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    EudraCT Number:2017-003108-27
    Sponsor's Protocol Code Number:AX8-001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-08-31
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2017-003108-27
    A.3Full title of the trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pilot study of efficacy, safety and tolerability of AX-8 in cough
    A.3.2Name or abbreviated title of the trial where available
    A pilot study of efficacy, safety and tolerability of AX-8 in cough
    A.4.1Sponsor's protocol code numberAX8-001
    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 SponsorAxalbion SA
    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 supportAxalbion SA
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAxalbion SA
    B.5.2Functional name of contact pointMarco Rüedi
    B.5.3 Address:
    B.5.3.1Street AddressEPFL-Innovation Park, Bâtiment C
    B.5.3.2Town/ cityLausanne
    B.5.3.3Post codeCH-1015
    B.5.4Telephone number+41 79 715 37 25
    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.3.4Pharmaceutical 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.3.9.1CAS number 1401555-39-2
    D.3.9.2Current sponsor codeAX-8
    D.3.9.3Other descriptive nameGly-OiPr, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester
    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. 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Refractory Chronic Cough (RCC).
    E.1.1.1Medical condition in easily understood language
    RCC is a cough that lasts 8 weeks or longer and does not respond to targeted treatment for underlying trigger diseases (e.g. reflux, asthma, post-nasal drip) or which cause is unknown.
    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 LLT
    E.1.2Classification code 10066656
    E.1.2Term Chronic cough
    E.1.2System Organ Class 100000016024
    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 effectiveness of AX-8 for the treatment of RCC and associated upper airway symptoms after one dose of treatment in reducing awake cough frequency compared to baseline, for the purpose of planning a future randomised controlled trial.
    E.2.2Secondary objectives of the trial
    •To evaluate the duration of effectiveness of AX-8 after 1 dose of treatment in reducing hourly objective cough frequency over a 24-hour period

    •To evaluate the effectiveness of AX-8 in:
    o Reducing the cough severity measured by a Visual Analog Scale (VAS)
    o Reducing the throat irritation and the urge to cough measured by a Visual Analog Scales (VAS)
    o Inducing a sensation of throat cooling (VAS)

    •To assess the safety and tolerability of AX-8 in patients with RCC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Females and males between 18 and 80 years of age inclusive
    2. Have a diagnosis of RCC or unexplained cough for at least one year (see BTS guidelines in Appendix C of the protocol) and associated upper airway symptoms (throat or laryngeal irritation, tickling, dryness or discomfort) of at least 8-week duration. Regular pattern of cough with expected daily episodes of cough that occur throughout the day, as ascertained by medical history.
    3. Chest radiograph or CT Thorax within the last 5 years not demonstrating any abnormality considered to be significantly contributing to the chronic cough in the opinion of the Principal Investigator and Axalbion SA Medical Monitor.
    4. At Screening have a score of ≥ 40mm on the Cough Severity VAS.
    5. At Baseline have a score of ≥ 40mm on the Cough Severity VAS.
    6. All female subjects who are of childbearing potential must practice highly effective contraception (i.e. pregnancy prevention method with a failure rate of < 1% per year) from the time of the initial Screening visit until 4 weeks after last dose of study drug. Please refer to Protocol section 7.1.5 for acceptable methods of contraception.
    7. BMI < 33kg/m2 at the baseline visit.
    8. Have provided written informed consent.
    9. Are willing and able to comply with all aspects of the protocol.
    E.4Principal exclusion criteria
    1. Prior treatment with AX-8.
    2. Hypersensitivity or intolerance to AX-8 or other TRPM8 agonists (e.g. menthol, menthol-like compounds), or any of the excipients of AX-8 ODT.
    3. Current smoker or individuals who have given up smoking within the past 12 months or ex-smoker with > 20 pack-years.
    4. FEV1/FVC < 60%.
    5. History of upper or lower respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0).
    6. History of cystic fibrosis.
    7. History of opioid use within 1 week of the Baseline Visit if used for the treatment of RCC. Opioids, if required for other indications are permitted providing that subject are receiving a stable dose for at least 1 week prior to the Baseline visit (Day 0) and are still experiencing a troublesome cough. Subjects must remain on a stable dose for the duration of the study until the follow up visit (in accordance with Protocol section 5.6)
    8. Requiring concomitant therapy with prohibited medications (see Protocol section 5.6).
    9. Treatment with biologic therapies within 8 weeks or 5 half-lives prior to the Baseline Visit (Day 0), whichever is longer.
    10. Treatment with any investigational therapy within 4 weeks prior to the Baseline Visit (Day 0).
    11. Clinically significant abnormality of hepatic function defined as Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x the upper limit of normal (ULN) during screening.
    12. Clinically significant abnormality of renal function, defined as e-GFR < 60 ml/min.
    13. Positive test for any drug-of-abuse (unless this can be explained by the subject’s medication).
    14. History of malignancy within 5 years prior to the Baseline Visit (Day 0), with the exception of completely treated and non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin.
    15. History of a major psychiatric condition (including major depressive disorder, bipolar disorder, or schizophrenia), suicidal ideation, or suicide attempt.
    16. Known active hepatitis infection.
    17. Known history of human immunodeficiency virus (HIV) infection.
    18. Presence of any medical condition or disability that, in the investigator’s opinion, could interfere with the assessment of safety or efficacy in this trial or compromise the safety of the subject, including clinically significant ECG abnormalities during screening, baseline (Day 0) or pre-dose (Day 1).
    19. Currently pregnant or breastfeeding female subject, or male subject with a pregnant or breastfeeding partner.
    20. Females of childbearing potential who are unable or unwilling to practice highly effective contraception (pregnancy prevention).
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the change from Baseline in awake objective cough frequency after 1 dose of treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline - Day -1 to Day 1 (24 hours)
    Treatment - Day 1 to Day 2 (24 hours)
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoints
    • Change from Baseline in hourly objective cough frequency over a 24-hour monitoring period;
    • Proportion of subjects with ≥ 30% reduction in 24-hour cough frequency per hour;
    • Proportion of subjects with ≥ 30% reduction in awake cough frequency per hour;
    • Change from Baseline in Cough Severity VAS;
    • Change from Baseline in urge-to-cough VAS;
    • Global Rating of Change Scale (GRCS).
    • Change in Throat Irritation and Throat Cooling VAS;

    Safety Endpoints:
    • Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs);
    • Changes in clinical laboratory parameters following study drug exposure;
    • Changes in vital sign and ECG parameters following study drug exposure.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Cough frequency: Baseline: Day-1 to Day1(24 hours), Treatment: Day1 to Day2(24 hrs)
    • Cough Severity, Urge-to-cough, Throat irritation VAS:
    - Baseline: pre-cough monitor –30 mins, post-cough monitor +1, +2, +3, +4,
    +5, +6 hrs
    - Treatment: pre-dose –30 mins, post-dose +1, +2, +3, +4, +5, +6 hrs and Day2
    for last 24 hrs
    - Day7-14(follow-up)
    • Throat Cooling VAS:
    - Day1: pre-dose –30 mins, post-dose: +30 mins, +1, +1.5, +2, +2.5, +3, +4, +5,
    +6 hrs. Day2 for last 24 hrs.
    • Global Rating of Change Scale:
    - Day1: +4 hrs post dose, Day2 and Day7-14 visits

    Safety Endpoints:
    • TEAEs and SAEs: Day 1 post dose onwards
    • Clinical laboratory: Screen and Day 7-14 visit
    • Vital sign and ECG: Screen, Day0, Day1 pre-dose, +4 hrs post-dose and Day7-14 visits
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 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
    Last visit of the last subject.
    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 months2
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days14
    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. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F. of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 15
    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)
    Medication will not be provided by the sponsor to study subjects at the end of the trial. After the end of study visit is performed, patient's routine standard of care will continue.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-06-11
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