Study of Dose Escalation of Liposomal Amikacin for Inhalation (ARIKAYCE™) - Extension Phase
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Intervention: Arikayce™
Intervention description: Amikacin (aminoglycoside) in a liposomal formulation.
Intervention MeSH terms: Amikacin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Extension phase for evaluation of safety, tolerability and efficacy. Single dose group of 560 mg of Arikase TM
Masking: None (Open Label)
Enrollment: 49.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No
Keywords: Cystic Fibrosis; Respiratory Infections; Pulmonary Cystic Fibrosis; CFTR

Summary:

      A major factor in the respiratory health of cystic fibrosis (CF) patients is acquisition of
      chronic Pseudomonas (P.) aeruginosa infections. The infection rate with P. aeruginosa
      increases with age and by age 18 years, 80% of patients with CF in the U.S. are infected.
      Liposomal amikacin for inhalation (LAI; Arikayce™) is a sterile aqueous liposomal suspension
      consisting of amikacin sulfate encapsulated in liposomes. This formulation of amikacin
      maximizes the achievable dose and delivery to the lungs of infected patients when delivered
      via a nebulizer. Because liposome particles are small enough to penetrate and diffuse through
      sputum into the bacterial biofilm, they deposit drug close to the bacterial colonies (Meers,
      et al., 2008) (Clancy, et al., 2013), thus improving the bioavailability of amikacin at the
      infection site. The clinically achievable doses of amikacin in the LAI formulation can
      effectively increase the half-life of the drug in the lungs, and decrease the potential for
      systemic toxicity. LAI offers several advantages over current therapies in treating patients
      with CF with chronic infection caused by P. aeruginosa.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written informed consent obtained from the patient or designated legal guardian prior
             to the performance of any study related procedures.

          2. Male or female study subjects ≥ 6 years of age or older.

          3. Confirmed diagnosis of CF defined as a positive sweat chloride > 60 milliequivalents
             (mEq)/liter (by pilocarpine iontophoresis) and/or a genotype with 2 identifiable
             mutations consistent with CF accompanied by one or more clinical features of the CF
             phenotype.

          4. History of chronic infection with P. aeruginosa (defined as 3 documented positive
             cultures in the prior 2 years of which at least one was obtained in the 3 months prior
             to randomization). The cultures could be obtained from the following respiratory
             secretions: sputum, throat swabs, nasopharyngeal swabs, or broncho-alveolar lavage
             fluid specimens.

          5. Study subjects must produce a screening specimen (expectorated or induced sputum,
             throat swabs, nasopharyngeal swabs, or broncho-alveolar lavage fluid) that is positive
             for growth of P. aeruginosa.

          6. FEV1 ≥ 40% of predicted at Screening.

          7. SaO2 ≥ 90% at Screening while breathing room air.

          8. Ability to comply with study medication use, study visits, and study procedures as
             judged by the investigator.

          9. Ability to produce 0.5 grams sputum or be willing to undergo an induction to produce
             sputum for clinical evaluation.

         10. Clinically stable with no evidence of acute upper or lower respiratory tract infection
             or history of pulmonary exacerbation within the 4 weeks prior to Screening.

        Main criteria for inclusion of patients participating in the 18-month extension period:

          1. Written informed consent obtained from the patient or designated legal guardian prior
             to the performance of any study-related procedures in the extension period.

          2. Patient meets all of the above listed inclusion criteria (1-10) of the main protocol.

        Exclusion Criteria:

          1. Administration of any investigational drug within 8 weeks prior to Screening.

          2. Emergency room visit or hospitalization for CF or respiratory-related illness within
             the 4 weeks prior to Screening.

          3. History of alcohol, medication, or illicit drug abuse within the 1 year prior to
             Screening.

          4. History of lung transplantation.

          5. Female of childbearing potential who is lactating or is not practicing an acceptable
             method of birth control (e.g., abstinence, hormonal or barrier methods, partner
             sterilization, or IUD).

          6. Positive pregnancy test. All women of childbearing potential will be tested.

          7. Use of any anti-pseudomonal antibiotics (IV antibiotics, all inhalation antibiotics,
             oral fluoroquinolones) within the 28 days prior to Screening.

          8. Initiation of chronic therapy (i.e. TOBI®, high-dose ibuprofen, rhDNase, macrolide
             antibiotics) within the 28 days prior to Screening.

          9. History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years
             of Screening.

         10. History of mycobacterial and/or Aspergillus infection requiring treatment within 2
             years prior to Screening, and/or history of allergic bronchopulmonary aspergillosis
             (ABPA).

         11. History of biliary cirrhosis with portal hypertension, or splenomegaly (refer to study
             manual).

         12. GGT, AST, or ALT ≥ 3 times the upper limit of normal at Screening visit.

         13. ANC ≤ 1000 performed at Screening visit.

         14. Serum creatinine > 1.5 times normal performed at Screening visit.

         15. History of daily, continuous oxygen supplementation or requirement for more than 2
             L/min at night.

         16. Change in chest x-ray at Screening (or within the 3 months prior to Screening) with
             new onset infiltrates or that which compromise the safety of the study patient or the
             quality of the study data.

        Main criteria for exclusion of patients participating in the 18 months extension period:

          1. Patient meets any criteria for exclusion as listed above in the main protocol.

          2. Patient who met any criteria for study drug discontinuation in the main protocol
             (TR02-105).