| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 100000004855 |
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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 evaluate the efficacy of once daily doses of 10 mg, 20 mg, and 30 mg orvepitant versus placebo in reducing awake objective cough frequency
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| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of once daily dosing of 10 mg, 20 mg, and 30 mg orvepitant versus placebo in:
- Reducing 24-hour objective cough frequency
- Reducing night-time (non-waking time) objective cough frequency
- Reducing subject assessed cough severity and Urge-to-Cough
- Improving Quality-of-Life and subject perception of change
To evaluate the dose-response relationship of 10 mg, 20 mg, and 30 mg orvepitant
To assess the safety and tolerability of 10 mg, 20 mg, and 30 mg orvepitant versus placebo over 12 weeks dosing
To evaluate the exposure-response relationship of orvepitant using population pharmacokinetics (PK) with sparse sampling
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects ≥18 years of age
2. Able to understand and comply with the requirements of the study and sign Informed Consent forms
3. Diagnosis of CRC or unexplained cough for at least 1 year prior to Screening (see American College Chest Physicians/British Thoracic Society [ACCP/BTS]guidelines Section 17)
4. An awake average cough frequency of ≥10 coughs/hour, as assessed using an ACM during the Screening period (note, the ACM will be worn for a 24-hour period and the average waking cough frequency determined)
5. Females must be non-pregnant and non-lactating with no intention of pregnancy during study treatment
6. Women of child-bearing potential (WOCP) (i.e. not surgically sterilised or post-menopausal*) must have a negative blood serum pregnancy test performed at the Screening visit and agree to use two methods of birth control, one of which must be a barrier method (note: the double barrier method is not considered acceptable) for the duration of participation in the study.
* Post-menopausal is defined as >1 year since the last menstrual period for women >55 years of age or >1 year since their last menstrual period and have an FSH level in the menopausal range for women <55years of age.
Acceptable methods of birth control are:
a. Surgical sterilization of the subject’s male partner (vasectomy with documented azoospermia) if he is the sole partner of that subject
b. Established hormonal contraception (implantable, patch, oral or intramuscular [IM]) administered for at least one month prior to IMP administration and to continue for at least 4 weeks after the last dose of IMP
c. An intrauterine device (IUD) or intrauterine system (IUS) with failure rate of less than 1% per year inserted by qualified physician at least one month prior to IMP administration and to remain in place for at least 4 weeks after the last dose of IMP
d. Barrier methods such as male condom or cap, diaphragm or sponge with spermicide
7. Male subjects and their partners of child-bearing potential must use two methods of acceptable birth control, one of which must be a barrier method; male subjects must make no donation of sperm from Screening until 90 days after the last dose of IMP |
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| E.4 | Principal exclusion criteria |
1. Subjects with recent respiratory tract infection <4 weeks prior to Screening
2. Females who are breast feeding or pregnant
3. Current smokers or ex-smokers with <6 months’ abstinence prior to Screening
4. Treatment with Angiotensin Converting Enzyme inhibitors within 3 months of Screening
5. A history of drug or alcohol abuse within 12 months of Screening
6. Both FEV1 <80% predicted and FEV1/FVC ratio < 0.7, measured at Screening using spirometry
7. History of cystic fibrosis, idiopathic pulmonary fibrosis, clinically significant bronchiectasis, moderate to severe asthma, chronic obstructive pulmonary disease
8. Evidence of uncontrolled hypertension at Screening or Baseline (As guidance, systolic >160 mm Hg or diastolic >90 mmHg should result in further evaluation which may include repeat measurements after a period of rest)
9. Recent myocardial infarction within 1 year prior to Screening, or history of congestive cardiac failure
10. Any clinically significant abnormalities on 12-lead ECG at Screening or Baseline/Day 1
11. Subjects with prior renal transplant, current renal dialysis, or history of renal tubular acidosis
12. Any clinically significant neurological disorder
13. Any clinically significant or unstable medical or psychiatric condition that would interfere with the subject's ability to participate in the study
14. Subjects with a prior medical history of or an increased risk of seizures (except febrile seizures in infancy), or who have a history of recent head trauma within the last 6 months prior to Screening that resulted in a loss of consciousness or concussion
15. Any malignancy in the past 5 years unless noninvasive and in remission (disease-free for >5 years prior to Screening) and written approval has been obtained from Sponsor, with the exception of skin cancers not including malignant melanoma
16. Any clinically significant abnormal laboratory test result(s) measured at Screening (The investigator should judge the clinical relevance of any abnormal laboratory parameters in the context of the subject’s current and past medical history and any know contributing factors)
17. Inability to comply with the use of prohibited and allowed medications as described below:
a. The use of opioids, dextromethorphan, gabapentin, pregabalin, baclofen, antihistamines or tricyclic antidepressants for treatment of cough is not allowed throughout the study. Subjects must have discontinued these drugs at least 1 month prior to Screening. Subjects may, however, be permitted to continue to use these drugs if they have been prescribed solely for the management of another disorder
b. The use of other drugs taken solely for the treatment of cough is also prohibited from at least 1 month prior to Screening
c. Concomitant respiratory medication (other than for management of cough) is allowed, but subjects must be stable on such medication and take it for the duration of the study
d. Use of digoxin is not allowed from Screening until 1 week after the last dose of IMP
e. Use of known CYP3A4 substrates with a narrow therapeutic range is not allowed from Screening until 1 week after the last dose of IMP (including but not limited to alfentanil. cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus)
f. Use of strong or moderate inhibitors of CYP3A4 is not allowed from Screening until 1 week after the last dose of IMP (including but not limited to clarithromycin, erythromycin, grapefruit juice, indinavir, lopinavir, ritonavir, saquinavir, atazanavir, itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole, cimetidine, cyclosporine, diltiazem, fluvoxamine, imatinib, verapamil, troleandomycin and ciprofloxacin)
g. Use of inducers of CYP3A4 is not allowed from Screening until 1 week after the last dose of IMP (including but not limited to rifampicin, carbamazepine, efavirenz, bosentan, modafinil, St. John's Wort)
h. Use of known P-glycoprotein inhibitors is not allowed from Screening until 1 week after the last dose of IMP (including but not limited to amiodarone, azithromycin, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir and ritonavir, quinidine, ranolazine, verapamil)
18. Participation in any clinical research study evaluating another investigational drug or therapy within 30 days or within 5 half-lives (whichever is longer) of the investigational drug prior to Screening. If the subject is in an observational clinical study no washout is required
19. Subjects receiving aprepitant (Emend® ) or fosaprepitant (Ivemend® ), NK-1 antagonists licensed as anti-emetics <4 weeks before the Screening visit
20. Subjects who have previously received orvepitant at any time
21. Known allergy to any of the excipients used in the IMP
22. Subjects who, in the opinion of the Investigator, should not participate in the study for any other reason
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from Baseline to Week 12 in awake objective cough frequency measured with an automated cough monitor (ACM), the ‘Vitalojak™’
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Change in awake objective cough frequency at Weeks 2, and 4 compared to Baseline
- Change in 24-hour objective cough frequency at Weeks 2, 4 and 12 compared to Baseline
- Change in night-time (non-waking time) objectivecough frequency at Weeks 2, 4 and 12 compared to Baseline
- Change in the Cough Severity visual analogue scale (VAS) at Weeks 2, 4, 8, and 12 compared to Baseline
- Change in the Urge-to-Cough VAS at Weeks 2, 4, 8, and 12 compared to Baseline
- Change in the Leicester Cough Questionnaire (LCQ) score (total and three domain scores) at Weeks 2, 4, 8, and 12 compared to Baseline
- Global Rating of Change in Cough Frequency and Severity at Weeks 2, 4, 8, and 12
Safety
- Change from Baseline in clinical laboratory assessments (hematology, clinical chemistry, urinalysis)
- Change from Baseline in vital signs (temperature, sitting/standing Blood Pressure (BP), pulse, respiration rate, weight)
- Change from Baseline in 12-lead Electrocardiogram (ECG) variables (heart rate and rhythm and RR, PR, QRS, QT, QTcF and QTcB intervals)
- Nature and severity of Adverse Events (AE)
- Withdrawals due to an AE
- Use of concomitant medications
Pharmacokinetics
- PK exposure-response relationship for the orvepitant groups (10 mg, 20 mg, and 30 mg) will be carried out to examine the possible relationship over time between clinical efficacy and plasma levels of the drug
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Week 2
- Week 4
- Week 8
- Week 12 |
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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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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