AeroVanc in the Treatment of Methicillin-resistant Staphylococcus Aureus Infection in Patients With Cystic Fibrosis

This is a multi-center, randomized phase III study to evaluate the clinical effectiveness of AeroVanc in persistent methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with cystic fibrosis (CF).

This is a phase III, 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 patients diagnosed with CF. After the Screening period to confirm study eligibility, participants are randomly assigned in a blinded fashion to receive either AeroVanc 30 mg twice daily (BID), or placebo BID (1:1 active to placebo) by inhalation for 24 weeks or 3 dosing cycles (Period 1). Upon completion of Period 1, participants receive open-label AeroVanc 30 mg BID for an additional 24 weeks or 3 dosing cycles (Period 2), to evaluate long-term safety of AeroVanc. A dosing cycle is defined as 28 days of treatment followed by 28 days of observation.

Participants on a 28-day cyclical on/off anti-Pseudomonal antibiotic regimen enter the Screening period at a time such that the Baseline visit coincide with the end of their anti-Pseudomonas antibiotic cycle. Study drug is thereby administered during the off-cycle, and participants can then resume anti-Pseudomonal therapy during the 28-day observation period. Participants continuing alternating anti-Pseudomonal therapy can continue their treatment during the study drug administration, and observation period.

The primary and secondary analyses are conducted in participants ≤21 years old. Subjects \>21 years old are analyzed separately as supportive analyses.

Eligibility Criteria:
Inclusion criteria

1. Participants ≥6 years of age at time of informed consent form or assent form signing.
2. Confirmed diagnosis of CF, determined by having clinical features consistent with the CF phenotype, plus one of the following:

   1. Positive sweat chloride test (value ≥60 milliequivalent/L),
   2. Genotype with 2 mutations consistent with CF (i.e., a mutation in each of the cystic fibrosis transmembrane conductance regulator genes).
3. Positive sputum culture or a throat swab culture for MRSA at Screening.
4. In addition to the Screening sample, have at least 2 prior sputum or throat swab cultures positive for MRSA, of which at least 1 sample is \>6 months prior to Screening. At least 50% of all MRSA cultures (sputum or throat swab culture) collected from the time of the first positive culture (in the previous 1 year) must have tested positive for MRSA. (Note: Screening sample may count towards 50% positive count)
5. FEV1 ≥30% and ≤90% of predicted that is normal for age, gender, race, and height, using the Global Lung Function Initiative equation.
6. At least 1 episode of acute pulmonary infection treated with non-maintenance antibiotics within 12 months prior to the Baseline visit (initiation of treatment with intermittent inhaled anti-Pseudomonal therapy will not qualify as treatment with non-maintenance antibiotics).
7. If female of childbearing potential, an acceptable method of contraception must be used during the study and must be combined with a negative pregnancy test obtained during Screening; sexually active male subjects of reproductive potential who are non-sterile (i.e., male who has not been sterilized by vasectomy for at least 6 months, and were not diagnosed with infertility through demonstration of azoospermia in a semen sample and/or absence of vas deferens through ultrasound) must be willing to use a barrier method of contraception, or their female partner must use an acceptable method of contraception, during the study.

   For purposes of this study, the Sponsor defines "acceptable methods of contraception" as:
   1. Oral birth control pills administered for at least 1 monthly cycle prior to administration of the study drug.
   2. A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle prior to the study drug administration but not beyond the 4th successive year following insertion.
   3. Intrauterine devices, inserted by a qualified clinician for at least 1 monthly cycle prior to study drug administration.
   4. Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1 monthly cycle prior to administration of the study drug and continuing through 1 month following study completion.
   5. Hysterectomy or surgical sterilization.
   6. Abstinence.
   7. Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive foam).

   Note: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal contraceptive exposure, reducing the effectiveness and increasing the incidence of menstruation-associated adverse reactions. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi.
8. Able and willing to comply with the protocol, including availability for all scheduled study visits and able to perform all techniques necessary to use the AeroVanc inhaler and measure lung function.
9. Agree not to smoke during any part of the clinical trial (Screening visit through end of study).
10. Participants with a Pseudomonas 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.

Exclusion criteria

1. Use of anti-MRSA treatments prescribed as maintenance therapy (intravenous \[IV\] or inhaled treatment within 28 days; oral treatment within 14 days) prior to the Baseline visit.
2. Use of non-maintenance antibiotic for pulmonary infection or extrapulmonary MRSA infection (IV or inhaled antibiotic within 28 days; oral antibiotic within 14 days) prior to the Baseline visit.
3. 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. Inability to tolerate inhaled products.
5. First time sputum culture or throat swab culture yielding Burkholderia cepacia, or nontuberculous Mycobacteria in the previous 6 months to Screening.
6. History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation.
7. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus aureus, or vancomycin intermediate resistant Staphylococcus aureus, with minimum inhibitory concentration ≥8 μg/mL).
8. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg prednisone every other day, or equipotent doses of other corticosteroids.
9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 14 days, or changes in cystic fibrosis transmembrane conductance modulators within 28 days, prior to the Baseline visit.
10. Abnormal laboratory findings or other findings or medical history at Screening that, in the Investigator's opinion, would compromise the safety of the subject or the quality of the study data.
11. Inability to tolerate inhalation of a short acting beta2 agonist
12. Oxygen saturation \<90% at Screening.
13. Changes in physiotherapy technique or physiotherapy scheduled within 1 week of the Baseline visit.
14. Administration of any investigational drug or device within 4 weeks prior to the Screening visit and during the study
15. Female with positive pregnancy test result during Screening, pregnant (or intends to become pregnant), lactating or intends to breastfeed during the study.
16. Renal insufficiency, defined as creatinine clearance \<50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation for children at the Screening visit.
17. Abnormal liver function, defined as ≥4x upper limit of normal of serum aspartate aminotransferase or serum alanine aminotransferase, or known cirrhosis at Screening.
18. Diagnosed with clinically significant hearing loss.
19. History of positive result for human immunodeficiency virus, hepatitis B virus or hepatitis C virus.
20. Planned hospitalizations for prophylaxis antibiotic treatment within 28 days prior to Baseline visit or during the double-blind period (Period 1).