| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Cough in Idiopathic Pulmonary Fibrosis |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of Cough in Idiopathic Pulmonary Fibrosis |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| 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 safety and tolerability of nalbuphine ER tablets in the study population.
• To evaluate the effect of NAL ER tablets on the mean daytime cough frequency (coughs per hour) at Day 22 (dose 162 mg BID) as compared to placebo tablets. Assessment is done using objective digital cough monitoring. Daytime is defined as the time the subject is awake in the 24 hours after the digital cough monitor is applied for use. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the
• Effect of NAL ER on mean relative change from baseline in 24-hr cough frequency at Day 22
• Effect of NAL ER on mean relative change from baseline in nighttime cough frequency at Day 22
• Effect of escalating doses of NAL ER on the mean change from baseline on the E-RS diary cough scale (Q2) by treatment at Days 9, 16 & 22
• Effect of escalating doses of NAL ER on mean change from baseline in Cough Severity Numerical Rating Scale at Days 8, 15 & 21
• Effect of escalating doses of NAL ER on mean change from baseline in E-RS diary breathlessness scale (Qs 7, 8, 9, 10 and 11) at Days 9, 16 & 22
• Effect of escalating doses of NAL ER on mean change from baseline in 14-item EXACT version 1.1 e-diary tool total score at Days 9, 16 & 22
• Effect of escalating doses of NAL ER on mean change from baseline in PROMIS Item Bank v1.0 Fatigue Short Form 7a scale at Day 21
• Change in CGI-C over time at Day 21
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of “definite” or “probable” IPF based on ATS/ERS/JRS/ALAT criteria.
2. Forced vital capacity (FVC) > 40% predicted of normal.
3. Diffusing capacity of the lung for carbon monoxide corrected for hemoglobin [DLco] > 25% predicted of normal within the past 6 months. Subjects who have not had DLco testing may be enrolled with medical monitor approval.
4. Chronic cough > 8 weeks.
5. Adequate swallow reflex as assessed by the ability to sip 3 fluid oz (or 89 ml) of water without coughing or choking.
6. Daytime cough severity score ≥ 4 on Cough Severity Numerical Rating Scale at screening.
7. Males or females age 18 years and older at the time of consent.
8. Females of childbearing potential must use an acceptable method of birth control (if sexually active). All females of childbearing potential must have a negative pregnancy test at the screening and baseline visits.
9. Willing and able to understand and provide written informed consent.
10. Willing and able to comply with study requirements and restrictions.
11. Agree to the confidential use and storage of all data and use of all anonymized data for publication including scientific publication.
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| E.4 | Principal exclusion criteria |
1. The following conditions are excluded:
a) Interstitial lung disease (ILD) known to be caused by domestic and occupational environmental exposures.
b) Interstitial lung disease (ILD) known to be caused by connective tissue disease.
c) Interstitial lung disease (ILD) known to be caused by drug related toxicity.
2. Currently on continuous oxygen therapy for longer than 16 hours at any level or delivered by any modality. Intermittent oxygen use of any duration over any given 24-hr period is allowed.
3. Upper or lower respiratory tract infection within 4 weeks of screening.
4. Clinical diagnosis of sleep apnea and/or use of continuous positive airway pressure (CPAP).
5. Clinical diagnosis of aspiration pneumonitis.
6. Documented or clinically suspected hypercapnia (pCO2 >6.0kPa).
Medication-related Exclusions:
7. Potential subjects cannot have received opiates, including opiate containing anti-cough agents, within 14 days prior to the screening period. Subjects are prohibited from using opioids, including naltrexone, for the duration of the study.
8. Change of IPF-related drug treatment regimen within 8 weeks of screening.
9. Potential subjects cannot currently be receiving benzodiazepines or other CNS Depressant Class Drugs that when used concomitantly with opioids are known to have the potential to cause added pharmacologic effects of depressing CNS activity.
10. Potential subjects cannot currently be receiving medications that affect serotonergic neurotransmission and that when used concomitantly with opioids can cause serotonin syndrome.
11. Alcohol consumption should be limited for the duration of study treatment (due to the potential cause of added pharmacologic effects of CNS depression when used concomitantly with opioids.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change in daytime cough frequency (coughs per hour) from baseline as assessed by objective digital cough monitoring at Day 22 by treatment. Daytime is defined as the time the subject is awake in the 24 hours after the digital cough monitor is applied for use. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Relative change in daytime cough frequency (coughs per hour) from baseline at Day 22 (dose 162 mg BID) by treatment.
• Relative change in 24-hour (combined daytime and nighttime) cough frequency (coughs per hour) from baseline at Day 22 (dose: 162 mg BID) by treatment.
• Relative change in nighttime cough frequency (coughs per hour) from baseline at Day 22 (dose: 162 mg BID) by treatment.
• Mean change in the E-RS diary cough subscale (E-RS diary question number 2) from baseline, at Days 9, 16, and 22 by treatment.
• Mean change in the Cough Severity Numerical Rating Scale at Days 8, 15, and 21 by treatment.
• Mean change in the E-RS diary breathlessness subscale (E-RS diary questions 7, 8, 9, 10, and 11) from baseline at Days 9, 16, and 22 by treatment.
• Mean change in the 14-item EXACT v1.1 e-diary tool total score from baseline at Days 9, 16, and 22 by treatment.
• Mean change in the PROMIS Item Bank v1.0 Fatigue Short Form 7a scale from baseline at Day 21 by treatment.
• Mean change in the CGI-C over time measured at Day 21 by treatment.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Days 8, 9, 15, 16, 21 and 22 |
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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 | Yes |
| 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 | 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | 2 |
| 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 | 15 |
| 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 | 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
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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 | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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