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    Summary
    EudraCT Number:2008-005048-17
    Sponsor's Protocol Code Number:VRP080415
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-11-11
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2008-005048-17
    A.3Full title of the trial
    A Combined Clinical Phase I/IIa Study of the Safety and Efficacy of Nebulised RPL554 in Healthy Subjects, Allergic Asthmatics, and Allergic Rhinitics
    A.3.2Name or abbreviated title of the trial where available
    Phase I/IIa Evaluation of Nebulised RPL554
    A.4.1Sponsor's protocol code numberVRP080415
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorVerona Pharma Plc
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameRPL554
    D.3.2Product code RPL554
    D.3.4Pharmaceutical form Inhalation vapour, solution
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPInhalation use
    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) Information not present in EudraCT
    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 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 Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typechemical synthetic medicinal product
    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 placeboInhalation vapour, solution
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Allergic Asthma and Allergic Rhinitis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10001705
    E.1.2Term Allergic asthma
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10001723
    E.1.2Term Allergic rhinitis
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety of nebulized RPL554 in healthy subjects, allergic asthmatics and allergic rhinitics using standard safety measures.
    E.2.2Secondary objectives of the trial
    1) To investigate whether nebulized RPL554 possesses:
    1.1) Bronchodilator (increase in FEV1) and bronchoprotective activity (increase in PC20 to inhaled methacholine), respectively, in patients with clinically stable allergic asthma, not on controller medications and without regular use of bronchodilators.
    1.2) Anti-inflammatory effects in subjects with allergic rhinitis not on controller therapy following a standardized nasal challenge with a relevant allergen (inhibition of the allergen-induced nasal eosinophilia in nasal brushes).
    2) To investigate RPL554’s effect on the following exploratory measures:
    2.1) Nasal composite symptom scores post-allergen (RPL554 versus placebo)
    2.2) Exhaled nitric oxide (changes in eNO following nasal allergen as compared with baseline as a surrogate for possible anti-inflammatory effects in the lower airways)
    3) To investigate RPL554’s pharmacokinetics in plasma and urine.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) General Inclusion Criteria for All Study Subjects (i.e., Healthy, Asthmatic, Rhinitic)
    1.1) Males aged or females of non-child bearing potential: a) following hysterectomy or b) tubal ligation, or c) post-menopausal for at least 12 months before start of study
    1.2) Age between 18 and 55 years at screening
    1.3) No clinically relevant history of cardiovascular (including arrhythmias) disease; no active hyperthyroidism
    1.4) No clinically relevant history of chronic or malignant diseases (except for in situ basalioma)
    1.5) Body mass index (BMI) between 18 and 33 kg/m2 (65-100 kg inclusive)
    1.6) Systolic blood pressure (SBP) 90-145 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and heart rate (HR) 45-90 beats per minute (inclusive), after resting for 5 minutes in the supine position
    1.7) No clinically significant findings on physical examination
    1.8) 12-lead ECG without clinically relevant abnormalities
    1.9) Non-smokers or ex-smokers (stopped for at least 6 months before screening, and <10 pack-years)
    1.10) Hematology, clinical chemistry and urinalysis test results not deviating from the normal range to a clinically relevant extent as deemed by the investigator
    1.11) Ability to communicate well with the investigator and to understand and comply with the requirements of the study
    1.12) Signed informed consent
    2) Specific for Healthy Subjects
    2.1) No pulmonary or airway disease including asthma and clinically active rhinitis
    2.2) Normal lung function: i.e. absence of airway obstruction, with FEV1 and FVC at least 90% of predicted and an FEV1/FVC ratio >80%
    2.3) No concomitant medication use, except for vitamins at a usual dose, occasional use of paracetamol or (influenza) vaccinations; other medications at the discretion of the investigator and with the written consent of sponsor
    3) Specific for Allergic Asthmatic Subjects
    3.1) No clinically significant findings on physical examination other than allergy and mild to moderate persistent asthma
    3.2) Documented history of mild to moderate persistent asthma, first diagnosed at least 6 months prior to the screening visit and currently controlled by beta-agonists on an “as needed” basis only
    3.3) Clinically stable asthma, i.e. stable use of “as needed” Short-Acting Beta2 Agonist (SABA), stable asthma symptoms, and baseline FEV1 values within 15% of each other on all study days (measured at the same time of day +/- 3 hours)
    3.4) Pre-bronchodilator FEV1 ≥70% of that predicted for the subject with a documented reversibility of at least 8% following 200-400 mcg inhaled salbutamol (i.e., an increase of 8% in pre-dose FEV1)
    3.5) Documented bronchial hyper-responsiveness to inhaled Methacholine bromide (MCh) with a PC20MCh of ≤4 mg/mL
    3.6) Documented allergy by a standardized Skin Prick Test (SPT): i.e. a positive wheal (a wheal response of at least 3 mm) to one or more of the common airborne allergens: Grass or tree Pollen, House Dust Mite, D. Farinae, cat, dog, or horse-dander, Aspergillus Fumigatus, A. Alternata, Artemisia Vulgaris
    3.7) Steroid-naïve, or not on inhaled/nasal or systemic corticosteroids for at least one month of inhaled therapy and 8 weeks of systemic therapy before the study
    3.8) No use of anti-IgE (omalizumab) in the past 6 months
    3.9) No systemic or aerosol use of the following: leukotriene receptor antagonists (LTRA), theophylline, long acting beta agonists (LABA), or antihistamine such as H1 receptor antagonist for 2 weeks before the study
    3.10) No nasal medications (steroids, antihistamines, cromones, or LTRA) for one month (for nasal steroids), or 2 weeks for other medications; xylomethazoline (1 week); nasal NaCl 0.9% allowed
    4) Specific for Allergic Rhinitic Subjects
    4.1) History of allergic rhinitis for at least 6 months
    4.2) No clinically significant findings on physically examination other than stable allergic rhinitis
    4.3) Proven allergy on skin prick testing for house dust mite (HDM) and/or grass pollen and/or cat-dander
    4.4) Clinically stable allergic rhinitis (i.e. a baseline Lebel score of max. 2 on all study-days, usually based on mild congestion and/or some rhinorrhoea) without the use of controller medications
    4.5) No use of systemic medications for at least 6 months (omalizumab) or 2 months (oral corticosteroids)
    4.6) No nasal medications for one month (nasal corticosteroids) or at least 2 weeks for other medications (antihistamines, cromones, or LTRA); vasoconstrictors, e.g., xylomethazoline (in the past week); and NaCl 0.9% allowed
    4.7) Documented sensitivity to intranasal allergen in terms of composite symptom scores (i.e. a Lebel composite symptom score of at least 6 following intranasal allergen), i.e. showing a nasal-allergen induced nasal response.
    4.8) For those with concomitant asthma: this should be clinically stable, not using other medications than a stable dose of inhaled bronchodilators in the previous month, and demonstrating an FEV1 at least 75% of predicted on all occasions
    E.4Principal exclusion criteria
    1) General Exclusion Criteria for All Study Subjects (i.e., Healthy, Asthmatic, Rhinitic)
    1.1) History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug
    1.2) Treatment with another investigational drug within 3 months prior to screening
    1.3) Known hypersensitivity to any excipients of the drug formulations
    1.4) History or clinical evidence of alcoholism within the 3-year period prior to screening (i.e. regular use of more than 21 units of alcohol/week for males and more than14 units/week for females)
    1.5) Excessive caffeine consumption, defined as > 8 cups/per day at screening – unable to discontinue caffeine consumption for at least 8 h before and during the testing
    1.6) History of anaphylaxis or severe allergy for food or medication
    1.7) Recent respiratory tract infections (within 3 weeks of screening and during study)
    1.8) Loss of 500 mL or more of blood within 3 months prior to screening
    1.9) Positive results for the HIV, HBV and HCV serology at screening
    1.10) Positive results for urine drug and cotinine screens (for nicotine use)
    1.11) Any abnormalities on lab or urine results outside the normal range, deemed clinically significant by the investigator (and with written consent of the sponsor)

    2) Specific Exclusion Criteria for Healthy Subjects
    2.1) Clinical evidence of asthma or any other pulmonary disease

    3) Specific Exclusion Criteria for Allergic Asthmatic Subjects
    3.1) Controller therapy with anti-IgE in the past 6 months, systemic corticosteroids in the past 8 weeks; intranasal corticosteroids in the past 1 month; leukotriene receptor antagonists, theophyllines or cromones in the past 2 weeks, antihistamines in the past 2 weeks, vasoconstrictors such as xylomethazoline (in the past week), and NaCl 0.9% allowed
    3.2) Desensitization therapy in the past
    3.3) Severe exacerbation requiring hospital evaluation and/or admission in the past 2 years
    3.4) Unstable disease

    4) Specific Exclusion Criteria for Allergic Rhinitic Subjects
    4.1) Controller therapy with anti-IgE in the past 6 months, systemic corticosteroids in the past 8 weeks; intranasal corticosteroids in the past 1 month; leukotriene receptor antagonists or cromones in the past 2 weeks, antihistamines in the past 2 weeks, vasoconstrictors such as xylomethazoline (in the past week), and NaCl 0.9% allowed
    4.2) Desensitization therapy in the past
    4.3) Nasal surgery in the past
    4.4) Evident or history of nasal polyps
    4.5) Unstable disease, i.e., active allergic rhinitis (apart from stable, mild nasal congestion), needing controller therapy
    E.5 End points
    E.5.1Primary end point(s)
    1) Safety of nebulised RPL554 in healthy subjects, allergic asthmatics and allergic rhinitics using standard safety measures:
    1.1) Respiratory safety (i.e., effects on the upper and lower airways (local irritation, effect on the voice, coughing, dyspnea/wheeze, sneezing and peripheral oxygen saturation).
    1.2) gastrointestinal safety (i.e., nausea, vomiting, and abdominal pain or diarrhoea)
    1.3) cardiovascular safety (i.e., effects on heart rate and rhythm, blood pressure, ECG (with particular care for the QTc interval), telemetry
    1.4) Blood chemistry and hematology
    2) Subjective tolerability (i.e., taste, aftertaste, and smell as well as nasal irritation)
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Adaptive Design
    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.8.3 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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    Last follow-up visit of the last subject entered into the study will be the end of the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Information not present in EudraCT
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state62
    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.
    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 Decision2008-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-01-27
    P. End of Trial
    P.End of Trial StatusCompleted
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