Efficacy and Safety Study of AeroVanc for the Treatment of Persistent MRSA Lung Infection in Cystic Fibrosis Patients

The purpose of this study is to determine whether AeroVanc treatment is safe and effective in reducing the number of MRSA colony forming units in the lungs of cystic fibrosis patients.

This is a Phase 2a randomized, multicenter, double-blind, placebo-controlled, parallel group study to examine the safety and efficacy of AeroVanc in the treatment of persistent MRSA lung infection in CF patients. Pharmacokinetics will be evaluated in a subgroup by measuring plasma and sputum concentrations of vancomycin.

Prior to treatment, patients will be randomized to receive either AeroVanc twice daily (bid), or placebo bid. Patients will be stratified based on the presence of a Pseudomonas aeruginosa (P. aeruginosa) co-infection that is being treated with a chronic suppression regimen. Patients with P. aeruginosa co-infection can be on any chronic inhaled suppression regimen (or nothing if the patient is considered stable in the opinion of the investigator despite the lack of treatment). Regardless of treatment regimen, if there is an off month, screening should be scheduled so that AeroVanc or placebo administration can be given during this time. Patients with no off month should be screened so that the AeroVanc or placebo administration period coincides with a treatment cycle other than TOBI (e.g., Cayston or colistin). All patients must have at least a 24-hour washout period after stopping their anti-Pseudomonas therapy and prior to the Visit 2 (Baseline) pre-dose microbiology sputum sample. The AeroVanc or placebo treatment duration is 28 days, during which efficacy and safety parameters will be measured, and after which patients will be followed up for 56 days.

There will be two treatment cohorts in this study, each comprised of 40 randomized (1:1 active to placebo) and treated patients (adults ≥18 and children ≥12 years of age). In Cohort 1, patients will be enrolled and randomized to receive the 32 mg dose of AeroVanc bid or placebo bid. Prior to starting enrollment in Cohort 2, a safety evaluation will be carried out by the Data Monitoring Committee (DMC) based on treatment data from the first 20 patients in Cohort 1. Subject to the Sponsor's written communication of the DMC's opinion of acceptable safety, the dose for the active arm in Cohort 2 will be escalated to 64 mg bid. Optionally, the active arm for Cohort 2 may also be kept the same (32 mg bid), or reduced to 16 mg bid, depending on the outcome of the DMC's safety evaluation.

Eligibility Criteria:
Inclusion Criteria:

1. Adults ≥18 years old (and the legally authorized representatives of children ≥12 but \<18 years old): Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form (ICF). Children ≥12 but \<18 years old: Able to communicate with site personnel and to understand and voluntarily sign the Assent Form.
2. Able and willing to comply with the protocol, including availability for all scheduled study visits.
3. Have a confirmed diagnosis of CF, determined by having clinical features consistent with the CF phenotype, plus one of the following: a) Positive sweat chloride test (value ≥60 mEq/L), or b) Genotype with two mutations consistent with CF (ie, a mutation in each of the cystic fibrosis transmembrane conductance regulator \[CFTR\] genes).
4. Be ≥12 years old at time of ICF/Assent Form signing.
5. Have sputum culture positive for MRSA at Screening, with at least 10,000 CFUs/mL of MRSA.
6. In addition to the screening sample, have at least two historical respiratory tract cultures (i.e., sputum and/or throat swab) positive for MRSA prior to Screening and evidence that the MRSA lung infection has persisted for at least 6 months prior to Screening.
7. Have forced expiratory volume in 1 second (FEV1) ≥30% and ≤100% of predicted that is normalized for age, gender, and height at Screening.
8. Evidence, defined as one or both of the following, that the persistent MRSA lung infection is suspected to be causing health consequences.

   * Have had at least one episode of acute pulmonary infection treated with non-maintenance antibiotics within 12 months from Screening. Initiation of treatment with intermittent inhaled anti-Pseudomonas therapy will not qualify as treatment with non-maintenance antibiotics.
   * Requires anti-MRSA treatment as part of a maintenance regimen to prevent pulmonary exacerbations or other respiratory symptoms.
9. Be able to perform all the techniques necessary to use the AeroVanc inhaler and measure lung function.
10. Be able to produce expectorated sputum samples or be able and willing to undergo standardized sputum induction.
11. Agree not to smoke from Screening through the end of the study.
12. Female patients of child-bearing potential are eligible to participate in this study only if they are NOT pregnant or lactating, and if the patient is using a highly effective method of birth control.
13. Patients with P. aeruginosa co-infection must either be stable on a regular suppression regimen of inhaled antibiotics or must be, in the opinion of the investigator, stable despite the lack of such treatment. Patients on a Cayston based therapy must have received at least 2 cycles of Cayston prior to Baseline (can be 2 consecutive months or 2 cycles over 4 months).

Exclusion Criteria:

1. Administration of any investigational drug or device within 28 days prior to ICF/Assent Form signing.
2. Use of iv or inhaled anti-MRSA drugs within 28 days or oral anti-MRSA drugs within 14 days prior to Visit 2 (ie, randomization, Baseline and AeroVanc/placebo treatment initiation).
3. A history of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug or placebo except for a history of red-man syndrome.
4. History of severe cough/bronchospasm upon inhalation of dry powder inhalation product, or nebulized vancomycin.
5. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus aureus \[VRSA\], or vancomycin intermediate resistant Staphylococcus aureus \[VISA\], with minimum inhibitory concentration \[MIC\] ≥4 mcg/mL).
6. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg prednisone every other day, or equipotent doses of another corticosteroid.
7. History of sputum culture or throat swab culture yielding B. cepacia or gladioli in the previous two years, or nontuberculosis mycobacteria in the previous six months.
8. An acute upper or lower respiratory infection, or pulmonary exacerbation within 7 days prior to Randomization.
9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 7 days prior to ICF/Assent Form signing.
10. Current daily continuous oxygen supplementation or requirement for more than 2 L/min at night.
11. Changes in physiotherapy technique or schedule within 7 days prior to ICF/Assent Form signing.
12. History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation.
13. A chest X-Ray at Screening with abnormalities indicating a significant acute finding (eg, pneumothorax, or pleural effusion).
14. Lactating female or female with a positive pregnancy test result. All women of childbearing potential will be tested.
15. Renal insufficiency, defined as creatinine clearance \<50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation in children, at Screening.
16. Diagnosed with clinically significant hearing loss.
17. Abnormal liver function, defined as ≥4x upper limit of normal (ULN), of serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT), or known cirrhosis at the time of Screening.
18. Serum hematology or chemistry screening results which in the judgment of the Investigator would interfere with completion of the study.
19. Positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).
20. Other findings or medical history at screening that, in the Investigator's opinion, would compromise the safety of the patient or the quality of the study data.