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Abstract
Rationale: Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC).
Objectives: To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease.
Methods: Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6.
Measurements and Main Results: Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08–8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00–7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively.
Conclusions: Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events.
Clinical trial registered with www.clinicaltrials.gov (NCT02344004).
Mycobacterium avium complex (MAC) lung disease is progressive, potentially life-threatening, and difficult to treat, particularly in patients with advanced underlying conditions, such as fibrocavitary lung disease. Treatment intensification for patients who do not respond to standard guideline-based therapy (GBT) is limited by safety issues associated with long-term parenteral antibiotic administration and is often unsuccessful. Amikacin liposome inhalation suspension (ALIS) increases amikacin uptake into alveolar macrophages, allows biofilm penetration, and limits systemic exposure. ALIS was FDA approved September 28, 2018, for the treatment of refractory MAC lung disease as part of combination therapy in patients with limited or no treatment options.
The prospective, open-label, randomized CONVERT study compared the efficacy and safety of ALIS + GBT with GBT alone in 336 adults with treatment-refractory MAC lung disease. ALIS + GBT significantly increased culture conversion rates by Month 6 compared with GBT alone (29.0% vs. 8.9%; odds ratio, 4.22; 95% confidence interval, 2.08–8.57; P < 0.001). Addition of ALIS to GBT was associated with higher rates of primarily respiratory adverse events. These findings suggest that ALIS may provide an important addition for the management of patients with MAC lung disease who have not responded to previous therapy.
Nontuberculous mycobacteria (NTM) are widespread environmental organisms that cause lung disease primarily in individuals with chronic underlying pulmonary pathologies, such as bronchiectasis and chronic obstructive pulmonary disease (1, 2). In the United States and Canada, epidemiologic studies have estimated the annual prevalence of diagnosed NTM lung disease to be 5.5–9.8 cases per 100,000 individuals and increasing, with a markedly higher prevalence (20–47 cases per 100,000) reported in individuals older than 65 years of age (1–4). International prevalence rates vary but are increasing in Europe, Australia, Japan, and possibly elsewhere (1, 5, 6). NTM lung disease is chronic and can be debilitating; 5-year mortality rates up to 40.1% have been reported (7–11).
Mycobacterium avium complex (MAC) bacteria are the most common cause of NTM lung disease in most countries in North and South America, Europe, Asia, and Australia (1). Recommended initial guideline-based therapy (GBT) for MAC lung disease, issued by the American Thoracic Society and the Infectious Diseases Society of America, includes a three-drug antibiotic regimen composed of a macrolide, ethambutol, and a rifamycin, with consideration given based on severity of disease and other patient characteristics (12). The microbiologic goal of treatment is 12 months of negative sputum cultures while on GBT. Culture conversion may be attained in most patients compliant with GBT (13, 14), although less frequently in those with more advanced disease, including previously treated patients and those with cavitary disease (15, 16). Therapeutic alternatives are limited for patients who do not respond to GBT (17).
Amikacin is a potent antimycobacterial agent given intravenously; however, because of renal and auditory toxicity (18), it is generally reserved for patients with severe NTM lung disease (12). Amikacin liposome inhalation suspension (ALIS; previously referred to as liposomal amikacin for inhalation) (19) is amikacin sulfate encapsulated in liposomes for inhalational delivery. ALIS increases amikacin uptake into alveolar macrophages, a refuge for NTM organisms; allows biofilm penetration; and limits systemic amikacin exposure (19–22). In a phase 2 study of treatment-refractory NTM lung disease, ALIS added to GBT (12) achieved the secondary endpoint of a higher rate of negative sputum cultures compared with GBT alone, and improved 6-minute-walk distance (19). Here we report the primary results at 6 months of the ongoing phase 3 CONVERT study (clinicaltrials.gov number NCT02344004) evaluating the use of ALIS in patients with MAC lung disease refractory to GBT. Some of these results were presented previously in the form of abstracts (23, 24).
Eligible patients were aged 18 years or older with active MAC lung disease as documented by MAC-positive sputum or bronchoscopy cultures within 6 months before screening and at screening. Patients had been off an aminoglycoside for at least 1 month at screening. Patients were MAC-positive while on stable GBT for at least 6 months and were either on GBT or had stopped GBT less than 12 months before screening. Patients met American Thoracic Society and the Infectious Diseases Society of America criteria for MAC lung disease, with evidence of characteristic lung pathology (e.g., nodular infiltrate, cavity) on a chest radiograph or chest computed tomography (12). Key exclusionary conditions included cystic fibrosis, active pulmonary tuberculosis, immunodeficiency syndromes, MAC isolates with amikacin resistance on culture screening (minimum inhibitory concentration [MIC] >64 μg/ml), and active malignancies. Complete eligibility criteria are in the online supplement.
Patients were randomly assigned in a 2:1 ratio to receive ALIS once daily added to GBT (ALIS + GBT) or GBT alone (Figure 1). An open-label non-placebo-controlled design was selected to provide a more complete assessment of the ALIS safety profile, because the nebulization of placebo (empty liposomes) may have made it difficult to distinguish adverse effects associated with liposome inhalation from ALIS inhalation. Randomization used an interactive web response system provided by the sponsor and was stratified by current smoking status and prior GBT (on treatment vs. off treatment for 3–12 mo). In this ongoing study, patients who achieved culture conversion by Month 6 (primary endpoint), and remained culture-negative at Month 6, continued in the study to receive 12 months of treatment from the first month that defines culture conversion (up to 16 mo), followed by 12 months of off-treatment observation. Patients who failed to convert by Month 6 left the study at Month 8 and may have been eligible to enroll in an open-label extension study (25). Study completion was defined differently, depending on culture conversion status at Month 6 (Figure 2). Patients who discontinued study drug could remain in the study until Month 8. Sputum samples were collected at each monthly visit and on each of the 2 preceding days and processed at one of three regionally based central laboratories (see online supplement). Patients and investigators were blinded to sputum culture results until the Month 8 visit. GBT was administered per guideline recommendations (12).
Figure 1. CONVERT study design. In this ongoing phase 3 open-label trial, adults with treatment-refractory Mycobacterium avium complex lung disease were randomly assigned (2:1) to receive amikacin liposome inhalation suspension + guideline-based therapy or guideline-based therapy alone. Patients who achieved culture conversion by Month 6 and remained culture-negative at Month 6 continued in the trial to complete a total of 12 months of treatment from the first negative culture that defined conversion (up to 16 mo in total). After completion of the treatment phase, patients remain in the study for an additional 12 months for follow-up. Patients who did not achieve conversion by Month 6 exited the study at Month 8, and eligible patients were permitted to enroll in an extension study. ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy; MAC = Mycobacterium avium complex; QD = once daily.
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Figure 2. Patient disposition: intention-to-treat population. Patient flow through the study is shown. The prespecified primary analysis was based on outcomes at Month 6 in the intention-to-treat population (n = 224 and n = 112 for the amikacin liposome inhalation suspension + guideline-based therapy and guideline-based therapy alone groups, respectively). Completion was defined as either a converter who successfully completed 12 months on the same treatment regimen beginning from the first of three negative cultures that defined conversion, and successfully completed the 12 months off-treatment end-of-study follow-up visit; or a nonconverter who successfully completed all dosing and protocol requirements up to and including the Month 6 study visit. aAs of data cutoff on July 7, 2017. ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy.
[More] [Minimize]ALIS is a sterile aqueous formulation of amikacin sulfate encapsulated in liposomes composed of dipalmitoylphosphatidylcholine and cholesterol in a 2:1 weight-to-weight lipid ratio, containing 70 mg/ml of amikacin base (19, 21). ALIS was administered by inhalation using an investigational eFlow nebulizer (PARI Pharma GmbH). On nebulization, ALIS liposomes release some amikacin, providing patients with both liposome-encapsulated amikacin (∼70%) and free amikacin (∼30%). ALIS was supplied in single-use vials containing 623 mg amikacin to deliver 590 mg of amikacin to the nebulizer. Patients assigned to GBT alone did not receive a matching placebo. Amikacin and streptomycin administered parenterally were considered rescue drugs and if used by patients in either arm, required withdrawal from the study. Bronchodilator use before ALIS administration was allowed for patients who developed bronchospasm. Short interruption of ALIS at the investigator’s discretion was permitted to manage treatment-emergent adverse events (TEAEs).
The primary endpoint was the proportion of patients achieving culture conversion, based on assessment of monthly sputum cultures from baseline through Month 6. Culture conversion was achieved if patients had three consecutive monthly negative sputum cultures, with all sputum samples collected at each visit required to be culture-negative. To meet the primary endpoint, Month 4 was the latest visit at which a negative sputum culture could be first detected. Secondary endpoints at 6 months were comparisons by treatment arm of change from baseline in the distance achieved in the 6-minute-walk test (6MWT), time to culture conversion, and change from baseline in St George’s Respiratory Questionnaire (SGRQ) scores. Prespecified exploratory endpoints included changes in 6MWT distance for converters versus nonconverters, both overall and within each treatment arm.
Clinic visits, at baseline and monthly through Month 6, included sputum collection for microbiologic analysis in duplicate or (preferably) triplicate (see online supplement), adverse event assessments, physical examinations, and standard laboratory tests. The 6MWT was administered at baseline and Months 4 and 6. Audiology tests were performed at baseline and Months 3 and 6. Blood samples were collected from 39 patients in the United States and Japan to determine amikacin concentrations 0–1 hour before and 1–4 hours after ALIS administration at Months 1, 3, and 6.
For analysis of the primary endpoint, assuming 2:1 randomization and culture conversion rates of 20% for the ALIS + GBT arm and 5% for the GBT-alone arm, 261 evaluable patients (defined as completing the Month 6 visit) would provide at least 90% power for the continuity-corrected chi-square test at the two-sided significance level of 0.05.
The primary efficacy analysis was performed on the intention-to-treat population (all randomized patients), using the stratified Cochran-Mantel-Haenszel test at the two-sided significance level of 0.05. The null hypothesis assumed that culture conversion is independent of treatment. The adjusted odds ratio primary endpoint (ALIS + GBT/GBT alone) with 95% confidence interval (CI) and P value is presented. Patients with missing sputum culture results that impacted the ability to assess culture conversion (i.e., three consecutive negative cultures) were considered nonconverters. The safety population included all patients who received at least one dose of study medication. Secondary objectives were assessed hierarchically in order as follows to address multiplicity across endpoints: 6MWT, time to conversion, SGRQ. Changes from baseline in 6MWT distance were analyzed using an ANCOVA model with pattern-mixture modeling of missing values because of dropout. Time to culture conversion was analyzed using a Cox regression model (hazard ratio). Kaplan-Meier estimates for the distribution of time to culture conversion by treatment arm were constructed. For patients not achieving culture conversion by Month 6, time to culture conversion was censored at the patient’s last day on study or on the day of their Month 4 visit, whichever was earlier. Changes from baseline in SGRQ total score were analyzed using ANCOVA.
The study was conducted in accordance with Good Clinical Practice, following local regulations and ethical principles described in the Declaration of Helsinki. All patients provided written informed consent. Data were collected by the investigators and analyzed by the sponsor per the prespecified statistical analysis plan. Drs. Griffith, Winthrop, and Eagle contributed to the study design. Study oversight was provided by an independent data monitoring committee. Drs. Griffith, Winthrop, and Eagle drafted the manuscript; all authors reviewed the manuscript and approved submission for publication. All authors vouch for the accuracy and completeness of the data and analysis.
Patients were enrolled from May 27, 2015, to January 10, 2017, at 127 clinical centers in 18 countries in North America, Asia-Pacific region, and Europe (see online supplement); the United States (141 patients) and Japan (48 patients) were the largest contributors. Data cutoff for this primary endpoint analysis was July 7, 2017 (date of last patient completion of Month 6 visit). Of 492 patients screened, 336 (intention-to-treat population) were randomly assigned to receive ALIS + GBT (n = 224) or GBT alone (n = 112), and 156 failed screening (Figure 2; see Table E1 in the online supplement). At least one dose of ALIS and/or GBT was received by 335 patients (safety population). Because the study was still ongoing at the time of the prespecified primary endpoint analysis, all randomized patients had either completed the study (146 patients; 43.5%), were continuing in the study (136; 40.5%), or had withdrawn from the study prematurely (54; 16.1%) (Figure 2). More patients withdrew from the study in the ALIS + GBT arm (19.6%) compared with the GBT-alone arm (8.9%). The most common reasons for study discontinuation (both treatment-emergent and non-treatment-emergent) in the ALIS + GBT group were withdrawal by patient (8.5%), adverse event (3.6%), and death (3.1%).
The overall mean age of enrolled patients was 64.7 years (SD, 9.8) (Table 1); most were female (69.3%) and white (69.9%). Treatment arms were generally well balanced; however, the ALIS + GBT arm had a higher proportion of females (73.7%) than the GBT-alone arm (60.7%). Concomitant respiratory diseases, based on medical history, were balanced across treatment arms and most commonly included bronchiectasis, chronic obstructive pulmonary disease, or both. A history of ear and labyrinth disorders was reported in 42.6% of patients, most commonly as tinnitus (11.0%), deafness (9.8%), hypoacusis (8.9%), and deafness neurosensory (7.4%) (see Table E2). Patients in the ALIS + GBT arm had a slightly longer median duration of MAC lung disease (4.5 ± 5.5 yr) compared with those in the GBT-alone arm (3.3 ± 3.9 yr). At screening, most patients were receiving GBT; only 10% of patients were off treatment for 3–12 months. Overall, 25.3% of patients had a history of aminoglycoside use. At baseline, 69.3% of patients were on a three-drug regimen, with 54.9% receiving regimens that included a macrolide, ethambutol, and a rifamycin (see Table E3). Antibiotic combinations in the GBT regimens were similar across treatment arms.
| Parameter | ALIS + GBT (n = 224) | GBT Alone (n = 112) | Overall (n = 336) |
|---|---|---|---|
| Age, yr, mean (SD) | 64.6 (9.6) | 64.9 (10.2) | 64.7 (9.8) |
| Female, n (%) | 165 (73.7) | 68 (60.7) | 233 (69.3) |
| Body mass index, kg/m2, mean (SD) | 21.3 (3.9) | 20.9 (3.8) | 21.2 (3.9) |
| Race, n (%) | |||
| White | 158 (70.5) | 77 (68.8) | 235 (69.9) |
| Black/African American | 3 (1.3) | 3 (2.7) | 6 (1.8) |
| Asian: Japanese | 35 (15.6) | 15 (13.4) | 50 (14.9) |
| Asian: other | 23 (10.3) | 10 (8.9) | 33 (9.8) |
| Other/not reported | 5 (2.2) | 7 (6.3) | 12 (3.6) |
| Underlying lung disease, n (%) | |||
| Bronchiectasis only | 146 (65.2) | 64 (57.1) | 210 (62.5) |
| COPD* only | 29 (12.9) | 19 (17.0) | 48 (14.3) |
| COPD* and bronchiectasis | 22 (9.8) | 18 (16.1) | 40 (11.9) |
| Clarithromycin-resistant MAC (MIC ≥32 μg/ml), n (%) | 51 (22.9) | 22 (19.6) | 73 (21.8) |
| Current smoker, n (%) | 26 (11.6) | 10 (8.9) | 36 (10.7) |
| Receiving GBT at enrollment, n (%) | 201 (89.7) | 101 (90.2) | 302 (89.9) |
The primary endpoint of sputum culture conversion by Month 6 was achieved by significantly more patients in the ALIS + GBT arm than in the GBT-alone arm (65 of 224 patients [29.0%] vs. 10 of 112 patients [8.9%], respectively; adjusted odds ratio, 4.22; 95% CI, 2.08–8.57; P < 0.001) (Figure 3). Patients treated with ALIS + GBT were nearly four times as likely to achieve culture conversion compared with GBT alone (hazard ratio, 3.90; 95% CI, 2.00–7.60) (Figure 4).
Figure 3. Proportion of patients achieving culture conversion, shown by the first month of conversion: intention-to-treat population. The cumulative proportion of patients achieving culture conversion is displayed by the first month at which sputum cultures were Mycobacterium avium complex negative. Month 4 was the latest time point at which a patient could achieve the first of three consecutive negative sputum cultures and be considered a converter in the primary endpoint analysis at Month 6. Patients with positive cultures during screening and negative cultures at baseline and Months 1 and 2 were considered converters at baseline. ALIS = amikacin liposome inhalation suspension; CI = confidence interval; GBT = guideline-based therapy; OR = odds ratio.
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Figure 4. Proportion of patients with culture conversion over time: intention-to-treat population. The study month at which patients first experienced a Mycobacterium avium complex–negative sputum culture is shown by Kaplan-Meier analysis. ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy.
[More] [Minimize]Amikacin MIC distributions at baseline (Day 1) were similar in both treatment arms (see Figure E1). Conversion rates in the ALIS + GBT arm ranged from 28.6% to 34.5% for patients with MAC isolates having amikacin MICs of 8–64 μg/ml (see Figure E2). During the study, 26 of 336 patients (7.7%) had MAC isolates with postbaseline amikacin MIC greater than 64 μg/ml (ALIS + GBT, 10.3% [23/224]; GBT-alone, 2.7% [3/112]). Of these, 26.9% subsequently had MAC isolates with MIC less than 64 μg/ml (ALIS + GBT, 21.7% [5/23]; GBT-alone, 66.6% [2/3]). In the ALIS + GBT arm, one patient converted after having a MAC isolate with amikacin MIC greater than 64 μg/ml, and one patient converted but subsequently had a MAC isolate with amikacin MIC greater than 64 μg/ml. In the GBT-alone arm, no patients with MAC isolates having amikacin MIC greater than 64 μg/ml converted. At baseline, 21.8% (73 of 335) of patients had clarithromycin-resistant MAC isolates (MIC ≥32 μg/ml). Among these, culture conversion was achieved by 7 of 51 (13.7%) patients in the ALIS + GBT arm and 1 of 22 (4.5%) in the GBT-alone arm.
There was no significant difference between treatment arms in the change in 6MWT distance from baseline to Month 6 (least squares mean difference [SE], −3.0 [9.0]; 95% CI, −20.64 to 14.65; P = 0.74) (Table 2). In the prespecified exploratory analysis of the overall study population, patients with culture conversion demonstrated greater improvement in 6MWT distance than patients without culture conversion (16.8 vs. −7.9 m, respectively; P = 0.011). This pattern of improvement with culture conversion was evident and consistent within both the ALIS + GBT arm (20.7 vs. −10.5 m in patients with vs. without culture conversion, respectively; P = 0.005) and GBT-alone arm (18.2 vs. −7.0 m in patients with vs. without culture conversion, respectively; P = 0.33). The lack of significance in the GBT-alone arm was likely related to the low number of converters.
| Analysis Arm (n) | Baseline* (m) [Mean (SD)] | LS Mean Change at Month 6 versus Baseline (95% CI) | P Value |
|---|---|---|---|
| Secondary endpoint analysis† | |||
| ALIS + GBT (223) | 424.2 (128.9) | −1.5 (−23.6 to 20.6) | 0.74 |
| GBT alone (112) | 421.0 (125.9) | 1.5 (−22.2 to 25.3) | |
| Exploratory endpoint analysis‡ | |||
| All converters (70) | 457.9 (120.6) | 16.8 (−10.2 to 43.8) | 0.011 |
| All nonconverters (191) | 427.7 (120.5) | −7.9 (−30.5 to 14.7) | |
| ALIS + GBT converters (61) | 460.5 (108.3) | 20.7 (−10.2 to 51.5) | 0.005 |
| ALIS + GBT nonconverters (98) | 430.5 (124.4) | −10.5 (−37.5 to 16.5) | |
| GBT converters (9) | 441.0 (187.7) | 18.2 (−44.3 to 80.6) | 0.33 |
| GBT nonconverters (93) | 424.5 (116.4) | −7.0 (−48.6 to 34.5) |
At Month 6, there was a numerical difference in SGRQ score change from baseline favoring the GBT-alone arm (least squares mean difference [SE], 3.8 [1.6]; 95% CI, 0.67–6.94). Least squares mean (SE) changes from baseline were 4.2 (2.0) in the ALIS + GBT arm and 0.4 (2.2) in the GBT-alone arm.
TEAEs were reported in 98.2% and 91.1% of patients in the ALIS + GBT and GBT-alone arms, respectively (Table 3; see Table E4). Most events were of moderate severity in the ALIS + GBT arm and mild in the GBT-alone arm. In the ALIS + GBT arm, 82.5% of TEAEs were considered ALIS-related by the investigator, and 17.4% of patients had TEAEs leading to discontinuation of ALIS.
| Parameter | ALIS + GBT (n = 223) | GBT Alone (n = 112) |
|---|---|---|
| Any TEAE | 219 (98.2) | 102 (91.1) |
| Any serious TEAE | 45 (20.2) | 20 (17.9) |
| Serious TEAE occurring in ≥1% of patients in either arm | ||
| Pneumothorax | 3 (1.3) | 1 (0.9) |
| Hemoptysis | 6 (2.7) | 5 (4.5) |
| Pneumonia | 8 (3.6) | 2 (1.8) |
| COPD exacerbation | 7 (3.1) | 1 (0.9) |
| Infective exacerbation of bronchiectasis | 5 (2.2) | 3 (2.7) |
| Dyspnea | 3 (1.3) | 0 |
| Worsening of MAC infection | 1 (0.4) | 2 (1.8) |
| Pulmonary cavitation | 0 | 2 (1.8) |
| Acute myocardial infarction | 0 | 2 (1.8) |
| TEAE leading to death | 6 (2.7) | 5 (4.5) |
| Respiratory failure | 2 (0.9) | 1 (0.9) |
| COPD exacerbation | 1 (0.4) | 0 |
| Pulmonary embolism | 1 (0.4) | 0 |
| Interstitial lung disease | 0 | 1 (0.9) |
| Lung infection | 1 (0.4) | 0 |
| Worsening of MAC infection | 0 | 1 (0.9) |
| Pneumonia | 0 | 1 (0.9) |
| Cardiogenic shock | 0 | 1 (0.9) |
| Cachexia | 1 (0.4) | 0 |
| TEAE leading to discontinuation of ALIS | 39 (17.5) | — |
| TEAE leading to discontinuation of GBT | 9 (4.0) | 3 (2.7) |
| TEAE leading to discontinuation of ALIS and GBT | 4 (1.8) | — |
| Serious TEAE leading to discontinuation of ALIS | 12 (5.4) | — |
| TEAE: pulmonary exacerbation | 57 (25.6) | 18 (16.1) |
| Serious TEAE: pulmonary exacerbation | 20 (9.0) | 8 (7.1) |
| TEAE: productive cough | 8 (3.6) | 3 (2.7) |
| Nebulizer-related TEAE | 12 (5.4) | — |
| TEAE: ototoxicity-related | ||
| Tinnitus | 17 (7.6) | 1 (0.9) |
| Dizziness | 14 (6.3) | 3 (2.7) |
| Hearing loss* | 10 (4.5) | 7 (6.3) |
| Balance disorder | 3 (1.3) | 0 |
| Vertigo | 2 (0.9) | 0 |
| Presyncope | 1 (0.4) | 0 |
| TEAE in ≥10% of patients in either arm | ||
| Dysphonia | 102 (45.7) | 1 (0.9) |
| Cough | 83 (37.2) | 17 (15.2) |
| Dyspnea | 48 (21.5) | 10 (8.9) |
| Hemoptysis | 39 (17.5) | 15 (13.4) |
| Fatigue | 36 (16.1) | 8 (7.1) |
| Diarrhea | 28 (12.6) | 5 (4.5) |
| Nausea | 25 (11.2) | 4 (3.6) |
| Oropharyngeal pain | 24 (10.8) | 2 (1.8) |
The most common TEAEs overall were respiratory events (Table 3; see Table E4) reported by 87.4% and 50.0% of patients in the ALIS + GBT and GBT-alone arms, respectively, and mostly of mild to moderate severity. TEAEs reported in at least 10% of patients in the ALIS + GBT arm included dysphonia, cough, hemoptysis, dyspnea, fatigue, diarrhea, nausea, and oropharyngeal pain (Table 3). All were more frequent with ALIS + GBT than with GBT alone. Most events of these types were initially reported in the first month of ALIS treatment, with declining incidence of new onset thereafter (Figure 5). These events infrequently led to early discontinuation of ALIS (dyspnea, 3.1%; dysphonia, 2.2%; all others <1%) or withdrawal from the study.
Figure 5. Onset of the most frequent adverse events over time: safety population. Time courses of the onset of the most frequent treatment-emergent adverse events (occurring in ≥10% of patients in either arm) are shown by treatment arm and study month. Data indicate the month at which the events were first reported after initiation of therapy. ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy.
[More] [Minimize]Serious TEAEs were reported in 45 patients (20.2%) and 20 patients (17.9%) in the ALIS + GBT and GBT-alone arms, respectively; TEAEs leading to death occurred in six patients (2.7%) and five patients (4.5%) (Table 3). Serious TEAEs and TEAEs leading to death were primarily respiratory events, including respiratory infections. Six additional deaths were not treatment-emergent, including three during screening and three after ALIS discontinuation. Adverse events associated with systemic exposure to amikacin were uncommon (see Table E5). Events related to nephrotoxicity were infrequent in both arms.
Audiologic TEAEs were generally similar in both arms (Table 3). Audiogram results at Months 3 and 6 were similar in both study arms, and the two-sided P value of least squares mean difference was not significant for either ear at any tested frequency (see Table E6). Tinnitus TEAEs were reported in 17 patients (7.6%; 20 events) in the ALIS + GBT arm. Among these, 17 events were of mild severity and three were moderate; six events led to ALIS interruption and one led to discontinuation. One tinnitus event (0.9%) was reported in the GBT-alone arm. Half of the reported events had resolved with continued ALIS treatment by the data cutoff for this report.
A population pharmacokinetic analysis was conducted as a substudy at five sites in the United States and seven sites in Japan. Amikacin concentration data from 39 patients in the ALIS + GBT arm (see Table E7) were used to estimate pharmacokinetic parameters in each patient in this substudy, applying a population pharmacokinetic model for ALIS administration (26). This analysis yielded a mean estimated amikacin steady-state Cmax (1–4 h after dosing) of 2.32 μg/ml (coefficient of variation, 59.7%) and a mean estimated area under the curve from 0 to 24 hours of 20.0 μg ⋅ h/ml (coefficient of variation, 55.2%) (Table 4). Values of both parameters were approximately 5% lower at Day 1 than at steady state.
| Parameter | Day 1 | Steady State |
|---|---|---|
| Estimated Cmax, μg/ml | ||
| Mean (CV%) | 2.21 (60.4%) | 2.32 (59.7%) |
| Median (min–max) | 1.75 (0.465–6.61) | 1.85 (0.482–6.87) |
| Estimated AUC24, μg ⋅ h/ml | ||
| Mean (CV%) | 19.0 (55.7%) | 20.0 (55.2%) |
| Median (min–max) | 15.8 (4.16–53.5) | 16.7 (4.31–55.6) |
In this study, treatment with ALIS + GBT, compared with GBT alone, resulted in a significantly higher rate of sputum culture conversion by Month 6 in patients with treatment-refractory lung disease caused by amikacin-susceptible MAC. Culture conversion in patients who are continuing treatment beyond Month 6 will be assessed in the open-label extension study (25). ALIS was associated with adverse events of generally mild to moderate severity.
These results are consistent with the initial phase 2 randomized study that compared ALIS + GBT with placebo (empty liposomes) + GBT in patients with treatment-refractory NTM (primarily MAC) lung disease (19). In that study, although the primary endpoint was not met, negative sputum cultures at Day 84 were achieved more frequently in the ALIS + GBT arm versus placebo + GBT (31.8% vs. 8.9%; P = 0.006). This phase 2 study suggested, and the CONVERT study confirmed, the first evidence from randomized controlled clinical trials of the therapeutic effect of any agent against treatment-refractory MAC lung disease.
Sputum culture conversion, the primary study endpoint, is a microbiologic goal of antibiotic therapy for MAC lung disease. The rigorous study design required duplicate or triplicate negative sputum samples for three consecutive months to confirm culture conversion, a stringent definition that aligns with the 2018 NTM-NET consensus statement (27). Furthermore, an in vitro study confirmed that the growth of MAC isolates in sputum samples is not influenced by residual amikacin (28). Culture conversion by 6 months was assessed for the primary endpoint; additional analyses will evaluate culture conversion sustainability at the end of the treatment phase, and durability of conversion in the off-treatment phase (Figure 1). Culture conversion rates in the ALIS + GBT arm were similar in patients with amikacin MICs for MAC isolates ranging from 8 to 64 μg/ml at baseline, and low for patients with MAC isolates whose MIC was greater than 64 μg/ml either at or after baseline. Whereas British Thoracic Society guidelines recommend macrolide and amikacin susceptibility testing before initiation of GBT, recommendations regarding use of susceptibility testing during ongoing treatment are less clear (29). In addition to antibiotic susceptibility, patient characteristics based on clinical phenotype including fibrocavitary versus nodular bronchiectatic disease are known to affect outcomes in therapy of MAC lung disease (30). However, in this study, the methods used to assess lung disease at screening varied across study sites and did not provide adequate diagnostic consistency for analysis of outcomes according to disease severity.
Systemic aminoglycoside exposure is a modifiable risk factor for both nephrotoxicity and ototoxicity (31, 32). Lower aminoglycoside exposure and less frequent dosing are associated with reduced nephrotoxicity risk, particularly with area under the curve values below 50 mg ⋅ h/L even with twice-daily dosing (33). In patients receiving extended amikacin therapy for multidrug-resistant tuberculosis, ototoxicity risk was associated with cumulative amikacin exposure and duration of treatment (31). In CONVERT, peak amikacin serum levels at steady state were at least fourfold lower than the estimated minimum Cmax observed with typical intravenous amikacin doses of 15 mg/kg/d in patients with mycobacterial infections (32). Moreover, pharmacokinetic parameters at steady state indicate that there is little accumulation of amikacin, even after 168 days of daily ALIS administration (19). In CONVERT, adverse events typically associated with systemic aminoglycoside therapy, such as hearing loss and renal function abnormalities (18), were infrequent and generally similar between treatment arms, with the exception of tinnitus (33).
The difference between treatment arms for changes in 6MWT distance from baseline to Month 6 was not statistically significant. In the overall population, a nominally significant improvement in 6MWT distance was observed in patients with culture conversion, versus deterioration in those without culture conversion (an absolute difference of 25.2 m). Improvements in 6MWT distance among converters suggest that eradication of MAC may benefit physical function and well-being, and support the concept that culture conversion is a clinically relevant outcome measure for therapy of MAC lung disease. Month 6 SGRQ results showed a modest difference favoring the GBT-alone arm that did not meet the Minimal Clinically Important Change Score of 4.0 established for other lung diseases, primarily chronic obstructive pulmonary disease and asthma (34). Most patients remained on therapy at Month 6, and SGRQ results may have been confounded by treatment burden and respiratory adverse events associated with initiation of inhalation antibiotic therapy (35, 36). Additionally, because the SGRQ has not been validated in NTM lung disease, interpretation of these findings is difficult.
Established treatment guidelines for MAC lung disease are based on disease severity at initial presentation, with therapy continued until culture conversion is achieved and sustained for 12 months (12). Amikacin has potent activity against MAC in vitro and is one of only two antibiotics for which in vitro susceptibility may predict clinical response (37, 38). Although supporting data are limited, guidelines since 1997 have endorsed parenteral amikacin for treating patients with severe or cavitary MAC lung disease (12). To avoid systemic toxicities, clinicians have turned to inhalation of standard amikacin solution for injection as an alternative to parenteral administration. However, published data are limited: since 2008 only five retrospective case presentations, together representing 57 patients, have described experience with inhalation of standard amikacin for injection in patients with MAC lung disease (36, 39–42).
Designed for inhalation, ALIS was developed to enhance amikacin delivery to the site of infection, with limited systemic exposure. MAC persists in the lung, both extracellularly and intracellularly and specifically within macrophages, and subverts normal cellular defense mechanisms (43). Preclinical studies indicate that the liposomal formulation of ALIS facilitates amikacin retention in the lung, increases amikacin uptake approximately fourfold in cultured macrophages, increases amikacin concentration fivefold to eightfold in alveolar macrophages, and allows biofilm penetration (22, 44). At this time there are no trials assessing the efficacy and safety of ALIS compared with the injectable formulation of amikacin, either inhaled or parenterally administered.
In conclusion, ALIS is a novel amikacin formulation that, combined with GBT, improved sputum conversion rates in adults with amikacin-susceptible, treatment-refractory MAC lung disease compared with GBT alone. Addition of ALIS to GBT was associated with higher rates of respiratory TEAEs; however, these were predominantly mild or moderate in severity. Data from the CONVERT study demonstrate that ALIS may have a role in the treatment of refractory MAC lung disease and support further evaluation of ALIS in other MAC patient populations.
The authors thank the patients and their families for their support and participation, and the study investigators, study coordinators, and support staff across all sites. Editorial assistance was provided by Richard Boehme, Ph.D., of MediTech Media, Ltd. Services for MAC culture, species identification, and susceptibility testing were provided by the University of Texas Health Science Center, Tyler, Texas; Radboud University Medical Center, Nijmegen, the Netherlands; and the Queensland Mycobacterium Reference Laboratory, Herston, Queensland, Australia.
The following individuals served as National Coordinators for CONVERT study sites in their respective countries: Bernd Lamprecht, M.D. (Austria); Dirk Wagner, M.D., Ph.D. (Germany); Charles Haworth, M.D., F.R.C.P. (United Kingdom); Wouter Hoefsloot, M.D., Ph.D. (the Netherlands); Luigi Codecasa, M.D. (Italy); Claire Andréjak, M.D. (France); Jordi Dorca-Sargatal, M.D. (Spain); Janusz Milanowski, M.D., Ph.D. (Poland); and Ronny Öhman, M.D., Ph.D. (Sweden).
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*A complete list of contributing investigators can be found in the online supplement.
Editorial assistance was provided by Richard Boehme, Ph.D., of MediTech Media, Ltd., and funded by Insmed Incorporated. Financial support for this study was provided by Insmed Incorporated.
Author Contributions: D.E.G., G.E., and K.L.W. contributed to the study design. R.T., T.R.A., N.H., K.M., D.J.A.-H., A.E.O’D., T.K.M., P.A.F., M.R.L., L.M., L.R.C., A.T.H., S.J.R., J.-J.Y., F.C.R., S.K.F., J.V.P., and K.L.W. enrolled study patients and collected the data. J.v.I., C.C., and R.J.W. provided microbiologic analyses. J.N. analyzed the data. D.E.G., G.E., and K.L.W. interpreted the data and drafted the manuscript. All authors reviewed and edited the manuscript and approved the final manuscript for submission.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.201807-1318OC on September 14, 2018
Author disclosures are available with the text of this article at www.atsjournals.org.
