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    Summary
    EudraCT Number:2018-002835-76
    Sponsor's Protocol Code Number:VX18-445-104
    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:2021-02-12
    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 number2018-002835-76
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the
    Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic
    Fibrosis Who Are Heterozygous for the F508del Mutation and a Gating or
    Residual Function Mutation (F/G and F/RF Genotypes)
    Studio controllato in doppio cieco, randomizzato, di fase 3 per la valutazione della
    sicurezza ed efficacia della terapia combinata di VX-445 nei soggetti con fibrosi
    cistica eterozigoti per la mutazione F508del e per la mutazione della funzione residuale
    o di gating (genotipi F/G e F/RF)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study of VX-445 Combination Therapy in Cystic Fibrosis (CF)
    Subjects Heterozygous for F508del and a Gating or Residual Function
    Mutation (F/G and F/RF Genotypes)
    Studio di fase 3 della terapia combinata di VX-445 nei soggetti con fibrosi cistica
    (FC) eterozigoti per F508del e per la mutazione della funzione residuale o di gating
    (genotipi F/G e F/RF)
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberVX18-445-104
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04058353
    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 Avenues
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA 02210-1862
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018776348789
    B.5.5Fax number0015105958183
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2116
    D.3 Description of the IMP
    D.3.1Product name100-mg VX-445 / 50-mg TEZ / 75- mg IVA FDC
    D.3.2Product code [VX-445/TEZ/IVA]
    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 INNelexacaftor
    D.3.9.1CAS number 2216712-66-0
    D.3.9.2Current sponsor codeVX-445
    D.3.9.3Other descriptive nameVX-445
    D.3.9.4EV Substance CodeSUB185183
    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 INNTEZACAFTOR
    D.3.9.1CAS number 1152311-62-0
    D.3.9.2Current sponsor codeVX-661
    D.3.9.3Other descriptive nameTEZ
    D.3.9.4EV Substance CodeSUB188271
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 nameIVA
    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 number75
    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 RoleComparator
    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 Symkevi 100mg/150mg Film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderVertex Pharmaceuticals (Ireland) Limited (MA n. EU/1/18/1306/001)
    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/3/14/1281
    D.3 Description of the IMP
    D.3.1Product nameVX-661 / VX-770
    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.3.9.1CAS number 1152311-62-0
    D.3.9.2Current sponsor codeVX-661
    D.3.9.3Other descriptive nameTEZ
    D.3.9.4EV Substance CodeSUB188271
    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 nameIVA
    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 RoleComparator
    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 (Ireland) Limited (MA n. EU/1/12/782/001-002)
    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/3/08/556
    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 codeIvacaftor
    D.3.9.3Other descriptive nameIVA
    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 placeboFilm-coated tablet
    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 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
    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 efficacy of VX-445/tezacaftor (TEZ)/ivacaftor (IVA) in CF subjects who
    are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF
    genotypes)
    Valutare l’efficacia di VX-445/tezacaftor (TEZ)/ivacaftor (IVA) in soggetti con FC
    eterozigoti per F508del e una mutazione di gating o con funzione residua (genotipi F/G
    e F/RF)
    E.2.2Secondary objectives of the trial
    - To evaluate the safety of VX-445/TEZ/IVA
    - To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA
    • Valutare la sicurezza di VX-445/TEZ/IVA
    • Valutare la farmacodinamica (PD) di VX-445/TEZ/IVA
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject (or his or her 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. Age 12 years or older, at the date of informed consent.
    4. Confirmed diagnosis of CF as determined by the investigator.
    5. Subject is heterozygous for F508del and either a gating or residual function mutation
    (F/G and F/RF genotypes) and is in a region where their genotype and age group are
    approved indications for treatment with IVA and/or TEZ/IVA (see Appendix A for
    qualifying mutations).
    6. Forced expiratory volume in 1 second (FEV1) value >=40% and <=90% of predicted mean for
    age, sex, race, 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.
    7. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at
    screening.
    8. Stable CF disease as judged by the investigator.
    9. Willing to remain on a stable CF treatment regimen through completion of study
    participation.
    1. Il soggetto (o il suo rappresentante legalmente nominato e autorizzato) firmerà e
    daterà un modulo di consenso informato (Informed Consent Form, ICF) e, ove opportuno, un
    modulo di assenso.
    2. Soggetto disposto e in grado di attenersi alle visite programmate, al piano di
    trattamento, alle restrizioni dello studio, agli esami di laboratorio, alle linee guida
    sui contraccettivi e ad altre procedure dello studio.
    3. Almeno 12 anni di età alla data del consenso informato.
    4. Diagnosi confermata di FC formulata dallo sperimentatore.
    5. Il soggetto è eterozigote per F508del e presenta una mutazione di gating o con
    funzione residua (genotipi F/G e F/RF) e si trova in una regione in cui il genotipo e il
    gruppo di età del soggetto sono indicazioni approvate per il trattamento con IVA e/o
    TEZ/IVA (vedere l’Appendice A per le mutazioni idonee).
    6. Valore del volume espiratorio forzato in 1 secondo (FEV1) >= 40% e <=90% della media
    prevista per età, sesso, razza e altezza (equazioni della Global Lung Function
    Initiative [GLI])11 alla visita di screening. Le misurazioni spirometriche devono
    soddisfare i criteri dell’American Thoracic Society/Società respiratoria europea in
    termini di accettabilità e ripetibilità.
    7. I soggetti devono essere in grado di produrre un campione di sudore valido (di
    quantità sufficiente) allo screening.
    8. FC stabile a giudizio dello sperimentatore.
    9. È disposto a restare su un regime di trattamento stabile per la FC fino al termine
    della partecipazione allo studio.
    E.4Principal exclusion criteria
    1. History of any illness or any clinical condition that, in the opinion of the
    investigator, might confound the results of the study or pose an additional risk in
    administering study drug(s) to the subject. This includes, but is not limited to, the
    following
    - Clinically significant cirrhosis with or without portal hypertension.
    - Solid organ or hematological transplantation.
    - Alcohol or drug abuse in the past year, including, but not limited to, cannabis,
    cocaine, and opiates, as deemed by the investigator.
    - Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0
    cervical carcinoma in situ (each being disease-free for the last 5 years).
    2. Any of the following abnormal laboratory values at screening.
    - Hemoglobin <10 g/dL
    - Total bilirubin >=2 × upper limit of normal (ULN)
    - Aspartate transaminase (AST), alanine transaminase (ALT), or gamma-glutamyl
    transferase (GGT) >=3 × ULN
    - Abnormal renal function defined as estimated glomerular filtration rate =50
    mL/min/1.73 m^2 (calculated by the Modification of Diet in Renal
    Disease Study Equation) for subjects >=18 years of age, or <=45 mL/min/1.73 m^2
    (calculated by the Counahan-Barratt equation) for
    subjects 12 to 17 years of age (inclusive)
    3. An acute upper or lower respiratory infection, pulmonary exacerbation (PEx), or
    change in therapy (including antibiotics) for sinopulmonary disease within 28 days
    before the first dose of study drug in the Run-in Period (Day -28).
    4. Lung infection with a microbial pathogen that is associated with a more rapid decline
    in pulmonary status (including, but not limited to, Burkholderia cenocepacia,
    Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history
    of a positive culture, the investigator will apply the following criteria to establish
    whether the subject is free of infection with such organisms:
    - The subject has not had respiratory tract culture positive for these organisms within
    the 12 months before the date of informed consent.
    - The subject has had at least 2 respiratory tract cultures negative for such organisms
    within the 12 months before the date of informed consent, with the first and last of
    these separated by at least 3 months, and the most recent one within the 6 months before
    the date of informed consent.
    5. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the
    first dose of study drug in the Run-in Period (Day -28).
    6. Ongoing or prior participation in a study of an investigational treatment other than
    a Vertex CFTR modulator within 28 days or 5 terminal half-lives (whichever is longer)
    before screening. The duration of the elapsed time may be longer if required by local
    regulations.
    7. Use of prohibited medications as defined in the protocol within the specified window
    before the first dose of study drug in the Run-in Period (Day -28).
    8. Pregnant or breast-feeding females. All female subjects, regardless of childbearing
    potential status, must have negative pregnancy tests at the Screening Visit (Day -56)
    and at the Day -28 Visit, before the first dose of study drug in the Run-in Period.
    9. 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 at that site. However, an adult (aged 18
    years or older) who is a relative of a study staff member may be enrolled 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 patologia o condizione clinica che, a giudizio dello
    sperimentatore, potrebbe inficiare i risultati dello studio o rappresentare un rischio
    aggiuntivo per la somministrazione del/i farmaco/i dello studio al soggetto. Sono
    inclusi, a titolo esemplificativo ma non esaustivo:
    • Cirrosi clinicamente significativa con o senza ipertensione portale.
    • Trapianto di organo solido o ematologico.
    • Abuso di alcol o droghe nel corso dell’anno precedente tra cui, a titolo
    esemplificativo ma non esaustivo, cannabis, cocaina e oppiacei, secondo quanto
    determinato dallo sperimentatore.
    • Tumore, ad eccezione del carcinoma cutaneo a cellule squamose, carcinoma cutaneo
    basocellulare e carcinoma della cervice in situ di stadio 0 (ciascuno di essi deve
    risultare libero da malattia negli ultimi 5 anni).
    2. Uno qualsiasi dei seguenti valori di laboratorio anomali allo screening.
    • Emoglobina <10 g/dl
    • Bilirubina totale >=2 volte il limite superiore della norma (Upper Limit of Normal,
    ULN)
    • Aspartato transaminasi (AST), alanina transaminasi (ALT) o gamma-glutamil
    transferasi (GGT) >=3 volte l’ULN
    • Funzionalità renale anomala stimata in base alla velocità di filtrazione glomerulare
    =50 ml/min/1,73 m2 (calcolata in base all’equazione MDRD [Modification of Diet in Renal
    Disease])13,14 per i soggetti >=18 anni di età oppure <=45 ml/min/1,73 m2 (calcolata in
    base all’equazione di Counahan-Barratt)15 per i soggetti di 12-17 anni di età (inclusi)
    3. Infezione acuta delle vie respiratorie superiori o inferiori, riacutizzazione
    polmonare (Pulmunary Exacerbation, PEx) o cambiamento della terapia (compresi gli
    antibiotici) per malattia sinopolmonare entro i 28 giorni precedenti alla prima dose di
    farmaco dello studio nel periodo di run-in (Giorno -28).
    4. Infezione polmonare con un patogeno microbico associato a un declino più rapido
    dello stato polmonare (tra cui, a titolo esemplificativo ma non esaustivo, Burkholderia
    cenocepacia, Burkholderia dolosa e Mycobacterium abscessus). Per i soggetti con anamnesi
    di coltura positiva, lo sperimentatore applicherà i criteri seguenti per stabilire se il
    soggetto è libero da un’infezione di tali organismi:
    • Il soggetto non presenta una coltura respiratoria positiva per questi organismi nei
    12 mesi precedenti alla data del consenso informato.
    • Il soggetto presenta almeno 2 colture delle vie respiratorie negative per questi
    organismi nei 12 mesi precedenti alla data del consenso informato, con la data della
    prima e dell’ultima coltura a distanza di almeno 3 mesi e la coltura più recente nei 6
    mesi precedenti alla data del consenso informato.
    5. Una malattia acuta non correlata alla FC (per es. gastroenterite) nei 14 giorni
    precedenti alla prima dose del farmaco dello studio nel periodo di run-in (Giorno -28).
    6. Partecipazione precedente o in corso a uno studio su un trattamento sperimentale
    diverso da un modulatore di CFTR di Vertex entro 28 giorni o 5 emivite terminali (a
    seconda di quale periodo sia più lungo) prima dello screening. La durata del tempo
    trascorso può essere più lunga se richiesto dalle normative locali.
    7. Uso dei farmaci vietati così come definiti nel protocollo entro la finestra
    temporale specificata prima della dose di farmaco dello studio nel periodo di run-in
    (Giorno -28).
    8. Soggetti di sesso femminile in gravidanza o in allattamento. Tutti i soggetti di
    sesso femminile, a prescindere dallo stato di fertilità, devono presentare un test di
    gravidanza negativo alla visita di screening (Giorno -56) e alla visita del Giorno -28,
    prima della prima dose di farmaco dello studio nel periodo di run-in.
    9. vedere inglese
    E.5 End points
    E.5.1Primary end point(s)
    Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1)
    from baseline through Week 8 for the VX-445/TEZ/IVA group
    Cambiamento assoluto della percentuale del valore previsto di volume espiratorio
    forzato in 1 secondo (ppFEV1) dal basale alla Settimana 8 per il gruppo VX-445/TEZ/IVA
    E.5.1.1Timepoint(s) of evaluation of this end point
    Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8; Early
    Treatment Termination (ETT) visit (if applicable)
    periodo di Run-in : Giorno -14; Periodo di trattamento: giorno 1, giorno 15,
    settimana 4, settimana 8; visita per la fine anticipata del trattamento ( se
    applicabile)
    E.5.2Secondary end point(s)
    Key Secondary Endpoints
    - Absolute change in sweat chloride (SwCl) from baseline through Week 8 for the VX-
    455/TEZ/IVA group
    - Absolute change in ppFEV1 from baseline through Week 8 for the VX-455/TEZ/IVA group
    compared to the control group
    - Absolute change in SwCl from baseline through Week 8 for the VX-455/TEZ/IVA group
    compared to the control group
    Other Secondary Endpoints
    - Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain (RD) score
    from baseline through Week 8 for the VX-455/TEZ/IVA group
    - Absolute change in CFQ-R RD score from baseline through Week 8 for the VX-
    455/TEZ/IVA group compared to the control group
    - Safety and tolerability assessments based on adverse events (AEs), clinical
    laboratory values, ECGs, vital signs, and pulse oximetry
    Endpoint secondari chiave
    • Cambiamento assoluto dei livelli di cloro nel sudore (SwCl) dal basale alla
    Settimana 8 per il gruppo VX-445/TEZ/IVA
    • Cambiamento assoluto di ppFEV1 dal basale fino alla Settimana 8 per il gruppo VX-
    445/TEZ/IVA rispetto al gruppo di controllo
    • Cambiamento assoluto di SwCl dal basale fino alla Settimana 8 per il gruppo VX-
    445/TEZ/IVA rispetto al gruppo di controllo
    Altri endpoint secondari
    • Cambiamento assoluto del punteggio relativo al dominio respiratorio (RD) del
    questionario revisionato per la FC (CFQ-R) dal basale alla Settimana 8 per il gruppo
    VX-445/TEZ/IVA
    • Cambiamento assoluto del punteggio RD del questionario CFQ-R dal basale fino alla
    Settimana 8 per il gruppo VX-445/TEZ/IVA rispetto al gruppo di controllo
    • Valutazioni della sicurezza e della tollerabilità basate su eventi avversi (AE),
    valori clinici di laboratorio, elettrocardiogrammi (ECG), segni vitali e
    pulsossimetria
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key Secondary Endpoints:
    - SwCl: Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8;
    ETT visit (if applicable)
    - ppFEV1: Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8;
    ETT visit (if applicable)
    Other Secondary Endpoints
    - CFQ-R RD score: Run-In period: Day -28; Treatment Period: Day 1, Day 15, Week 4,
    Week 8; ETT visit (if applicable)
    - Safety and tolerability assessments:
    a. AEs: Continuous (signing of ICF until completion of study participation)
    b. clinical laboratory values, ECGs, vital signs, pulse oximetry: Day -28;
    Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable); SFU
    visit (if applicable); Endpoint secondari chiave:
    - SwCl: periodo di Run-in : giorno -14; periodo di trattamento: giorno 1, giorno
    15, settimana 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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    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
    Belgium
    Canada
    Denmark
    France
    Germany
    Ireland
    Italy
    Netherlands
    Spain
    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 months1
    E.8.9.1In the Member State concerned days3
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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: 75
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 175
    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
    Subject under age incapable of giving consent personally
    soggetti al di sotto dell'età per dare personalmente il consenso
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state17
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 125
    F.4.2.2In the whole clinical trial 250
    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)
    Plans for future treatment and medical care of the subjects after the
    end of this clinical trial will be at the discretion and responsibility of the
    subject's treating physician. Vertex will offer subjects the opportunity
    to enroll in an open label extension study (protocol No. VX18-445-110)
    if they have completed all study visits in this parent study and are
    eligible. Should subjects not be eligible or choose not to participate
    they will return to standard of care treatment.
    I piani per il trattamento futuro e le cure mediche per i soggetti dopo la fine di
    questo studio saranno a discrezione del medico che ha trattato il soggetto. Vertex
    offrirà ai soggetti l'opportunità di essere arruolati nello studio di estensione in
    aperto (protocollo No. VX18-445-110) se essi hanno completato tutte le visiste dello
    studio, nello studio parente, e sono elegibili. Se i soggetti non saranno elegibili o
    sceglieranno di non partecipare ritorneranno al trattamento standard.
    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 Decision2019-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-17
    P. End of Trial
    P.End of Trial StatusCompleted
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