The Effect of Inhaled PUL-042 on Rhinovirus-induced Symptoms in Smokers With GOLD Stage 0 COPD

Study Overview
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Brief Summary
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This is a study examining the effect of inhaled PUL-042 on peak lower respiratory symptoms as measured by subject diary in early stage COPD subjects who are experimentally infected with rhinovirus. Subjects will receive 1 dose of PUL-042 followed by inoculation with HRV A16 virus 24 hours later. An additional dose of PUL-042 will be administered 48 hours post-inoculation. Subjects will be followed for 6 weeks post-inoculation

Detailed Description
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This is a randomized, double-blind, placebo-controlled Phase 2 study examining the effects of inhaled PUL-042 on Lower Respiratory Symptom Score (LRSS) in GOLD stage 0 COPD patients. Smoking subjects (>10 pyh) with symptoms suggestive of early COPD (cough, sputum production but normal spirometry, meeting GOLD 0 criteria) will be screened. Following screening (days -21 to -11 prior to infection), eligible subjects will be enrolled and will undergo a baseline sampling visit on study day -8 and will complete questionnaires from study day -8 to -2 (7 days total) recording their baseline symptoms There will be two treatment arms in the study. The arms will be: Placebo administered on study day -1 and study day 2 PUL-042 administered on study day -1 and PUL-042 administered on study day 2 On day 0 subjects will be experimentally infected with HRV A16 (100 TCID50) via an atomizer to the upper airway. Subjects will subsequently be required to attend the clinic on study days 1-7, 9, 12, 15, 21 and 42 for follow up visits. Subjects will continue their diaries at home during the period when not attending clinic visits, namely days 8, 10, 11, 13, 14, 16-20 and 22-41. Spirometry assessments will be conducted by clinic staff on clinic visit days. PEF, FEV1, FVC and FEV1/FVC ratio will be completed at the visit using the clinic study-supplied spirometry equipment. Sputum samples and serum will be analyzed for inflammatory markers. Serum samples will be obtained from subjects at screening and during clinic visits on study days -1, 0, 2, 3, 5, 7, 9, 12, 15, 21 and 42. Sputum samples will be obtained at baseline (BL) and on study days -1, 0, 2, 5, 7, 9, 12, 15, and 21. Nasal lavage samples will be collected during baseline (BL) and on study days -1, 0, 1-7, 9, 12, 15, 21 and 42 for assessment of virus load and pro-inflammatory cytokines etc. in the upper airway. Subjects will be asked to complete the following questionnaires on days -8 to day 42 during the study: The lower respiratory symptom scores as measured by Mallia The upper respiratory symptoms measured by the Jackson score as measured by Mallia The COPD Assessment Test (CAT) score The EXACT-RS Lower Respiratory Symptom questionnaire The Wisconsin Upper Respiratory Symptom Survey-11 (WURSS-11) Subjects will record any medication use in a specific diary.

Official Title
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A Phase 2, Single-Center, Double-Blind, Placebo-Controlled, Study of PUL-042 Inhalation Solution in Rhinovirus-induced Symptoms in Current Smokers With Gold Stage 0 Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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COPD

Intervention / Treatment
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* Drug: Sterile Water Injection
* Drug: PUL-042 Inhalation Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, with symptoms (cough, sputum production) suggestive of GOLD stage 0 COPD for at least one year prior to the screening visit in accordance with the GOLD 2014 guidelines; Current smokers with >10 pyh; Subject has risk of COPD defined by GOLD Staging Criteria level 0 where the subjects' post-bronchodilator FEV1/FVC ratio >0.70 and FEV1 is >80% normal predicted; CAT score at screening >3 and < 15; Sero-negativity to HRV A16 neutralizing antibody; Patients together with their partners of reproduction potential (males and females) must practice an acceptable method of birth control with a failure rate of a Pearl index of less than 1% per year, to be used consistently and correctly throughout the course of the study. Ability to understand and give informed consent. Exclusion Criteria: Sero-positivity to HRV A16 Use of systemic or nasal topical steroids, inhaled corticosteroids (ICS), systemic immunosuppressants, antibiotics, LABA, and LAMA and oral theophylline and/or roflumilast within 30 days; Subjects with evidence of an upper or lower respiratory infection within 6 weeks; A history or current evidence of bronchiectasis, cystic fibrosis, interstitial lung disease or other significant chronic lung disease; A history within the last 5 years or current evidence of carcinoma of the bronchus; A history within the last 5 years or current evidence of asthma; A history of active tuberculosis or history of significant lung disease as a result of previous tuberculosis infection; A medical history or current clinical evidence of significant hematological, gastrointestinal, renal, hepatic, cerebrovascular, immunologic, psychiatric or cardiovascular disease or event (including uncontrolled hypertension as determined by the Investigator), or any clinical condition that may, in the opinion of the Investigator or Medical Monitor, impact on the subject's ability to participate in the study; Clinical laboratory values at screening for neutrophils, hemoglobin and hematocrit which reflect grade 2 or higher reductions from normal range, or ALT results which reflect grade 2 or higher elevations per the 'CTCAE' guidelines. Subjects with other clinical laboratory abnormalities outside normal reference ranges will be considered for inclusion, if in the opinion of the Principal Investigator or Medical Monitor the abnormalities are not clinically significant, or will not jeopardize the safety of the subject or the validity of the study; Use of cold preparations, anti-cholinergics, nasal lavage preparations or sprays, cough medications, or prescription or over-the-counter nasal decongestants within 30 days; Current abuse of alcohol or illicit drugs, or history of alcohol or illicit drug abuse within the preceding 2 years; A positive pregnancy test at screen; Received an investigational drug or vaccine within 30 days or 5 half-lives (whichever is longer), or use of an investigational medical device within 30 days prior to the screening visit or in the interval between screening and study day -1; Inability to tolerate nebulization based on the Principal Investigator's medical judgment or a ≥12% drop in FEV1, at either 15 or 30 minutes after the completion of administration of a dose of nebulization test solution (SWFI) of the same volume and under the same nebulization conditions that is planned to be used for study drug administration, compared to the FEV1 obtained immediately prior to administration of the nebulization test solution.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PUL-042<br>PUL-042 Inhalation Solution | Drug: PUL-042 Inhalation Solution<br>* PUL-042 Inhalation Solution<br>|
| Placebo Comparator: Placebo<br>Sterile Water for injection | Drug: Sterile Water Injection<br>* Inhaled Sterile Water Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lower Respiratory Symptom Score as measured by Mallia et al (Am J Respir Crit Care Med. 2011) | The peak daily lower respiratory symptom score as measured by Mallia recorded in the 6 weeks post-infection period. This is a measure of a number of lower respiratory symptoms in a 24 hour period that include: shortness of breath (scale 0-4; 0 = not breathless, 4 = breathless at rest) wheeze (0-4; 0 = no wheeze, 4 = wheeze at rest), cough (0-3; 0 = no cough, 3 = severe cough), sputum quantity (0-3; 0 = none, 3 = large volume , more than 100 ml) sputum quality (0-3; 0 = none, 3 = purulent, green in colour). The total lower respiratory symptom score is the sum of all the above measurements (minimum 0, maximum 17) recorded on each day. These values will be recorded via a study diary over a six week period (day 0-42). Peak value is the highest daily total value over the 6 week post-infection period. | Daily Scores Day 0-42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lower Respiratory Symptoms | The EXAcerbations of Chronic obstructive disease Tool-Respiratory Symptoms (EXACT-RS) | Daily Scores Days 0-42 | 
| Lower Respiratory Symptoms | COPD Assessment Test (CAT) | Daily Scores Days 0-42 | 
| Upper Respiratory Symptoms | Jackson Score as measured by Mallia et al (Am J Respir Crit Care Med. 2011). A modified Jackson score will be utilized which assesses the following eight upper respiratory symptoms daily: nasal congestion, runny nose, sneezing, cough, sore throat, general malaise, headache, chilliness (each scored 0-3 where 0 = none, 3 = severe). Minimum daily score= 0, maximum daily score= 24. | Daily Scores Days 0-42 | 
| Upper Respiratory Symptoms | Wisconsin Upper Respiratory Symptom Survey-11 (WURSS-11) | Daily Scores Days 0-42 | 
| Lung Function | Peak Expiratory Flow (PEF) L/min | Days 0-42 | 
| Lung Function | Forced Expiratory Volume in 1 Second (FEV1) L/second | Days 0-42 | 
| Lung Function | Forced Vital Capacity (FVC) L | Days 0-42 | 
| Lung Function | FEV1/FVC ratio | Days 0-42 | 
| Inflammatory Mediator | CXCL 10/IP-10 measured by ELISA in nasal secretions, sputum and serum. Results reported in pg/mL | Days 0-42 | 
| Inflammatory Mediator | IL-6 measured by ELISA in nasal secretions, sputum and serum. Results reported in pg/mL | Days 0-42 | 
| Number of successfully infected patients | Detectable virus load; seroconversion | Days 0-42 |