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

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

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.

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.

Inclusion Criteria:

1. 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

2. Presence of Pseudomonas aeruginosa, Staphylococcus aureus or Stenotrophomonas maltophilia in the screening sputum culture.

3. 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).

4. 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.

5. Willing to be off of inhaled antibiotic therapy from Day 1 to Day 15

6. Male or female subjects ≥18 years

7. FEV1 <85% and >35% at screening and baseline

8. SaO2 >90% on room air at screening and baseline

9. Clinically stable with no significant changes in health status within 14 days prior to Baseline

10. Written Informed Consent and HIPAA authorization

11. Non-smoker for at least 6 months prior to screening and agrees not to smoke during the study

12. Chest x-ray within the last six (6) months. If none, a chest x-ray is required before randomization.

13. Willing and able to comply with the treatment schedule and procedures.

Exclusion Criteria:

1. Initiation of any new chronic therapy (e.g., ibuprofen, Pulmozyme®, hypertonic saline, azithromycin, TOBI®, Cayston®) within 4 weeks prior to screening.

2. Use of antibiotics [oral, intravenous (iv), and/or inhaled] for acute respiratory symptoms within 2 weeks prior to baseline.

3. 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)

4. 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

5. Cardiac (left heart) insufficiency (defined as LVEF <35%) at screening

6. 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

7. 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)

8. 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)

9. Use of an investigational drug within 30 days prior to screening

10. Intravenous or oral steroids in the 14 days prior to screening

11. Current use of inhaled steroids >500 micrograms twice daily of Fluticasone or equivalent in the 30 days prior to screening

12. Use of supplemental oxygen (daytime or nocturnal) in the 7 days prior to screening

13. 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