E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Refractory Chronic Cough (RCC). |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066656 |
E.1.2 | Term | Chronic cough |
E.1.2 | System Organ Class | 100000016024 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change from Baseline in awake objective cough frequency after 1 dose of treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline - Day -1 to Day 1 (24 hours) Treatment - Day 1 to Day 2 (24 hours) |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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Last visit of the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 14 |