Efficacy and Safety of Inhaled Nitric Oxide (NO) in Cystic Fibrosis (CF) Patients

Study Overview
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Brief Summary
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Prospective, randomized, placebo controlled, phase II clinical study of subjects crossing over from an approved inhaled antibiotic to inhaled nitric oxide as compared to a placebo control arm.

Detailed Description
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This is a multi-center, randomized, placebo controlled, phase II clinical study comparing an investigational drug to a placebo control. Screening data will be reviewed to determine subject eligibility. All subjects including screen failure subjects will be recorded on screening logs at their respective sites. Upon successful completion of all screening procedures, a subject will be considered eligible for enrollment. The subject will be enrolled and randomized in as close a time proximity to the first treatment application as is possible in order to minimize the possibility of dropout while enrolled but before undergoing treatment. With a 1:1 investigational treatment to placebo control, subjects will be randomized to one of the two arms. Subjects in the investigational treatment arm will be administered doses of NO (0.5% NO in 99.5% nitrogen) diluted in room air by inhalation four times daily (30-minute inhalations at least 3 hours apart) for 7.5 days on Days 1, 2, 3, 4, 5, 8, 9, and 10 (three treatments on Days 1 and 10). Subjects in the placebo arm will breathe 100% nitrogen diluted in room air in the same proportion as the investigational arm. Subjects will remain in the clinic for 30 minutes after completing the last treatment of each day. All subjects will be asked to return to the clinic for additional evaluations on Days 15 and 36.

Official Title
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Prospective, Randomized, Placebo Controlled Trial of the Efficacy and Safety of Inhaled Nitric Oxide (NO) in Cystic Fibrosis (CF) Patients

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Nitric Oxide 160 ppm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of Cystic Fibrosis based on the following criteria: positive sweat chloride 60 mEq/liter (by pilocarpine iontophoresis); and/or a genotype with two identifiable mutations consistent with CF Presence of Pseudomonas aeruginosa, Staphylococcus aureus or Stenotrophomonas maltophilia in the screening sputum culture. Chronic microbial lung colonization (≥6 months) with presence of Pseudomonas aeruginosa, Staphylococcus aureus or Stenotrophomonas maltophilia in at least two (2) sputum cultures in the past year (the screening culture can count as one of the two positive cultures). Ongoing chronic inhaled antibiotic therapy for at least 3 months prior to (screening or baseline). • For subjects on cycled therapy, at least 2 cycles of drug need to have been completed prior to baseline. Willing to be off of inhaled antibiotic therapy from Day 1 to Day 15 Male or female subjects ≥18 years FEV1 <85% and >35% at screening and baseline SaO2 >90% on room air at screening and baseline Clinically stable with no significant changes in health status within 14 days prior to Baseline Written Informed Consent and HIPAA authorization Non-smoker for at least 6 months prior to screening and agrees not to smoke during the study Chest x-ray within the last six (6) months. If none, a chest x-ray is required before randomization. Willing and able to comply with the treatment schedule and procedures. Exclusion Criteria: Initiation of any new chronic therapy (e.g., ibuprofen, Pulmozyme®, hypertonic saline, azithromycin, TOBI®, Cayston®) within 4 weeks prior to screening. Use of antibiotics [oral, intravenous (iv), and/or inhaled] for acute respiratory symptoms within 2 weeks prior to baseline. Significant hemoptysis within 30 days prior to screening (≥5 mL of blood in one coughing episode or >30 mL of blood in a 24 hour period) History of colonization with nontuberculosis mycobacterium in sputum culture. The investigator can be guided by the following suggested criteria for a subject to be considered free of colonization: Two respiratory tract cultures negative for NTM in the last year, with no subsequent positive cultures; and these 2 respiratory cultures must be separated by at least 3 months; and one of these two cultures has to have been obtained within the last 6 months Cardiac (left heart) insufficiency (defined as LVEF <35%) at screening Use of a nitric oxide donor agent such as nitroglycerin or drugs known to increase methemoglobin such as lidocaine, prilocaine, benzocaine or dapsone at screening Any of the following abnormal lab values at Screening: Hemoglobin < 10 g/dl Methemoglobn >3% Platelet count <100,000/mm3 Prothrombin time international ratio (INR) > 1.5 Abnormal liver function defined as any two of the following: ALT >3 x ULN AST >3 x ULN ALP > 3 x ULN GGT > 3 x ULN Abnormal liver function defined as: ALT >5 x ULN AST >5 x ULN Abnormal renal function defined as: Calculated Creatinine Clearance < 50 mL (as calculated by Cockcroft/Gault) For women of child bearing potential: positive pregnancy test at screening or lactating or unwilling to practice a medically acceptable form of contraception from screening to Day 36 (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent) Use of an investigational drug within 30 days prior to screening Intravenous or oral steroids in the 14 days prior to screening Current use of inhaled steroids >500 micrograms twice daily of Fluticasone or equivalent in the 30 days prior to screening Use of supplemental oxygen (daytime or nocturnal) in the 7 days prior to screening Any condition that the Investigator believes would interfere with the intent of this study or would make participation not in the best interest of the subject

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitric oxide gas at 160 ppm<br>Nitric oxide gas at 160 ppm inhaled four times daily for 30 min delivered with air as the carrier via nasal inhalation for a total of 7.5 days. Total dose of 2400 ppm hours. | Drug: Nitric Oxide 160 ppm<br>* Nitric Oxide 160 ppm<br>|
| Placebo Comparator: Breathing 20.3% oxygen<br>Breathing 20.3% oxygen inhaled four times daily for 30 min delivered with air as the carrier via nasal inhalation for a total of 7.5 days.. 100% nitrogen will be injected into the breathing circuit (instead of 99.5% nitrogen and 0.5% NO). | Drug: Nitric Oxide 160 ppm<br>* Nitric Oxide 160 ppm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FEV1 % predicted from baseline to Day 15 | The primary efficacy variable for this study is absolute change from baseline FEV1% predicted to Day 15. For each subject, the change will be calculated as the FEV1% value minus the baseline FEV1%, i.e., a positive change in FEV1% values will indicate an increase in FEV1% after treatment. The primary endpoint for this trial is the comparison of the mean absolute change from baseline in FEV1% between treatment groups. | 15 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean absolute change in FEV1% from baseline to Day 15 in the NO group (within group test). | Clinical Measurement of Mean absolute change in FEV1% from baseline to Day 15 in the NO group (within group test). | 15 days | 
| Mean change in prevalent recovered organisms' sputum CFU g (log 10) from baseline to Days 10, 15 and 36 | Clinical Measurement of Mean change in prevalent recovered organisms' sputum CFU g (log 10) from baseline to Days 10, 15 and 36 | 36 days | 
| Mean change in distance walked in the six-minute walk test from baseline to Days 15 and 36. | Clinical Measurement of Mean change in distance walked in the six-minute walk test from baseline to Days 15 and 36. | 36 days | 
| Mean absolute change in FEV1 % predicted from baseline to Days 10 and 36. | Clinical Measurement of Mean absolute change in FEV1 % predicted from baseline to Days 10 and 36. | 36 days | 
| Mean change in FEV1 % predicted (relative) from baseline to Days 10, 15, and 36. | Clinical Measurement of Mean change in FEV1 % predicted (relative) from baseline to Days 10, 15, and 36. | 36 days | 
| Mean change in FVC from baseline to Days 10, 15 and 36 | Clinical Measurement of Mean change in FVC from baseline to Days 10, 15 and 36 | 36 days | 
| Mean change in FEF25-75 from baseline to Days 10, 15 and 36 | Clinical Measurement of Mean change in FEF25-75 from baseline to Days 10, 15 and 36 | 36 days | 
| Mean change in CFQ-R scores for each domain from baseline to Days 15 and 36 | Clinical Measurement of Mean change in CFQ-R scores for each domain from baseline to Days 15 and 36 | 36 days | 
| Counts of CFRSD-CRISS symptom scores for each symptom from evening prior to Day 1 to each day of the study (Days 1-35) | Clinical Measurement of Counts of CFRSD-CRISS symptom scores for each symptom from evening prior to Day 1 to each day of the study (Days 1-35) | 35 days | 
| Number of subjects with a relative improvement between baseline and Day 10 in FEV1 % predicted of ≥7.5% | Clinical Measurement of Number of subjects with a relative improvement between baseline and Day 10 in FEV1 % predicted of ≥7.5% | 10 days | 
| Number of subjects with an absolute improvement in CFQ-R survey scores ≥5 between baseline and Days 15 and 36 | Clinical Measurement of Number of subjects with an absolute improvement in CFQ-R survey scores ≥5 between baseline and Days 15 and 36 | 36 days | 
| Number of subjects with a positive response in the 6 minute walk test at Days 15 and 36 | Clinical Measurement of Number of subjects with a positive response in the 6 minute walk test at Days 15 and 36 | 36 days |