6. Semana 12 (parte 4).
    7. Semana 12 (parte 4).
    8. Dia 29 ( partes 1 y 2) y semana 12 ( parte 4).
    9. Día 1, 8, 15, 29, 43 y EoT Visit ( parte 1 Cohorte A); Día 1, 15, 29, 43, EoT visit ( parte 1 Cohorte B); Día 1, 15, 29, 43, EoT visit ( parte 2); Día 1, 15, Semana 4, Semana 8, Semana 12, EoT visit ( parte 4).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    Tolerabilidad.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Denmark
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial 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
    LVLS
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days20
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days20
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 168
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    children 12-17 years old
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 198
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguno.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-01-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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