Clinical trial NCT01315236: Liposomal Amikacin for Inhalation (LAI) for Nontuberculous Mycobacteria
Official title: A Randomized, Double-Blind, Placebo-Controlled Study of Liposomal Amikacin for Inhalation in Patients With Recalcitrant Nontuberculous Mycobacterial Lung Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Mycobacterium Infections, Nontuberculous
Keywords: Amikacin Liposome Inhalation Suspension (ALIS)
Arikayce
Lead sponsor: Insmed Incorporated
Sponsor class: INDUSTRY
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-03-15
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy, safety and tolerability of 84 days of daily dosing of 590 mg of LAI versus placebo in patients with treatment refractory NTM lung disease.

The first part of the study is the 84-day double-blind phase to evaluate the primary and secondary endpoints.

Detailed description: This was a Phase 2, randomized, double-blind study of efficacy, safety, and tolerability of once daily (QD) dosing of LAI 590 mg versus placebo for 84 days in subjects with treatment refractory NTM lung infection on a stable multidrug regimen. At the conclusion of the randomized double-blind phase of the study, subjects who consented to continue in the open-label phase of the study received LAI 590 mg QD for 84 additional days. All subjects were required to complete a 28-day safety follow-up after their end of treatment study visit (Day 168). Subjects completing this study were consented for enrollment in a long-term follow-up phase and were asked to return to the study site at 12 months and 24 months (per protocol Amendment #3, the 24-month follow-up visit was no longer required) (visit window ± 2 months) after the last dose of study drug (either after completing the randomized double-blind phase or the open-label phase). Subjects were stratified upon entering the study based on the presence or absence of cystic fibrosis (CF) and Mycobacterium avium complex versus M abscessus as the predominate NTM organism at baseline and were block randomized to receive either LAI or placebo in a 1:1 ratio in the double-blind phase.

Subjects completing the main study, and subjects who completed the 84-day open-label phase, were consented for enrollment in a post-LAI safety follow-up assessment and were asked to return to the study site 12 months (visit window ± 2 months) after the last dose of study drug (either after completing the randomized double-blind phase or the open-label phase). The screening period required obtaining 3 morning sputum specimens (spontaneous or induced) for mycobacteriology. At each post-screening sputum timepoint, at least 2 and preferably 3 sputum specimens were obtained. At Day 1 (baseline), subjects were evaluated pre-dose and post-dose at the study site. Subjects returned to the study site briefly on Day 2 for collection of serum samples to determine creatinine clearance. On Days 28, 56, and 84, study drug was administered at the site and the efficacy, safety, and tolerability of study drug were evaluated. At Day 85, those subjects continuing in the open-label phase of the study received LAI 590 mg at the study site with pre-dose and post-dose assessments for safety and efficacy. Subjects returned every 28 days (Days 112, 140, and 168) in the open-label phase. A 28-day, post-dose follow-up visit occurred at either Day 112 for those subjects who did not continue in the open-label phase or at Day 196 for those subjects who continued in the open-label phase.

Subjects completing the main study, and subjects who completed the 84-day open-label phase, were consented for enrollment in a post-LAI safety follow-up assessment and were asked to return to the study site 12 months (visit window ± 2 months) after the last dose of study drug (either after completing the randomized double-blind phase or the open-label phase). Arikace™, Arikayce™, Liposomal Amikacin for Inhalation (LAI), and Amikacin Liposome Inhalation Suspension (ALIS) may be used interchangeably throughout this study and other studies evaluating amikacin liposome inhalation suspension.

Eligibility criteria: 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.

Subjects with CF or primary ciliary dyskinesia were eligible to participate in the study if all eligibility criteria defined above were met. Subjects with CF were required to have documented confirmation of CF to be eligible for the study. The CF diagnosis had to be documented by a positive sweat test ≥ 60 mmol/L or by DNA analysis revealing both mutated alleles consistent with CF disease.

Primary outcomes:
measure: Change in Semi-Quantitative Mycobacterial Culture Results From Baseline to Day 84.
timeFrame: Baseline and end of double-blind phase of 84 days
Secondary outcomes:
measure: Number of Subjects With Negative NTM Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84
timeFrame: 84 days double-blind phase
measure: Time to Negative NTM Culture….During the 84-day Double-blind Treatment Phase
timeFrame: 84 days double-blind phase
measure: Ordinal, 3-level Response From Baseline on the SQS for Mycobacterial Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84
timeFrame: Baseline and end of double-blind phase of 84 days
measure: Change From Baseline in Respiratory and Systemic Symptoms Questionnaire (RSSQ) Score at Day 84 for the LAI Arm Compared to the Placebo Arm
timeFrame: Baseline to day 84.
measure: Change From Baseline in Global Rating of Health (GRH) at Day 84 for the LAI Arm Compared to the Placebo Arm
timeFrame: Baseline and end of double-blind phase of 84 days
measure: Number of Participants Requiring "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day Double-blind Phase
timeFrame: 84 days double-blind phase
measure: Number of Subject for "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day Double-blind Phase
timeFrame: 84 days double-blind phase
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Stanford
country: United States
state: California
city: Denver
country: United States
state: Colorado
city: Washington
country: United States
state: District of Columbia
city: Gainesville
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Kansas City
country: United States
state: Kansas
city: Bethesda
country: United States
state: Maryland
city: Rochester
country: United States
state: Minnesota
city: New York
country: United States
state: New York
city: Chapel Hill
country: United States
state: North Carolina
city: Cleveland
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Philadelphia
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Tyler
country: United States
state: Texas
city: Milwaukee
country: United States
state: Wisconsin
city: Hamilton
country: Canada
state: Ontario
Study officials:
affiliation: Insmed Incorporated
name: Gina Eagle
role: STUDY_DIRECTOR
References:
citation: Rubino CM, Onufrak NJ, van Ingen J, Griffith DE, Bhavnani SM, Yuen DW, Mange KC, Winthrop KL. Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment-Refractory Nontuberculous Mycobacterial Lung Disease. Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):277-287. doi: 10.1007/s13318-020-00669-7. Epub 2021 Feb 17.
citation: Olivier KN, Griffith DE, Eagle G, McGinnis JP 2nd, Micioni L, Liu K, Daley CL, Winthrop KL, Ruoss S, Addrizzo-Harris DJ, Flume PA, Dorgan D, Salathe M, Brown-Elliott BA, Gupta R, Wallace RJ Jr. Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease. Am J Respir Crit Care Med. 2017 Mar 15;195(6):814-823. doi: 10.1164/rccm.201604-0700OC.