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    The EU Clinical Trials Register currently displays   38898   clinical trials with a EudraCT protocol, of which   6392   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2018-001010-15
    Sponsor's Protocol Code Number:REVC003
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2018-11-23
    Trial 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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-001010-15
    A.3Full title of the trial
    A Phase 2a Open-Label Study in Infants with REspiratory Syncytial VIRus Lower RespirAtory Tract Infection, Followed by a DoubLe-blind, Placebo-controlled Part, to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Effect of RV521 (REVIRAL 1)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 2a Study in Infants with RSV lower respiratory tract infection, to evaluate the safety, tolerability, pharmacokinetics and antiviral effect of RV521.
    A.3.2Name or abbreviated title of the trial where available
    REVIRAL1
    A.4.1Sponsor's protocol code numberREVC003
    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 SponsorReViral Ltd.
    B.1.3.4CountryUnited Kingdom
    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 supportReViral Ltd.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSyneos Health
    B.5.2Functional name of contact pointMary Luz Aparicio
    B.5.3 Address:
    B.5.3.1Street AddressStefan-George-Ring 6
    B.5.3.2Town/ cityMünchen
    B.5.3.3Post codeD-81929
    B.5.3.4CountryGermany
    B.5.4Telephone number49899939 1 3127
    B.5.6E-mailmaryluz.aparicioalvarado@syneoshealth.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.3.2Product code RV521
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    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 INNnot applicable
    D.3.9.2Current sponsor codeRV521
    D.3.9.3Other descriptive name1'-{[5-(aminomethyl)-1-(4,4,4-trifluorobutyl)-1H-1,3-benzodiazol-2-yl]methyl}-6'-fluoro-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2'-one hydrochloride 1'-{[5-(aminomethyl)-1-(4,4,4-trifluorobutyl)-1,3-benzodiazol-2-yl]methyl}-6'-fluorospiro[cyclopropane-1,3'-indole]-2'-one hydrochloride
    D.3.9.4EV Substance CodeSUB184917
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10-50
    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 placeboPowder for oral solution
    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
    Respiratory Syncytial Virus Infection
    E.1.1.1Medical condition in easily understood language
    Respiratory Syncytial Virus Infection
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10061603
    E.1.2Term Respiratory syncytial virus infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with Respiratory Syncytial Virus (RSV) lower respiratory tract infection (LRTI)
    Part C: Evaluate the effect of RV521, compared to placebo, on the clinical course of RSV LRTI
    E.2.2Secondary objectives of the trial
    To characterise the pharmacokinetics (PK) of single (Part A) and multiple (Part B) oral doses of RV521 in infants hospitalised with RSV LRTI.
    To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI.
    Part B: Evaluate the effect of RV521 compared to placebo on the clinical course of RSV infection
    Part C: Evaluate the safety of RV521 given as a multiple dose regimen
    Part C: Effect of RV521, compared to placebo, on nasopharyngeal shedding of RSV
    Part C: To evaluate the PK and PK-PD relationship through correlation of RV521 plasma levels with changes in viral load after repeated oral dosing
    Part C: Comparison between RV521 and placebo on the development of viral mutations associated with in vitro resistance
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ≥ 1 month and ≤ 36 months of age
    2. Weight ≥ 3.5 kg
    3. Clinical diagnosis of LRTI defined by
    a. Evidence of respiratory infection by one or both of the following with or without fever:
    i. Rhinitis/coryza
    ii. Cough
    AND
    b. Evidence of LRTI by the presence of one or more of the following:
    i. Increased respiratory rate PLUS other evidence of lower respiratory tract disease (eg, laboratory or radiographic evidence).
    ii. Increased respiratory effort as evidenced by one or more of the following:
    1. Grunting with expiration
    2. Nasal flaring
    3. Retraction: intercostal or subcostal
    iii. Wheezing: audible or on chest auscultation
    4. A positive RSV diagnostic test (RSV infection confirmed either according to routine site practice [polymerase chain reaction or diagnostic quick test], or using a [Sponsor-provided] commercial kit.
    5. Hospitalised because of RSV LRTI (bronchiolitis or bronchopneumonia)
    6. For Part B, symptoms of LRTI must be present for no more than 1 week before the Screening Visit, with the first day of symptoms counting
    as Day 1.
    7. For Part C, symptoms of LRTI must be present for no more than 5 days prior to the Screening Visit, with the first day of symptoms counting
    as Day 1.
    8. Expected to remain in hospital for a minimum of 3 days (administration of 6 doses for both Parts B and C)
    9. The parent(s)/legal guardian(s) of the subject have provided written informed consent for the subject to participate
    10. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol
    E.4Principal exclusion criteria
    1. Premature (gestational age less than 37 weeks) AND <1 year of postnatal age
    2. Known to have significant comorbidities, including genetic disorders (eg, trisomy 21); cardiopulmonary diseases (eg, haemodynamically significant congenital heart disease); pulmonary disease (eg, bronchopulmonary dysplasia, cystic fibrosis); history of surgery for diaphragmatic hernia; any hereditary or acquired metabolic diseases; haematological or other malignancy; or is known to be HIV positive; or has evidence of severe neurologic impairment or developmental delay that would limit the ability to administer study drug or evaluate the safety or clinical response to IMP.
    3. Malformation of the gastrointestinal tract including unresolved pyloric stenosis, history of necrotising enterocolitis, short bowel, or other significant condition that would alter drug absorption or increase the risk of diarrhoea.
    4. Any clinically significant ECG abnormalities.
    5. Known to be immunocompromised
    6. High risk of having developing asthma. Features that indicate a high likelihood of asthma in a young child include:
    a. Symptoms (cough, wheeze, heavy breathing) for > 10 days during upper respiratory infections
    b. > 3 wheezing episodes per year (during the previous 12 months) or severe episodes and/or night wheezing
    c. Between episodes, child has cough, wheeze, or heavy breathing during play or when laughing
    d. Atopy or family history of asthma in a first degree relative
    7. Suspected of having a clinically significant bacterial infection as indicated by symptoms or laboratory findings consistent with a bacterial infection including but not limited to: elevated white blood cell count, elevated C-reactive protein, chest X-ray consistent with bacterial pneumonia, unstable vital signs, hypotension, or evidence of shock or poor perfusion.
    8. Has significant oral and/or maxillofacial malformations that would limit the ability to administer IMP.
    9. History of renal failure including renal anomalies likely to be associated with renal insufficiency (eg, clinical conditions of renal dysplasia, polycystic renal disease, renal agenesis)
    10. Clinical evidence of hepatic decompensation (eg, hepatic disorder with associated coagulopathy or associated encephalopathy) or significantly elevated liver enzymes (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3 × the upper limit of normal)
    11. History of epilepsy or seizures, including febrile seizures
    12. Allergy to test medication or constituents
    13. Requires any prohibited medication/therapy as listed in the body of the protocol.
    a. Receiving treatment with inhaled, oral, or IV corticosteroids and requires continued corticosteroid therapy
    b. Has taken within 21 days before dosing, any drug that could impact by any mechanism of action on the PK of the investigational product including any substrates, inducers, inhibitors of CYP3A4 and/or Pglycoprotein (P-gp); or the use of prescription medications, over-thecounter (OTC) medications, herbal remedies or dietary supplements containing St. John's Wort, or the consumption of drugs or other substances (eg, grapefruit, Seville oranges, or cranberry juice-containing products) known to be potent inhibitors or inducers of CYP P450s.
    c. Requires the use of Heliox, Leukotriene receptor antagonist (eg, Montelukast, exogenous surfactant, mucolytics or Hypertonic saline [allowed in the Part A of the study]).
    14. Has received 1 or more doses of palivizumab at any time before Screening or received treatment with antiviral therapy for RSV (eg, ribavirin or intravenous [IV] immunoglobulin) within 3 months before the Screening Visit. NOTE: Subjects eligible for palivizumab treatment or other RSV prophylaxis cannot be included in the study.
    15. The subject's parent(s) or legal guardian(s) is a study team member (ie, has direct involvement in this study or other studies under the direction of the Investigator or the study centre) or is a family member of either the Investigator or other team members
    16. Currently participating in any investigational study or has participated in an investigational study within 3 months before the Screening Visit
    17. Any other reason which in the opinion of the Investigator makes the participant unsuitable for a clinical trial
    E.5 End points
    E.5.1Primary end point(s)
    Safety and tolerability parameters to be assessed will include, but are not limited to:
     Adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs), and withdrawals due to TEAEs
     Physical examinations
     Vital sign parameters (ie, systolic and diastolic blood pressure [BP], temperature, respiration rate [RR], heart rate [HR], and pulse oximetry), and changes from baseline in these parameters at predefined time points
     Laboratory tests (haematology, chemistry, and urinalysis test results) and changes from baseline in these parameters, at predefined time points
     Electrocardiogram (ECG) measurements and changes from baseline in these parameters at predefined time points

    Part C:
    Time to resolution of symptoms
    Time to improvement of symptoms
    Reduction in severity of symptoms by RV521, compared to placebo, measured by a composite score over time
    Use of supplemental oxygen, including, but not limited to, duration and maximum level of O2 provided
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline, evaluations will be made throughout the course of the study, including following discharge from hospital
    E.5.2Secondary end point(s)
    Secondary endpoints related to PK will include but are not limited to:
     Time to maximum plasma concentration (tmax)
     Maximum observed plasma concentration(Cmax)
     Area under the plasma concentration time curve from time zero to 12 hours (AUC0-12)
     Area under the plasma concentration time curve from time zero to last measurable plasma concentration (AUC0-t)
     Terminal half-life (t1/2)
     Area under the plasma concentration time curve from time zero to infinity (AUC0-∞)
     Predicted plasma clearance
     Apparent volume of distribution of the drug after extravascular administration (V/F)
     Trough concentration at the end of first dosing interval (C12) (data permitting)
    In addition for Part B:
     Accumulation ratio, percent fluctuation
     Area under the plasma concentration time curve from time zero to the end of last dosing interval (AUC0-tau)
     Average plasma concentration over dosing interval (Cave)
     Minimum observed plasma concentration (Cmin)
     Plasma trough concentration (Ctrough)
     Any other relevant parameters

    Secondary endpoints related to assessment of antiviral activity and efficacy in Part B include but are not limited to:
     RSV viral load measured in nasopharyngeal swabs by quantitative reverse transcription polymerase chain reaction (RT-qPCR)
     RSV viral load measured in nasopharyngeal swabs by cell-based infectivity assay (CBIA)

    Secondary endpoints related to assessment of the effect of RV521 compared to placebo on the clinical course of RSV infection:
    Time to resolution of symptoms
    Time to improvement evaluated by reduction in severity of symptoms
    Reduction in severity of symptoms by RV521, compared to placebo, measured by a composite score over time

    Safety of RV521 compared to placebo assessed by incidences of AEs, discontinuations due to AEs, SAEs, and clinically significant changes in clinical laboratory tests
    Comparison between RV521 and placebo for changes in viral load over time as for Part B
    Correlation between plasma PK parameters and RSV viral load
    Incidence of viral genome mutations associated with resistance to the antiviral effect of RV521
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline, evaluations will be made throughout the course of the study, including following discharge from hospital
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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.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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    In Part A the trial is Open Label. In Part B and C the trial is double-blinded
    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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Argentina
    Chile
    Costa Rica
    Hungary
    Latvia
    Malaysia
    New Zealand
    Panama
    Philippines
    Poland
    Spain
    Taiwan
    Thailand
    Ukraine
    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
    LSLV
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    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: 184
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 62
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 61
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 61
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    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 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
    Patients of ≥1 month and ≤36 months of age.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 46
    F.4.2.2In the whole clinical trial 184
    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)
    normal treatment - standard of care
    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 Decision2019-02-07
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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