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    Summary
    EudraCT Number:2016-004803-30
    Sponsor's Protocol Code Number:R2060
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-01-19
    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 ConcernedUK - MHRA
    A.2EudraCT number2016-004803-30
    A.3Full title of the trial
    A multi-centre, randomised, placebo and active-controlled, double-blind, cross-over, phase IIa proof-of-concept trial to investigate the efficacy and safety of AX-8 Tablets 5 mg in patients with chronic refractory cough and associated upper airway symptoms
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of AX-8 in patients with chronic cough
    A.3.2Name or abbreviated title of the trial where available
    Efficacy and safety of AX-8 in patients with chronic cough.
    A.4.1Sponsor's protocol code numberR2060
    A.5.4Other Identifiers
    Name:AX-8Number:Trial acronym
    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 SponsorHull and East Yorkshire Hospitals NHS Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDevelco Pharma Schweiz AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHull and East Yorkshire Hospitals NHS Trust
    B.5.2Functional name of contact pointTrial Co-ordinator
    B.5.3 Address:
    B.5.3.1Street AddressR&D Department, Office 13, 2nd floor, Daisy Building, Castle Road,
    B.5.3.2Town/ cityCottingham, East Yorkshire
    B.5.3.3Post codeHU16 5JQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01482461883
    B.5.5Fax number01482461886
    B.5.6E-mailJane.Pacynko@hey.nhs.uk
    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 nameAX-8
    D.3.2Product code AX-8
    D.3.4Pharmaceutical form Orodispersible tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOromucosal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRecommended International Nonproprietary Name (rINN): [(1R,2S,5R)-5-Methyl-2-isopropyl cyclohexane carbonyl]aminoacetic acid isopropylester
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.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 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 nameMenthol
    D.3.2Product code Menthol
    D.3.4Pharmaceutical form Orodispersible tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOromucosal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMenthol
    D.3.9.1CAS number 2216-51-5
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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
    Chronic refractory cough and associated upper airway symptoms.
    E.1.1.1Medical condition in easily understood language
    Long-term troublesome cough.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary research question is to study the efficacy of AX-8 Tablets 5 mg in suppressing cough in patients with chronic refractory cough and associated upper airway symptoms when compared to 5mg menthol (active comparator) and placebo. As assessed by measuring the changes from baseline in cough frequency over 8 hours (4hrs after intake of 1st dose and 4hrs after intake of 2nd dose) for AX-8, menthol and placebo.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to further study the efficacy and also to study the safety of AX-8 Tablets 5 mg as assessed by measuring the changes from baseline of:
    - cough severity (as measured on a visual analogue scale - VAS)
    - urge to cough (VAS)
    - cough intensity (VAS)
    - Necastle Laryngeal Hypersensitivity questionnaire
    - Hull Airways Reflux Questionnaire
    - modified LeicesterCough Questionnaire
    - incidence of adverse events (AEs)
    - vital signs
    - safety lab tests
    - ECG
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female patients, aged 18 to 80 years.
    2. Chronic refractory cough with upper airway symptoms (throat or laryngeal discomfort) of at least 8 weeks duration. Regular pattern of cough with expected daily episodes of cough that occur in the morning and throughout the day, as ascertained by medical history.
    3. Chest X-ray within 5 years of screening showing no evidence of significant lung disease.
    4. Cough severity (worst value over the last 24 hours) according to visual analogue scale (VAS) greater than or equal to 35.
    E.4Principal exclusion criteria
    1. Hypersensitivity or intolerance to transient receptor potential cation channel subfamily M member 8 (TRPM8) agonists, menthol, menthol-like compounds, or any of the excipients of the IMP.
    2. Current or suspected pulmonary or upper respiratory tract infection (URTI) within the last 4 weeks.
    3. Current smoker, recent smoker within the last 6 months, or ex-smoker with more than 20 pack-years.
    4. Asthma (as judged by the investigator), chronic obstructive pulmonary disease (COPD), or bronchiectasis.
    5. Forced expiratory volume in 1s (FEV1) to forced vital capacity (FVC) ratio less than 60% at screening (V1).
    6. Chronic upper respiratory tract disorder, e. g. chronic allergy.
    7. Other known respiratory (e. g. malignant disease) or non-respiratory (e. g. congestive heart failure) conditions that may have significant impact on cough occurrence or worsening.
    8. Any history of laryngeal pathology and surgery of the larynx or ongoing investigation on the larynx.
    9. Administration of angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to screening (V1) and during the participation in the study.
    10. Administration of antitussives, opioids, pregabalin, gabapentin, corticosteroids, proton pump inhibitors, amitryptyline or any other therapy that may modulate cough within 2 weeks prior to screening (V1) and during the participation in the study.
    11. Administration of Dextromethorphan, Guaifenesin, Chlorpheniramine Maleate extended release tablets and Benzonatate for the treatment of cough will not be allowed from Screening throughout the study.
    12. Long-term therapy for any chronic disease, if suspected to be unstable during the course of the trial.
    13. Known or suspected convulsive disorder.
    14. History or presence of severe psychiatric disorder (e.g. severe depression, schizophrenia or acute psychosis).
    15. Evidence of impaired hepatic function (total bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], or alkaline phosphatase [AP] > 3 times the upper limit of normal)
    16. Evidence of moderate or severe renal impairment (creatinine clearance [CRCL] < 60 ml/min) or patients with renal failure who are on any form of dialysis.
    17. For women: Pregnancy or breast-feeding. Women of childbearing potential (WOCBP) unable or unwilling to undergo pregnancy tests and use highly effective contraceptive methods. Contraceptive methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner and sexual abstinence.
    For men: Men unable or unwilling to practice adequate contraceptive measures, i.e. condom or contraception for the non-pregnant partner of childbearing potential.
    18. Any other condition of the patient that in the opinion of the investigator may compromise evaluation of the trial treatment or may jeopardize patient’s safety, compliance or adherence to protocol requirements.
    19. Previous enrolment in this trial, or participation in any other clinical trial within the past 30 days prior to enrolment.
    20. Persons committed to an institution by virtue of an order issued either by the judicial or other authorities.
    21. Employees of the investigator or study centre, with direct involvement in the proposed study or other studies under the direction of that investigator or study centre, as well as family members of the employees or the investigator.

    Exclusion criteria at V2, V3, V4 and V5:
    22. Consumption of cough sweets, caffeine, chilli or products containing mint within the last 6 hours and during visit days.

    Exclusion criteria 9, 10, 11, 16 and 22 will be re-checked at V2, V3, V4 and V5.
    E.5 End points
    E.5.1Primary end point(s)
    Absolute and relative changes from baseline in cough frequency over 8 hours (covering periods of 4 hours after 1st IMP intake and 4 hours after 2nd IMP intake) for AX-8 Tablets 5 mg, compared to 5 mg active comparator and placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    As specified above.
    E.5.2Secondary end point(s)
    Efficacy outcome measures
    1. Absolute and relative changes from baseline in severity cough VAS score pre-dose as well as 1 hour, 2 hours and 4 hours after 1st and 2nd intake of AX-8 Tablets 5 mg when compared to 5 mg active comparator and placebo.
    2. Absolute and relative changes from baseline in urge to cough VAS score pre-dose as well as 1 hour, 2 hours and 4 hours after 1st and 2nd intake of AX-8 Tablets 5 mg when compared to 5 mg active comparator and placebo.
    3. Absolute and relative changes from baseline in intensity of cough VAS score pre-dose as well as 1 hour, 2 hours and 4 hours after 1st and 2nd intake of AX-8 Tablets 5 mg when compared to 5 mg active comparator and placebo.
    4. Absolute and relative changes from baseline in Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ) total score pre-dose as well as 1 hour, 2 hours and 4 hours after 1st and 2nd intake of AX-8 Tablets 5 mg when compared to 5 mg active comparator and placebo.
    5. Absolute and relative changes from baseline in the modified Hull Airway Reflux Questionnaire (mHARQ) total score compared to 4 hours after 1st and 2nd intake of AX-8 Tablets 5 mg, 5 mg active comparator and placebo.
    6. Absolute and relative changes from baseline in the modified Leicester Cough Questionnaire (mLCQ) acute total score compared to 4 hours after 1st and 2nd intake of AX-8 Tablets 5 mg, 5 mg active comparator and placebo.

    Safety outcome measures
    1. Incidence of adverse events (AEs).
    2. Change from baseline in vital signs.
    3. Change from baseline in safety laboratory parameters.
    4. Change from baseline in electrocardiogram (ECG).
    E.5.2.1Timepoint(s) of evaluation of this end point
    As specified above.
    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 No
    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.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 No
    E.8.1.6Cross over Yes
    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.8.3 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 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 No
    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
    LVLS
    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 days1
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 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 state30
    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)
    There will be no continued provision of AX-8 Tablets 5 mg after patients have completed the trial, although patients will continue their routine care in the Cough Clinic.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation CRN: Yorkshire & Humber, Sheffield Teaching Hospitals NHS Foundation Trust
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-03-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-31
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-04-17
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