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    The EU Clinical Trials Register currently displays   42883   clinical trials with a EudraCT protocol, of which   7063   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2019-003650-92
    Sponsor's Protocol Code Number:VX19-814-101
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-03-10
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2019-003650-92
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of VX-814 in PiZZ Subjects

    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of the Efficacy and Safety of VX-814 in Subjects With the PiZZ
    A.4.1Sponsor's protocol code numberVX19-814-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04167345
    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
    B.5.3.3Post code02210-1862
    B.5.3.4CountryUnited States
    B.5.4Telephone number1877634 8789
    B.5.5Fax number1510595 8183
    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.3.2Product code VX-814
    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-814
    D.3.9.2Current sponsor codeVX-814
    D.3.9.4EV Substance CodeSUB194921
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alpha-1 Antitrypsin Deficiency
    E.1.1.1Medical condition in easily understood language
    Alpha-1 Antitrypsin Deficiency
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    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-814 in PiZZ subjects as measured by plasma functional AAT levels
    - To evaluate the safety and tolerability of VX-814 in PiZZ subjects

    E.2.2Secondary objectives of the trial
    - To evaluate the efficacy of VX-814 in PiZZ subjects as measured by plasma antigenic AAT levels
    - To evaluate the pharmacokinetics (PK) of VX-814 in PiZZ subjects
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject will sign and date an informed consent form (ICF).
    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 18 through 80 years of age, inclusive, at the time of signing of the ICF.
    4. All female subjects must have a negative pregnancy test at screening (serum test). Premenopausal female subjects of child-bearing potential must also have a negative pregnancy test on Day 1 (urine test) and must not be nursing or planning to become pregnant during the study or within 90 days after the last study drug dose.
    5. Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive.
    6. Subjects must have a PiZZ genotype confirmed at screening.
    NOTE: PiZZ genotype must be tested at the central laboratory. Historical genotype results can be used to determine eligibility if they were obtained as part of a different Vertex study. In addition, if the screening PiZZ genotype result is not received before randomization, a previous non-Vertex PiZZ genotype laboratory report (approved by the medical monitor or designee) may be used to establish provisional eligibility. Subjects who have been randomized and whose screening genotype subsequently does not confirm study eligibility must be discontinued from the study (Section 9.10).
    7. Plasma antigenic AAT level <8 ìM during screening.
    For subjects who have been on augmentation therapy at any time, results used to confirm eligibility must be drawn >42 days after the last dose of augmentation therapy. Antigenic AAT levels must be obtained from the central laboratory and results confirmed before randomization.
    8. Willing to remain off of augmentation therapy from >42 days before antigenic AAT levels are obtained for eligibility through the last Safety Follow-Up Visit
    E.4Principal exclusion criteria
    1. History or presence of any illness or clinical condition that, in the opinion of the investigator, might affect the subject's safety or compliance or 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:
    • Solid organ, lung, or hematological transplantation or is currently on a transplant list
    • Subjects who have undergone gastrectomy or other gastrointestinal tract surgery, except appendectomy, cholecystectomy, and hemorrhoid surgery
    • Cancer, except for squamous cell skin cancer, basal cell skin cancer, Stage 0 cervical carcinoma in situ, and stage 0 or 1 melanoma(all 4 with no recurrence during the last 5 years)
    2. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before screening, defined as more than 14 drinks/week for females or 21 drinks/week for males (1 drink=5 ounces(150 mL)of wine or 12 ounces(360 mL)of beer or 1.5 ounces (45 mL) of hard liquor)
    3. Illegal drug use within 1 year before screening as deemed by the investigator, including but not limited to cocaine, heroin, and other opioids
    4. Ongoing or prior participation in a study of an investigational treatment 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
    5. History of use of gene therapy or RNAi therapy at any time previously
    6. Use of oral corticosteroids(at any dose)for a duration of greater than 3 months at any time within the 3 months before screening
    7. A post-bronchodilator forced expiratory volume in 1 second(FEV1) value<30% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative[GLI])during screening. Post-bronchodilator spirometry measurements must meet American Thoracic Society(ATS)/European Respiratory Society(ERS)criteria for acceptability and repeatability
    8. All clinically important pulmonary disease other than AATD-related COPD, including but not limited to physician-diagnosed COPD not related to AATD, interstitial lung disease, cystic fibrosis, pulmonary hypertension with or without cor pulmonale, history of pulmonary embolism, or malignant lung cancer
    9. Unstable AATD-related COPD as deemed by the investigator
    10. Documented chronic need for positive airway pressure therapy beyond nocturnal use
    11. Documented medical history or diagnosis of clinically evident liver disease including but not limited to a prior diagnosis of hepatitis of any etiology, cirrhosis, portal hypertension, or confirmed or suspected esophageal varices
    12. Any of the following abnormal laboratory values at screening:
    . Platelet count <150 ~ 109/L
    . Albumin .3.5 g/dL
    . International normalized ratio .1.2
    . Hemoglobin <10 g/dL
    . Total bilirubin > upper limit of normal (ULN)
    . Aspartate transaminase(AST), alanine transaminase(ALT), gamma-glutamyl transferase(GGT), or alkaline phosphatase(ALP)>2 ~ ULN
    . Estimated glomerular filtration rate .30 mL/min/1.73 m2
    13. Risk factors for Torsade de Pointes or concomitant medications that prolong the QT/QTc interval or any history of unstable cardiac disorder that, in the opinion of the investigator, might put the subject at risk or may confound the results of the study
    14. Any clinically significant ECG abnormality (as determined by the investigator) or median QTcF of triplicate standard 12-lead ECGs >450 msec at screening
    15. History of Gilbert's Syndrome
    16. Positive for HBsAg, HCV RNA, or HIV-1 and HIV-2 antibodies during screening
    17. Use of the substances, activities, or devices during the time periods indicated in Section 9.5
    18. Cigarette smoking during the past 6 months or a positive cotinine test at screening that is due to smoking or an electronic nicotine delivery system. Positive cotinine test due to nicotine replacement therapy for the purposes of smoking cessation, as attested by the investigator, is permitted
    19. Male subjects who plan to donate sperm or who have a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days after the last study drug dose
    20. The subject or a close relative of the subject is the investigator or a sub-investigator, 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 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
    21. Hypersensitivity to any component of the investigational drug product or placebo
    22. Subjects for whom discontinuation of augmentation therapy is not considered to be in their best interest, based on the clinical judgement of the treating physician
    E.5 End points
    E.5.1Primary end point(s)
    - Change from baseline in plasma functional AAT levels at Day 28
    - Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12 lead ECGs, vital signs and pulse oximetry
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Baseline in plasma functional AAT levels at Day 28
    - All through study duration
    E.5.2Secondary end point(s)
    - Change from baseline in plasma antigenic AAT levels at Day 28
    - PK parameters of VX-814 derived from plasma concentration time data

    E.5.2.1Timepoint(s) of evaluation of this end point
    - Change from baseline in plasma antigenic AAT levels at Day 28
    - PK samples: Predose: within 60mins before dosing, all other times points: at the nominal time (±30 minutes) relative to dosing
    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 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. 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) No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    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 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 26
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 17
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 43
    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)
    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 Decision2020-04-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-11-14
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