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    Summary
    EudraCT Number:2016-000454-36
    Sponsor's Protocol Code Number:VX15-440-101
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-02-27
    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 ConcernedItaly - Italian Medicines Agency
    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
    Studio di Fase 2, randomizzato, in doppio cieco,
    controllato per valutare la sicurezza e l’efficacia di VX-440 in terapia combinata in soggetti di 12 o più anni di età affetti da fibrosi cistica
    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
    Studio di valutazione della sicurezza e dell’efficacia di VX-440 in terapia combinata in soggetti affetti da fibrosi cistica
    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 number001 877 634 8789
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVX-440
    D.3.9.2Current sponsor code
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtezacaftor
    D.3.9.1CAS number 1152311-62-0
    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.3.9.2Current sponsor codeVX-770
    D.3.9.3Other descriptive nameIVACAFTOR
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTezacaftor (TEZ)
    D.3.9.1CAS number 1152311-62-0
    D.3.9.2Current sponsor code
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 IMP
    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.3.9.3Other descriptive nameIVACAFTOR
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cystic fibrosis
    Fibrosi Cistica
    E.1.1.1Medical condition in easily understood language
    Cystic fibrosis
    Fibrosi Cistica
    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 20.0
    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
    • Valutare la sicurezza e la tollerabilità di VX-440 in doppia e tripla combinazione con tezacaftor (TEZ) e ivacaftor (IVA)
    • Valutare l’efficacia di VX-440 in doppia e tripla combinazione 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
    • Valutare l’effetto farmacodinamico (PD) di VX-440 in doppia e tripla combinazione con TEZ e IVA sulle concentrazioni di cloruro nel sudore
    • Valutare la farmacocinetica (PK) di VX-440 somministrato in combinazione doppia e tripla con TEZ e IVA
    • Valutare la PK di TEZ, IVA e dei rispettivi metaboliti se somministrati 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. Il soggetto (o il rappresentante legalmente nominato e autorizzato del soggetto) dovrà firmare e datare un modulo di consenso informato (ICF) e, ove appropriato, un modulo di assenso.
    2. Disponibilità e capacità di rispettare le visite programmate, il piano di trattamento, le restrizioni previste dallo studio, sottoporsi agli esami di laboratorio, attenersi alle linee guida relative alle misure contraccettive e alle altre procedure dello studio.
    3. I soggetti dovranno avere un’età minima di 18 anni per le Parti 1 e 2 e un’età minima di 12 anni per la Parte 4 alla data della firma del consenso informato e, ove appropriato, alla data della firma dell’assenso.
    4. Peso corporeo ≥ 35 kg.
    5. Valore del cloruro nel sudore ≥ 60 mmol/l dai risultati del test ottenuti durante lo screening. Se non è possibile determinare il valore dal test di screening, per stabilire se il soggetto sia idoneo si potrà utilizzare un valore di cloruro nel sudore documentato nella cartella clinica del soggetto. (È accettabile utilizzare un valore del cloruro nel sudore ottenuto prima di un trattamento precedente con IVA, LUM/IVA o un modulatore di CFTR sperimentale).
    6. I soggetti devono avere un genotipo di CFTR idoneo come indicato più oltre. Se non si riceve il risultato del genotipo di CFTR allo screening prima della randomizzazione (Parti 1 e 4) o prima del Giorno -28 (Parte 2), è possibile utilizzare un referto di laboratorio del genotipo di CFTR precedente per stabilire l’idoneità. Nota: i soggetti randomizzati il cui genotipo rilevato allo screening non conferma l’idoneità a partecipare allo studio devono essere ritirati (sezione 9.5).
    - Parte 1 e Parte 4: eterozigote per F508del con un secondo allele di CFTR con mutazione MF che probabilmente non risponderà a terapia con TEZ e/o IVA (appendice A)
    - Parte 2: omozigote per F508del
    7. Il valore del FEV1 dei soggetti della Parte 1, 2 e 4 deve essere compreso fra ≥ 40% e ≤ 90% del valore normale previsto per età, sesso e altezza (equazioni della Global Lung Function Initiative [GLI]) 13 alla visita di screening. Le misurazioni spirometriche devono soddisfare i criteri della American Thoracic Society/European Respiratory Society in termini di accettabilità e ripetibilità.
    8. CF stabile secondo il giudizio dello sperimentatore.
    9. Disponibilità a osservare un regime farmacologico per la CF stabile fino al termine previsto del trattamento o, se applicabile, fino alla visita di follow up di sicurezza.
    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:
    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 halflives,
    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.Anamnesi di qualsiasi comorbilità che potrebbe confondere i risultati dello studio o esporre il soggetto ad un rischio aggiuntivo durante la somministrazione del farmaco in studio.
    2.Anamnesi di cirrosi con ipertensione portale.
    3.Fattori di rischio per torsade de pointes,inclusa, per esempio,anamnesi di una delle patologie seguenti:sindrome familiare del QT lungo, ipocaliemia cronica, insufficienza cardiaca, ipertrofia ventricolare sinistra, bradicardia cronica, infarto del miocardio, cardiomiopatia, anamnesi di aritmia,obesità,eventi neurologici acuti o neuropatia autonomica.
    4.Anamnesi di emolisi.
    5.Carenza di G6PD, secondo la definizione di attività di G6PD inferiore al limite più basso dell’intervallo normale (LLN) o 70% della media di LLN e ULN, a seconda di quale è maggiore.
    6.Uno qualsiasi dei seguenti valori di laboratorio anomali allo screening:
    •Emoglobina < 10 g/dl
    •Bilirubina totale ≥2 × ULN
    •Aspartato aminotransferasi,alanina aminotransferasi, gamma glutamil transpeptidasi o fosfatasi alcalina≥3 × ULN
    •Funzione renale anomala intesa come velocità di filtrazione glomerulare ≤50 ml/min/1,73 m2 per i soggetti di età ≥18 anni e ≤45 ml/min/1,73 m2 per i soggetti di età compresa fra 12 e 17 anni
    7.Un’infezione acuta delle vie respiratorie superiori o inferiori, esacerbazione polmonare o variazioni della terapia (inclusi antibiotici) per malattia polmonare nei 28 giorni antecedenti la prima dose del farmaco in studio (Giorno 1 per Parti 1 e 4, Giorno -28 per Parte 2).
    8.Infezione polmonare a causa di organismi associati con un deterioramento più rapido dello stato polmonare.Per i soggetti con anamnesi di coltura positiva in passato,lo sperimentatore applicherà i criteri seguenti per stabilire se il soggetto ha superato l’infezione da questi organismi:
    •Negli ultimi 12 mesi il soggetto ha ottenuto 2 colture del tratto respiratorio negative in relazione a questi organismi, e nessuna coltura positiva successiva.
    •Queste 2 colture del tratto respiratorio sono avvenute a una distanza di almeno 3 mesi e una di esse è stata effettuata negli ultimi 6 mesi.
    9.Una malattia acuta non correlata alla CF (es. gastroenterite) nei 14 giorni precedenti la prima dose del farmaco in studio(Giorno 1 per Parti 1 e 4, Giorno-28 per parte 2).
    10.ECG digitale standard dimostrativo di QTc>450 msec allo screening.
    11.Anamnesi di trapianto ematologico o d’organi solidi.
    12.Anamnesi o evidenza di cataratta o opacità del cristallino ritenuta clinicamente significativa dall’oftalmologo o dall’optometrista in base a esame oftalmico durante il periodo di screening. 13.Anamnesi di abuso di alcol o droghe nello scorso anno, inclusi, a titolo non esaustivo, cannabis, cocaina e oppiacei, secondo opinione dello sperimentatore.
    14.Partecipazione ancora in corso o precedente a uno studio su un farmaco sperimentale, fatta eccezione per:
    •Partecipazione in corso o precedente a una sperimentazione su TEZ/IVA, IVA, LUM/IVA o un altro modulatore CFTR. Per le Parti 1 e 4, prima del Giorno 1 deve trascorrere un periodo di washout di 28 giorni. Per i soggetti che partecipano allo studio 661-110 è possibile estendere il periodo di screening della Parte 1 o 4 di 4 settimane. Per la Parte 2 non è richiesto un periodo di washout prima del Giorno-28,e i soggetti che partecipano allo studio 661-110 passeranno direttamente dal loro trattamento precedente al periodo di run-in TEZ/IVA, a condizione che soddisfino i criteri di idoneità. Per tutte le parti, i soggetti che partecipano allo studio 661-110 possono essere sottoposti alle valutazioni di screening mentre continuano a partecipare allo studio 661-110
    •Per i soggetti potenziali che stanno partecipando o hanno partecipato a tutti gli altri studi interventistici,prima dello screening deve trascorrere un periodo di washout di 28 giorni o 5 emivite terminali,a seconda di quale periodo è più lungo.
    •È consentito continuare a partecipare a uno studio non interventistico (inclusi studi osservazionali e studi che richiedono valutazioni senza somministrazione del farmaco in studio o assegnazione ad altri interventi)
    15.Utilizzo di un modulatore di CFTR disponibile in commercio nei 14 giorni precedenti lo screening (Parti 1 e 4 solo).
    16.Utilizzo di farmaci limitati secondo la definizione riportata in Tab.9-1, entro la finestra specificata prima della prima dose del farmaco in studio (Giorno 1 nelle Parti 1 e 4, Giorno-28 nella Parte 2)
    17.Donne in gravidanza o in allattamento:i soggetti di sesso femminile in età fertile devono risultare negativi al test di gravidanza allo screening e al Giorno 1.
    18.Il soggetto o un parente stretto del soggetto è lo sperimentatore o uno sperimentatore secondario o altro personale direttamente coinvolto nella conduzione dello studio. Un adulto imparentato con un membro del personale dello studio può essere randomizzato nello studio a condizione che
    •l’adulto abbia condizione abitativa indipendente
    •l’adulto partecipi allo studio presso un centro diverso
    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)
    • Valutazioni di sicurezza e tollerabilità basate su eventi avversi (AE), valori di test clinici di laboratori, elettrocardiogrammi (ECG) a 12 derivazioni standard, parametri vitali e pulsossimetria
    • Variazione assoluta del volume espiratorio forzato in 1 secondo espresso come percentuale del valore teorico (ppFEV1) dal basale fino al Giorno 29 (Parti 1 e 2) e fino alla Settimana 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)
    Fino al giorno 29 (Parti 1 e 2) e fino alla settimana 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 and2) 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. Variazione assoluta delle concentrazioni di cloruro nel sudore dal basale fino al Giorno 29 (Parti 1 e 2) e fino alla Settimana 12 (Parte 4)

    2. Variazione relativa del ppFEV1 dal basale fino al Giorno 29 (Parti 1 e 2) e fino alla Settimana 12 (Parte 4)

    3. Numero di esacerbazioni polmonari fino alla Settimana 12 (Parte 4)

    4. Tempo fino alla prima esacerbazione polmonare fino alla Settimana 12 (Parte 4)

    5. Variazione assoluta dell’indice di massa corporea (BMI) dal basale alla Settimana 12 (Parte 4)

    6. Variazione assoluta del punteggio z dell’indice di massa corporea (BMI) dal basale alla Settimana 12 (Parte 4)

    7. Variazione assoluta del peso corporeo dal basale alla Settimana 12 (Parte 4)

    8. Variazione assoluta del punteggio del dominio respiratorio del questionario sulla fibrosi cistica revisionato (CFQ-R) dal basale al Giorno 29 (Parti 1 e 2) e alla Settimana 12 (Parte 4)

    9. Parametri PK di VX-440, TEZ, M1-TEZ, IVA, e M1-IVA
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Fino al giorno 29 (Parti 1 e 2) e fino alla settimana 12 (Parte 4)

    2. Fino al giorno 29 (Parti 1 e 2) and fino alla settimana 12 (Parte 4)

    3. Fino alla settimana 12 (Parte 4)

    4. Fino alla settimana 12 (Parte 4)

    5. Settimana 12 (Parte 4)

    6. Settimana 12 (Parte 4)

    7. Settimana 12 (Parte 4)

    8. Al giorno 29 (Parti 1 e 2) e alla settimana 12 (Parte 4)

    9. Giorni 1, 8, 15, 29, 43, visita ETT (Parte 1 Coorte A); Giorni 1, 15, 29, 43 , visita ETT (Parte 1 Coortet B); Giorni 1, 15, 29, 43, visita ETT (Parte 2); Giorni 1, 15, Settimana 4, settimana 8, settimana 12, Visita ETT (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
    Tollerabilità
    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 Information not present in EudraCT
    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
    LVLS
    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: 1
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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
    bambini/adolescenti di 12-17 anni
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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
    Nessuno
    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 Decision2017-01-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-11
    P. End of Trial
    P.End of Trial StatusCompleted
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