Arikace® for Nontuberculous Mycobacteria

• Proportion of subjects with culture conversion to negative [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Time to "rescue" anti-mycobacterial drugs [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Change from baseline in 6-minute walk distance and oxygen saturation [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Change from baseline in Patient Reported Outcomes [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Evaluation of safety and tolerability [ Time Frame: For entire study duration ] [ Designated as safety issue: Yes ]

• Proportion of subjects with culture conversion to negative [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Time to "rescue" anti-mycobacterial drugs [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Change from baseline in computed tomography scan abnormalities [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Change from baseline in 6-minute walk distance and oxygen saturation [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Change from baseline in Patient Reported Outcomes [ Time Frame: 84 days ] [ Designated as safety issue: Yes ]
• Evaluation of safety and tolerability [ Time Frame: For entire study duration ] [ Designated as safety issue: Yes ]

Nontuberculous mycobacteria (NTM) are organisms common in the soil and in environmental and potable water, and have been associated with lung disease in select patient groups. Treatment requires lengthy multi-drug regimens that can be poorly tolerated and are often not very effective, especially in patients with severe disease or in those who have failed prior treatment attempts. There have been very few clinical trials to support current treatment recommendations and no new drugs have been assessed for this disease in many years.

Amikacin is an established antibiotic that is effective against a variety of NTM. However, intravenous amikacin treatment is limited by its systemic route of administration. Arikace®, liposomal amikacin for inhalation, is a sustained-release formulation of amikacin encapsulated inside very small liposomal carriers (fat particles) designed for administration via inhalation. This formulation allows for targeting the drug to the lungs and the site of disease. The purpose of this study is to determine whether Arikace® is effective in treating recalcitrant nontuberculous mycobacterial lung disease. The safety and tolerability of Arikace® in this patient population will also be assessed.

This is a randomized, double-blind study evaluating the efficacy and safety of Arikace® administration compared to placebo for 84 days in subjects with recalcitrant non-tuberculous mycobacterial lung disease on a stable multi-drug regimen. Subjects will be randomized 1:1 to either 560 mg Arikace® or placebo administered once a day via a PARI Investigational eFlow® nebulizer. Subjects will visit the clinic about every 28 days for efficacy, safety and tolerability evaluations. At the conclusion of the double-blind portion of the study, subjects who have consented to additional treatment, will participate in an 84 day open label phase of once daily Arikace® treatment. A follow-up safety visit will occur 28 days after the conclusion of the open label treatment phase. Throughout the entire study, sputum, blood and urine specimens will be collected to assess drug concentrations in subjects who consent for Pharmacokinetic (PK) evaluation.

• Drug: Liposomal amikacin for inhalation
  • Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization.
  • 560 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer.
  • Administration time is approximately 13 minutes.
  • Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study.
  • Subjects can continue with 84 additional days of dosing in the open label extension.
• Drug: placebo
  • Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization.
  • Administration procedures, volume and administration time is the same as for Arikace™.
  • Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.

• Experimental: Arikace®
  Intervention: Drug: Liposomal amikacin for inhalation
• Placebo Comparator: Placebo
  Intervention: Drug: placebo

Key Inclusion Criteria:

1. Diagnosis of pulmonary nontuberculous mycobacterial lung disease in accordance with the 2007 ATS/IDSA criteria with evidence of nodular bronchiectasis and/or cavitary disease by chest computed tomography (CT).
2. History of chronic infection with either Mycobacterium avium complex or Mycobacterium abscessus or mixed infection with both species (defined as at least 2 documented positive cultures in the prior 2 years, of which at least one was obtained in the 6 months prior to screening).
3. Positive sputum culture obtained at screening visit with either Mycobacterium avium complex or Mycobacterium abscessus or mixed infection with one dominant species.
4. Receiving ATS/IDSA guidelines-based treatment regimen defined as: adherent to a multi-drug regimen for at least 6 months prior to screening with persistently positive mycobacterial cultures.
5. Ability to produce at least 3 mL of sputum or be willing to undergo an induction that produces at least 3 mL of sputum for clinical evaluation.
6. Female of childbearing potential agrees to practice an acceptable method of birth control (e.g., abstinence, hormonal or barrier methods, partner sterilization, or IUD).

Key Exclusion Criteria:

1. Forced Expiratory Volume in 1 second (FEV1) <30% of predicted at Screening.
2. Presence of any clinically significant cardiac disease as determined by Investigator. The QTc criteria for Exclusion is QTc> 450 msec for males or QTc> 470 msec for females.
3. Subjects with hemoptysis of ≥60 mL in a 24 hour period within 4 weeks prior to screening.
4. Active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within one year prior to screening or anticipated during the study period.
5. Active allergic bronchopulmonary mycosis or any other condition requiring systemic steroids at a dose ≥ equivalent of 10 mg/day of prednisone within 3 months prior to screening or anticipated during the study period.
6. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to screening.
7. History of lung transplantation.
8. Hypersensitivity to aminoglycosides.
9. Any change in chronic NTM multi-drug regimen within 28 days prior to Study Day 1.
10. Evidence of biliary cirrhosis with portal hypertension.
11. History of daily, continuous oxygen supplementation.
12. Smoking tobacco or any substance within 6 months prior to screening or anticipated inability to refrain from smoking throughout the study.