Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease

BackgroundIn the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001).Research QuestionIn patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion?Study Design and MethodsAdults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation.ResultsMore patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment.InterpretationIn a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion.Trial RegistryClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov Nontuberculous mycobacteria (NTM) are a ubiquitous and diverse group of environmental organisms that vary in virulence and the ability to cause clinical disease in humans.1Falkinham III, J.O. Environmental sources of nontuberculous mycobacteria.Clin Chest Med. 2015; 36: 35-41Google Scholar In susceptible individuals, including those with underlying structural pulmonary disease, acquisition of NTM in the respiratory tract through inhalation of environmental aerosols can lead to chronic lung disease. Over an 8-year period in the United States, significant average annual increases in both the incidence (+5.2%; 95% CI, 4.0%-6.4%; P < .01) and prevalence (+7.5%; 95% CI, 6.7%-8.2%; P < .01) of NTM lung disease were reported, with Mycobacterium avium complex (MAC) identified as the leading cause of NTM lung disease in the United States and most regions of the world.2Prevots D.R. Marras T.K. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review.Clin Chest Med. 2015; 36: 13-34Google Scholar,3Winthrop K.L. Marras T.K. Adjemian J. Zhang H. Wang P. Zhang Q. Incidence and prevalence of nontuberculous mycobacterial lung disease in a large U.S. managed care health plan, 2008-2015.Ann Am Thorac Soc. 2020; 17: 178-185Google Scholar The management of MAC lung disease can be challenging and complex.4Kwon Y.S. Koh W.J. Daley C.L. Treatment of Mycobacterium avium complex pulmonary disease.Tuberc Respir Dis (Seoul). 2019; 82: 15-26Google Scholar, 5Ryu Y.J. Koh W.J. Daley C.L. Diagnosis and treatment of nontuberculous mycobacterial lung disease: clinicians' perspectives.Tuberc Respir Dis (Seoul). 2016; 79: 74-84Google Scholar, 6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar Treatment outcomes, which can vary by MAC species and the presence of antibiotic resistance or cavitary disease, often are poor.6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar,7Griffith D.E. Aksamit T.R. Therapy of refractory nontuberculous mycobacterial lung disease.Curr Opin Infect Dis. 2012; 25: 218-227Google Scholar Conversion of sputum culture results from positive to negative for MAC is the microbiological goal of therapy, with treatment success defined as 12 months of negative sputum culture results while receiving therapy.6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar,8Diel R. Nienhaus A. Ringshausen F.C. et al.Microbiologic outcome of interventions against Mycobacterium avium complex pulmonary disease: a systematic review.Chest. 2018; 153: 888-921Google Scholar,9Griffith D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Google Scholar Failure to achieve culture conversion or the emergence of microbiologic recurrence of the same MAC strain while receiving treatment (relapse) are common, despite lengthy treatment with a guideline-based multidrug regimen.6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar,8Diel R. Nienhaus A. Ringshausen F.C. et al.Microbiologic outcome of interventions against Mycobacterium avium complex pulmonary disease: a systematic review.Chest. 2018; 153: 888-921Google Scholar,10Johnson M.M. Odell J.A. Nontuberculous mycobacterial pulmonary infections.J Thorac Dis. 2014; 6: 210-220Google Scholar,11van Ingen J. Aksamit T. Andrejak C. et al.Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement.Eur Respir J. 2018; 51: 1800170Google Scholar Even with treatment success, the risk for reinfection remains high given that most patients persistently are vulnerable to infection because they will often encounter environmental re-exposure to NTM.12Nishiuchi Y. Iwamoto T. Maruyama F. Infection sources of a common non-tuberculous mycobacterial pathogen, Mycobacterium avium complex.Front Med (Lausanne). 2017; 4: 27Google Scholar,13Wallace Jr., R.J. Brown-Elliott B.A. McNulty S. et al.Macrolide/azalide therapy for nodular/bronchiectatic Mycobacterium avium complex lung disease.Chest. 2014; 146: 276-282Google Scholar Amikacin liposome inhalation suspension (ALIS; Arikayce) was developed for nebulized administration to limit systemic amikacin exposure while increasing uptake into alveolar macrophages at the site of infection.14Meers P. Neville M. Malinin V. et al.Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections.J Antimicrob Chemother. 2008; 61: 859-868Google Scholar,15Zhang J. Leifer F. Rose S. et al.Amikacin liposome inhalation suspension (ALIS) penetrates non-tuberculous mycobacterial biofilms and enhances amikacin uptake into macrophages.Front Microbiol. 2018; 9: 915Google Scholar In the phase 3 CONVERT study, ALIS added to ongoing guideline-based treatment (GBT) in patients with refractory MAC lung disease met the primary end point of increased likelihood of culture conversion by 6 months of use (29.0% for ALIS plus GBT vs 8.9% for GBT alone; P < .0001).16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar Secondary microbiologic end points reported here are the sustainability of culture conversion during long-term treatment with ALIS plus GBT (12 months of negative sputum results), as well as the durability of conversion after treatment discontinuation. In addition, we report the long-term safety of ALIS in patients from the CONVERT study in whom culture conversion was achieved.16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar Preliminary sustainability and durability results from the CONVERT study were presented previously as abstracts at congresses.17Griffith DE, Thomson R, Addrizzo-Harris DJ, et al. Durability of culture conversion in patients receiving amikacin liposome inhalation suspension (ALIS) for treatment-refractory Mycobacterium avium complex lung disease (MAC-LS) in the CONVERT study. Paper presented at: European Respiratory Society Meeting; September 28-October 2, 2019; Madrid, Spain. Abstract oa4951.Google Scholar,18Griffith D.E. Eagle G. Wallace R. et al.Relationship between in vitro clarithromycin susceptibility and sputum culture conversion with add-on amikacin liposome inhalation suspension (ALIS) for treatment of refractory Mycobacterium avium complex (MAC) lung disease [abstract].Chest. 2018; 154: 109A-110AGoogle Scholar The detailed methodology of CONVERT—a phase 3, randomized, open-label study of ALIS in patients with treatment-refractory lung disease caused by MAC (ClinicalTrials.gov Identifier: NCT02344004)—was published previously in a primary analysis article.16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar Eligible patients were adults with confirmed MAC lung disease9Griffith D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Google Scholar and amikacin-susceptible (minimum inhibitory concentration, ≤ 64 μg/mL) MAC-positive sputum results within 6 months of screening and at screening despite treatment with GBT (antimicrobial regimen of ≥ 2 antibiotics) for ≥ 6 months; the complete eligibility criteria for CONVERT have been previously published.16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar The patients in this additional analysis were those who met protocol-defined culture conversion by month 6 (ie, three consecutive monthly negative sputum culture results for MAC) in the original CONVERT primary analysis.16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar Patients were randomized 2:1 to receive once-daily ALIS 590 mg administered by an investigational PARI eFlow Technology nebulizer (PARI Pharma GmbH, Munich, Germany) added to ongoing GBT (ALIS plus GBT) or to continue GBT alone (Fig 1). Patients who did not achieve culture conversion by month 6 exited the study at the month 8 visit, when culture conversion results were unblinded. Converters continued their assigned treatment for 12 months from the first month that defined conversion, followed by a 12-month off-treatment phase. Patients who discontinued the study before completing 12 months of postconversion treatment were assessed in accordance with the end-of-treatment (EOT) visit and follow-up procedures. At the investigator's discretion, brief interruptions of ALIS were allowed to manage adverse respiratory events. Additional details are published in the primary analysis article.16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar The primary end point of culture conversion by month 6 was reported previously.16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar Secondary end points of the CONVERT study reported in this article are the percentage of randomized patients who showed sustained conversion at the completion of 12 months of postconversion treatment and durable culture conversion through 3 months after treatment in the ALIS plus GBT arm vs the GBT alone arm. Exploratory end points reported are the percentage of patients whose status remained culture negative 12 months after all treatment and the number of patients with reinfection at the end of the study. Post hoc analyses were conducted to evaluate the percentage of patients with culture conversion who showed sustained and durable conversion and the percentage of patients who achieved sustained conversion through the EOT (regardless of the duration of postconversion treatment) and subsequent durable conversion 3 months after treatment. Sputum samples were collected at screening, baseline (day 1), months 1 through 6, months 8 and 12, EOT, and during the 12-month off-treatment phase at day 28 and months 3, 6, and 12 (end of study). Culture conversion was defined as having three consecutive monthly negative sputum sample results for MAC, and microbiological recurrence was defined as either 1 culture test with positive results for MAC on solid medium or ≥ 3 consecutive culture test with positive results for MAC on liquid medium. As soon as a patient met the definition of having a recurrent MAC infection, variable-number tandem-repeat genotyping was used to determine whether the recurrence was the result of a relapse (same MAC species and strain that was isolated at screening or baseline) or of reinfection (new infection with a different MAC species or the same MAC species but a different strain from that isolated at screening or baseline).11van Ingen J. Aksamit T. Andrejak C. et al.Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement.Eur Respir J. 2018; 51: 1800170Google Scholar Additional methodologic details for the study are provided in e-Appendix 2. Adverse event reporting,19International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Medical Dictionary for Regulatory Activities, version 22.0. Medical Dictionary for Regulatory Activities website.https://www.meddra.orgGoogle Scholar physical examinations, and standard laboratory tests were conducted at clinic visits. Safety outcomes included the frequency of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to death, TEAEs leading to withdrawal from study, and TEAEs of special interest (respiratory related and those generally associated with parenteral aminoglycoside administration). Audiology test results were reported for patients with both baseline and month 12 assessments. The change in 6-min walk test (6MWT) distance from baseline was evaluated at 3 months after treatment (exploratory end point). The sample size was determined for the primary analysis between treatment arms with respect to the proportion of patients achieving culture conversion by month 6. Because of a lack of durability data, it was difficult to estimate the power with a total sample size of 261 patients for the comparison between treatment arms with respect to the proportion of patients achieving culture conversion with durability 3 months after treatment. Assuming the proportion of patients achieving culture conversion with durability is 16% and 4% for ALIS plus GBT and GBT alone, respectively, and a 2:1 randomization ratio, a sample size of 261 patients (174 for ALIS plus GBT and 87 for GBT alone) would provide at least 83% power for the Pearson χ2 test at the 2-sided significance level of 0.05. The secondary end point of percentage of randomized patients (intention-to-treat population) achieving culture conversion with sustainability while receiving treatment, durability 3 months after treatment, and the percentage whose culture results remained negative at end of study were analyzed using the Cochran-Mantel-Haenszel test (stratified by smoking status and prior multidrug regimen). Patients with missing sputum culture data (eg, because of death or missed visit) were considered to have positive culture results unless missing culture results were because of a patient's inability to produce sputum despite reasonable efforts. Patients who did not complete a full course of treatment (ie, 12 months after conversion) were considered to have positive culture results. Treatment adherence was determined by the following formula: vials used / vials prescribed × 100, where vials prescribed was the number of days study medication was to be taken. Testing was performed sequentially; specifically, conversion at month 6 was tested first at a 2-sided α level of 0.05, and then durability of culture conversion at the 3-month follow-up was tested. All other testing and associated P values are provided for informational purposes only. Results for relapse and reinfection are reported using descriptive statistics only. All statistical analyses were performed using SAS version 9.4 or later software (SAS Institute). Additional sensitivity analyses are included in e-Appendix 2. The study was conducted in accordance with Good Clinical Practice following local regulations and the ethical principles outlined in the Declaration of Helsinki.20World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.JAMA. 2013; 310: 2191-2194Google Scholar The study protocol, informed consent form, and all other related materials were reviewed and approved by an independent ethics committee or institutional review board for each site (see e-Appendix 3 for committee names and approval numbers for each study site). All patients provided written informed consent in accordance with the International Conference for Harmonisation.21International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonized tripartite guideline: Guideline for Good Clinical Practice.J Postgrad Med. 2001; 47: 45-50Google Scholar To ensure patient safety, an independent data monitoring committee of noninvestigator physicians with pulmonary expertise provided a centralized review. Patients were enrolled from May 27, 2015, through January 10, 2017; the last patient's end-of-study visit was April 3, 2019. As described previously,16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar 492 patients at 127 sites in North America, Europe, Australasia, and Asia were screened, and 336 patients were randomized to receive ALIS plus GBT (n = 224) or GBT alone (n = 112). Seventy-five patients achieved culture conversion by month 6 (ALIS plus GBT, n = 65; GBT alone, n = 10) (Fig 2). Among those who achieved conversion in the ALIS plus GBT arm (n = 65), the median duration of ALIS treatment from baseline to EOT was 13.1 months (interquartile range [IQR], 11.8-14.5 months); 81.5% of patients showed ≥ 80% treatment adherence. Of the 65 ALIS plus GBT-treated patients who achieved culture conversion by month 6 (primary end point), 59 patients (90.8%) completed the study (Fig 2) according to the case report form completed by the investigator. Of the 10 patients who achieved culture conversion by month 6 while treated with GBT alone (median duration of GBT treatment, 11.2 months [IQR, 8.2-14.7 months]), five patients (50%) completed the study according to the case report forms completed by the investigator. At month 8, all those who did not achieve conversion exited the study per protocol (ALIS plus GBT, n = 104; GBT alone, n = 93). Patients who achieved conversion were predominantly White and female without a history of smoking (Table 1). At baseline, the median duration of NTM lung disease in the converter group was 4.0 years (IQR, 2.0-7.0 years) for patients treated with ALIS plus GBT (n = 65) and 3.0 years (IQR, 1.8-6.0 years) for patients treated with GBT alone (n = 10); 89.2% (n = 58/65) and 90.0% (n = 9/10) were receiving a multidrug regimen at baseline.Table 1Baseline Demographics and Characteristics for Patients Who Achieved Conversion by Month 6ParameterALIS Pus GBT (n = 65)GBT Alone (n = 10)Age, mean ± SD, y63.2 ± 10.268.6 ± 9.7Age group, No. (%), y 18-454 (6.2)0 46-6427 (41.5)5 (50.0) ≥ 6534 (52.3)5 (50.0) ≥ 755 (7.7)3 (30.0)Female sex, No. (%)55 (84.6)6 (60.0)Race, No. (%) White54 (83.1)9 (90.0) Asian11 (16.9)0 Not reported01 (10.0)Current smoker, No. (%)2 (3.1)1 (10.0)Duration of MAC disease, median (IQR), y4.0 (2.0-7.0)3.0 (1.8-6.0)Duration of treatment, median (IQR), mo13.1 (11.8-14.5)11.2 (8.2-14.7)Receiving GBT at enrollment, No. (%)58 (89.2)9 (90.0)ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy; IQR = interquartile range; MAC = Mycobacterium avium complex. Open table in a new tab ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy; IQR = interquartile range; MAC = Mycobacterium avium complex. In the intention-to-treat population, 29.0% of patients (65/224) in the ALIS plus GBT arm achieved culture conversion by month 6 compared with 8.9% (10/112) in the GBT alone arm (P < .0001)16Griffith D.E. Eagle G. Thomson R. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Google Scholar; 16.1% of patients (36/224) in the ALIS plus GBT arm and no patients (0/112) in the GBT alone arm achieved culture conversion that was both sustained at the completion of 12 months after conversion treatment and durable 3 months after all MAC treatment (P < .0001) (Table 2). In a sensitivity analysis that included a more conservative definition of durable culture conversion (achieving culture conversion by month 6, completing 12 months of postconversion treatment, and having no liquid or solid positive culture results up to 3 months after treatment and no visits missing liquid or solid culture results, including those because of an inability to produce sputum), 13.4% of patients (30/224) in the ALIS plus GBT arm and no patients (0/112) in the GBT alone arm achieved durable culture conversion (P < .0001; see e-Appendix 2 for details).Table 2Sustained and Durable Culture ConversionVariableALIS Pus GBTGBT AloneP ValueaCalculated using the Cochran-Mantel-Haenszel test, with stratification factors of the combination of smoking status and prior multidrug regimen as fixed factors.Full 12 mo of postconversion treatment group Intention-to-treat analysisbProportion of the enrolled population who achieved sustained and durable conversion.No.224112...Sustained conversion at 12 mo of treatmentcA total of 13 patients did not complete a full 12-month postconversion treatment course (ALIS plus GBT, n = 12; GBT alone, n = 1), and thus were considered to show positive culture results in the intention-to-treat analysis.41 (18.3)3 (2.7)< .0001Durable conversion at 3-mo follow-up36 (16.1)0< .0001Negative culture results 12 mo after treatment30 (13.4)0< .0001 Converter analysisdProportion of patients who achieved conversion by month 6 and showed sustained and durable conversion.No.6510...Sustained conversion at 12 mo of treatmentcA total of 13 patients did not complete a full 12-month postconversion treatment course (ALIS plus GBT, n = 12; GBT alone, n = 1), and thus were considered to show positive culture results in the intention-to-treat analysis.41 (63.1)3 (30.0).0644Durable conversion at 3-mo follow-up36 (55.4)0.0017Negative culture results 12 mo after treatment30 (46.2)0< .0001Conversion regardless of treatment duration Intention-to-treat analysisbProportion of the enrolled population who achieved sustained and durable conversion.No.224112...Sustained conversion at end of treatment52 (23.2)3 (2.7)< .0001Durable conversion at 3-mo follow-up41 (18.3)0< .0001Negative culture results 12 mo after treatment35 (15.6)0< .0001 Converter analysisdProportion of patients who achieved conversion by month 6 and showed sustained and durable conversion.No.6510...Sustained conversion at end of treatment52 (80.0)3 (30.0).0014Durable conversion at 3-mo follow-up41 (63.1)0.0002Negative culture results 12 mo after treatment35 (53.8)0< .0001Data are presented as No. (%) or No., unless otherwise indicated. ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy.a Calculated using the Cochran-Mantel-Haenszel test, with stratification factors of the combination of smoking status and prior multidrug regimen as fixed factors.b Proportion of the enrolled population who achieved sustained and durable conversion.c A total of 13 patients did not complete a full 12-month postconversion treatment course (ALIS plus GBT, n = 12; GBT alone, n = 1), and thus were considered to show positive culture results in the intention-to-treat analysis.d Proportion of patients who achieved conversion by month 6 and showed sustained and durable conversion. Open table in a new tab Data are presented as No. (%) or No., unless otherwise indicated. ALIS = amikacin liposome inhalation suspension; GBT = guideline-based therapy. Most patients (63.1% [41/65]) in the ALIS plus GBT arm who achieved conversion showed a sustained response at the completion of 12 months of postconversion treatment compared with 30.0% (3/10) of converters in the GBT alone arm (P = .0644) (Table 2, Fig 3). A total of 55.4% of patients (36/65) who achieved conversion in the ALIS plus GBT arm showed durable responses 3 months after treatment compared with none (0/10) in the GBT alone arm (P = .0017) (Table 2, Fig 3). At 12 months after the end of all MAC treatment, 46.2% of patients (30/65) who achieved conversion in the ALIS plus GBT arm continued to show negative culture results (Table 2, Fig 3). Additional analyses that assessed culture status at the EOT regardless of the duration of postconversion treatment are included in Table 2. At the EOT, 80.0% of converters in the ALIS plus GBT arm (52/65) demonstrated negative culture sputum results, 7.7% (5/65) showed sputum results positive for MAC that met the definition of relapse, 4.6% (3/65) had sputum results positive for MAC that met the definition of reinfection, and 7.7% (5/65) were missing culture data (Fig 3). In the GBT alone arm at EOT, 30.0% of patients (3/10) showed negative culture results, 30.0% of patient (3/10) showed sputum results positive for MAC that met the definition of relapse, 10% of patients (1/10) showed sputum results positive for MAC that met the definition of reinfection, and 30% of patients (3/10) were missing culture data (Fig 3). All instances of relapse