PRospective Evaluation of Nontuberculous Mycobacteria Disease in CysTic Fibrosis: The design of the PREDICT study

Abstract

Background:

Nontuberculous mycobacteria (NTM) are an important cause of airway infections in people with cystic fibrosis (pwCF). Isolation of NTM from respiratory specimens of pwCF do not mandate treatment in the absence of clinical and radiologic features of NTM pulmonary disease (NTM-PD), as some pwCF clear the infection without treatment and others do not appear to progress to NTM-PD despite persistent infection. An evidence-based protocol to standardize diagnosis of NTM-PD is needed to systematically identify pwCF who may benefit from treatment.

Methods:

In this multicenter observational study, eligible pwCF who are 6 years of age and older and who have had a recent positive NTM culture are systematically evaluated for NTM-PD. Participants are identified based on positive NTM culture results obtained during routine clinical care and following enrollment are evaluated for NTM-PD and CF-related comorbidities. Participants are followed in PREDICT until they meet NTM-PD diagnostic criteria and are ready to initiate NTM treatment, or until study termination. Active participants who have not met these criteria are re-consented every 5 years to enable long-term participation.

Results:

The primary endpoint will summarize the proportion of participants who meet the NTM-PD diagnosis definition. The time from enrollment to NTM-PD diagnosis will be derived from Kaplan-Meier estimates.

Conclusion:

A prospective protocol to identify NTM-PD in pwCF will test if this standardized approach defines a cohort with signs and symptoms associated with NTM-PD, to assist with clinical decision making and to build a framework for future therapeutic trials.

Trial Registration:

ClinicalTrials.gov Identifier: NCT02073409

Graphical Abstract

1. Introduction

Nontuberculous mycobacteria (NTM) are important pathogens in cystic fibrosis (CF) and non-CF bronchiectasis. The CF population has the highest known risk for NTM, and poses unique challenges with regards to diagnosis and treatment (1, 2). The overwhelming majority of NTM species recovered in CF samples in the U.S. are from either the M. avium complex (MAC) or subspecies of M. abscessus (3–5), with MAC being the most common(3, 6). Historically, NTM infections have been attributed to environmental exposure (7–9), although reports of NTM outbreaks support the potential for direct or indirect patient-to-patient transmission within CF Centers (10–13).

In the setting of CF, the diagnosis of NTM pulmonary disease (NTM-PD) is challenging, as similar, overlapping clinical symptoms can occur due to the near universal presence of co-infections with virulent pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus, and radiographic signs suggestive of NTM are nonspecific. Consensus recommendations for diagnosis were proposed by the U.S. Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) and were generally adopted from the 2007 American Thoracic Society statement (14). For NTM-PD, diagnostic criteria include: >1 positive culture from the airway, characteristic clinical symptoms and radiographic findings, with the exclusion of other co-infections and co-morbidities (15). Of note, the recommendations for NTM-PD diagnosis for any patient population have not been validated in a clinical trial. The diagnosis of NTM-PD in the clinical setting is consequential, as in most pwCF, NTM infection appears indolent or transient (3), and treatment is arduous with uncertain outcomes (16). Likewise, clinical trials of potential therapies require an accurate and reproduceable diagnosis of NTM-PD in order to verify eligibility criteria and meet efficacy endpoints. Thus, there is intense interest in standardizing the diagnosis of NTM-PD in the CF population.

In response to these unmet needs, we have designed a multicenter observational study to implement a standardized approach to establishing a diagnosis of NTM-PD in pwCF with one or more recent positive NTM cultures that have never been treated. The goal of this study is to more accurately and rapidly identify individuals with NTM-PD who may benefit from antibiotic treatment and facilitate the identification of clinical features and biomarkers of NTM-PD in the CF population.

2. Methods

2.1. Study design

PREDICT is a prospective observational clinical study that started enrollment in December 2013 at two sites, the Colorado Adult CF Center at National Jewish Health (NJH), Denver, CO and the Colorado Pediatric CF Center at Children’s Hospital Colorado, Aurora, CO. The study was expanded to 10 CF Programs in 2017 and is now enrolling in 20 CF Programs in the U.S. and managed by the CF Foundation (CFF) Therapeutics Development Network Coordinating Center (TDNCC). The current list of study sites is available at clinicalTrials.gov (Identifier: NCT02073409). The study is funded by the U.S. CFF through 2026 (Award NTM-OB-17). The study is approved by the NJH Institutional Review Board (HS 2798), the Colorado Multiple Institutional Review Board (COMIRB 14–0336), and Advarra Institutional Review Board (Pro00026422). We comply with the Declaration of Helsinki and Good Clinical Practice guidelines. Written consent is obtained from all participants. Up to 400 participants may be enrolled and systematically evaluated for NTM-PD.

2.2. Inclusion and exclusion criteria

Potential participants are identified based on positive NTM culture results in the 2 years prior to enrollment, obtained during the course of standard care. Participants are required to have a diagnosis of CF consistent with the 2017 CFF Guidelines (17) and be enrolled in the U.S. CFF Patient Registry (CFFPR) (18). Participants must be willing and able to adhere to study procedures and protocol requirements in the context of clinical care, be ≥ 6 years of age at enrollment (in order to best monitor pulmonary function), be willing to undergo sputum induction (if necessary), and willing to discontinue chronic azithromycin use for the duration of the study (if taking azithromycin chronically at time of enrollment) to avoid single-agent treatment of NTM per guideline recommendations (15).

Participants are excluded if they had, at any point in life, a prior or active antibiotic treatment of the NTM species or sub-species for which the subject is being considered for this study. Participants are also excluded for a history of solid organ or hematological transplantation or any other condition that, in the opinion of the site Primary Investigator (PI)/designee, would preclude informed consent or assent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives. A timeline of the schedule of events is shown in Table 1.

TABLE 1:

SCHEDULE OF EVENTS FOR PREDICT

Procedure	Enrollment1	Follow-up Visits1
Informed Consent	X2
Review of Eligibility, Demographics, Collect CFF Registry ID, CF Diagnosis	X
CFQ-R Administration3	X	Quarterly
Limited Concomitant Medication Review4	X	X
Sputum for clinical care (on-site) NTM Culture5	X	X
Sputum for Biomarker Studies and Banking	X	Annually and at Disease Diagnosis
Dispense Home Sputum Kit for Culture at NJH		Annually
Blood for Biomarker Studies and Banking5	X	Annually and at Disease Diagnosis
Urine for Biomarker Studies and Banking5	X	Annually and at Disease Diagnosis
NTM History	X
Best (Highest) BMI/FEV1 in past 2 years	X
Acute Antibiotics for Resp. Disease Review6	X	X
Height and Weight	X	X
Spirometry	X	X
Comorbidity Assessment	X	X
NTM Radiological Assessment	X7	Annually and Before treatment7
NTM Clinical Syndrome Review	X	X
NTM Disease Diagnosis Evaluation	X	X

¹Follow up visits should occur per normal clinic practice and can be in clinic or via telehealth. Refer to PREDICT NTM Disease Diagnosis Flow Chart.

²Participants who have not met the NTM Diseases Diagnostic Criteria will be re-consented every 5 years.

³The CFQ-R will be completed quarterly and ideally within a week prior to a visit (office or telehealth) and prior other procedures.

⁴All CFTR modulator use as well as participation in any clinical trials during the study will be recorded on the Limited Concomitant Medications log.

⁵Obtain sputum, blood and urine research and banking samples at enrollment in PREDICT, annually, and at time of NTM Disease Diagnosis or end of study, if prior to NTM Disease Diagnosis. If a collection was performed within one month prior of disease diagnosis, an additional sample is not required.

⁶All acute use of antibiotics for respiratory disease occurring from the 1 year prior to enrollment and during the study will be recorded.

⁷Perform high-resolution chest CT per NTM CFF guidelines: Annually, shortly before starting NTM treatment and at the end of NTM treatment.

2.3. Assessment of NTM-PD

Written informed consent, and assent when applicable, is obtained from participant or participant’s legal representative. Visits are scheduled based on clinical need (per current CFF guidelines) (19). No therapies for CF are restricted except the use of azithromycin (15, 16). During the visits, participants are evaluated for NTM-PD and CF-related comorbidities following the PREDICT Study Visit Flowchart (Figure 1).

Figure 1.

PREDICT study visit flowchart.

Following a positive NTM culture a potential subject is notified, and if clinically appropriate a clinic visit may be schedule sooner than standard intervals. The initial visit includes recording demographic information, CFFPR identification number, and CF transmembrane-conductance regulator (CFTR) genotype. With every visit, a clinical assessment is conducted utilizing data collected during the visit and clinical events occurring since the last visit. The clinical assessment includes height and weight to calculate Body Mass Index (BMI) in adults or BMI percentile in children, spirometry to determine percent predicted forced expiratory volume in one second (ppFEV₁), NTM culture history, and a review of concomitant medications. A focused clinical history is obtained, including presence or absence of respiratory symptoms (cough, sputum production, hemoptysis, dyspnea) and constitutional symptoms (fevers, night sweats, decreased appetite, fatigue), provider and participant report of frequency of pulmonary exacerbations, and other significant clinical events such as pregnancy or COVID-19 infection and immunization are reviewed and recorded.

A high-resolution computed tomography (HRCT) of the chest is obtained per institutional standards, as part of clinical care if one has not been performed in the past year. Based on these results, clinicians will determine if a “clinical syndrome” is present, defined by the presence of one or more of the following: 1) worsening of HRCT scan in a pattern highly suggestive of NTM-PD, 2) participant experiencing constitutional symptoms, 3) participant experiencing increased respiratory symptoms, 4) participant perception that he/she has experienced increased frequency of exacerbations, 5) provider perception that the participant has experienced increased frequency of exacerbations, 6) current ppFEV₁ less than 90% of their best (previous 2 years) ppFEV₁, 7) current BMI (or BMI percentile) less than 90% of the participants best (previous 2 years) BMI (or BMI percentile). In addition, results of recent sputum cultures are reviewed, as well as the management of identified comorbidities.

Participants also complete the CF Questionnaire-Revised (CFQ-R). Initially a paper version was utilized, then transitioned to a validated electronic version (20). The CFQ-R is a disease-specific, health-related quality of life instrument for pwCF, asking about symptoms and mood over the preceding 2 weeks. Only the Respiratory and Treatment Burden Domains are collected, a subset of questions from the CFQ-R, which takes approximately 5 minutes to complete (20). If the participant has a compatible device and is willing, the participant is instructed to download and register the Medidata ePRO application onto their personal device(s). The study sites review and provides the participant with the application instructions to complete questionnaires. If the participant is unable to download the Medidata ePRO application, questionnaires are not collected from them. For participants ≤ 14 years, an age-modified version of the CFQ-R is completed by the participant’s legal guardian.

Based on the clinical assessment, an NTM-PD diagnosis (Table 2) is considered at every clinical encounter. The NTM-PD diagnosis requires all of the following requirements be met: 1) microbiological criteria, 2) presence of a clinical syndrome, 3) persistence of symptoms (or the clinical syndrome) despite treatment of other, non-NTM, co-pathogens and other co-morbidities, and 4) the consensus opinion by the CF Care Team that the participant’s clinical syndrome and/or decline is due to NTM infection. Recommended treatment of non-NTM co-pathogens is typically 2 weeks of antibiotic therapy directed by culture and drug sensitivity testing. Eradication of co-pathogens such as P. aeruginosa or S. aureus is not expected, but rather the goal is to adequately suppress these infections to eliminate the potential that the participant is experiencing a sub-acute exacerbation from other bacterial pathogens. It is recognized that in the individual subject, efforts to treat other co-pathogens or address co-morbidities may not be entirely successful, possibly in part to the presence of NTM-PD. In such cases treatment of NTM-PD should proceed without resolution of these other issues. Examples of this situation could include individuals with poorly control CF-related diabetes or sub-optimal nutritional status because of NTM-PD. Participants who meet diagnostic criteria for NTM-PD through participation in the PREDICT study are offered the opportunity to participate in the Prospective Evaluation of a Standardized Approach to treatment of Nontuberculous Mycobacteria Disease in Cystic Fibrosis (PATIENCE, NCT02419989), which evaluates response to a standardized NTM treatment algorithm based on current guidelines for standards of care (15, 16).

TABLE 2:

NTM DISEASE DIAGNOSIS EVALUATION

Meets microbiological criteria   • 2 positive NTM cultures from sputum (same species/subspecies) in last 2 years OR  • 1 positive NTM culture from BAL (Note: a consultation with the study lead investigators is required)	◻ Yes ◻ No (diagnosis of NTM cannot be made at this visit)
Clinical syndrome present	◻ Yes ◻ No (diagnosis of NTM cannot be made at this visit)
Was definitive treatment completed for non-NTM co-pathogens and or acute exacerbation?	◻ Yes- co-pathogens have been definitively treated or no known copathogens ◻ Other- definitive co-pathogens treatment was not completed, but there is compelling evidence to treat NTM ◻ No – current acute pulmonary exacerbation or co-pathogen is under evaluation/treatment. ◻ No, co-pathogens were treated, but not definitively. No compelling evidence of NTM, will reassess at next visit.
Evaluation of other comorbidities:  • Are all aspects of care satisfactory, and not deemed responsible for the clinical syndrome? Or  • Are some aspects of care not optimal, and there is compelling evidence that NTM disease needs to be treated? Note which comorbidities not considered well-controlled when making a diagnosis of NTM disease.	◻ Yes- all aspects of care are optimal ◻ Yes- Not all aspects of care are well-controlled, but there is compelling evidence to treat NTM ◻ No – other comorbidity under evaluation/treatment.
In the opinion of the CF Care Team, clinical worsening is likely due to NTM disease and is severe enough to recommend antibiotic treatment	◻ Yes ◻ No
If ALL responses above are YES, date of NTM Disease Diagnosis	Date of NTM Disease Diagnosis: _____/_____/_____
Is participant willing to begin NTM disease treatment?	◻ Yes, consent into PATIENCE ◻ No, schedule participant’s next PREDICT Follow Up visit until participant is ready to begin NTM disease treatment

2.4. Sputum collection for clinical care

Sputum collection is attempted at each visit and cultured for CF pathogens and NTM at the local institutional clinical laboratory supporting each site per CFF consensus guidelines (15, 21). If available, result from bronchioalveolar lavage (BAL) are also recorded. NTM species and sub-speciation is requested for all isolates. Drug susceptibility testing is requested when required for making appropriate treatment selections, including at the time a diagnosis of NTM-PD is made. When NTM is isolated from participant’s sputum at the local clinical laboratory, the isolate is saved and sent to the CFF-sponsored Colorado NTM Outcome Measure Advancement Core National Resource Center at NJH (https://www.cff.org/national-resource-centers) for banking, whole genome sequencing, and additional analyses, including confirming the subspecies identification. Beginning in 2023, participants are also provided annually with a home sputum collection kit. Raw sputum samples collected at home are shipped to the NJH clinical laboratory within 3 days of collection for NTM culture. Results from this analysis are provided back to the site PI to assist with the NTM-PD diagnosis and clinical decision-making.

2.5. Sample collection for biomarker identification and validation

Blood, sputum and urine specimens for banking are requested at the time of enrollment, annually, and at the time of NTM Disease Diagnosis or the end of study participation. If a research sample collection was performed within one month of NTM-PD diagnosis, an additional sample is not required. Instructions for specimen collection, processing, storage, and shipping of samples are provided to each CF Center participating in the trial. Sputum is frozen and banked without processing. Blood (16cc) is processed for both serum and plasma. Urine is centrifugated and frozen. All specimens are labeled with barcodes and stored promptly in a −70°C freezer. Specimens are shipped frozen on dry ice at the specified time frames throughout the study to the CFF Biorepository (https://www.cff.org/researchers/cf-foundation-biorepository) for ongoing and future evaluation of treatment response and culture-independent methods of diagnosis. All available HRCT scans are sent to NJH for deidentification and digital archiving for further analysis. At the Colorado Adult Program (NJH), saliva is also collected and banked.

3. Data collection and management

Each site PI is responsible for all information collected on participants enrolled in this study. The PI prepares and maintains adequate and accurate source documents designed to record all observations and other pertinent data for each participant who signs informed consent. Study personnel at each center enter data from source documents corresponding to a participant’s visit into the protocol specific electronic case report form (CRF) when the information is available. Participants are identified by a site number, participant number and initials. CRFs are periodically audited by the TDNCC study team. If a clarification or correction is required for a CRF.

All data collected during this study are reviewed and verified for completeness and accuracy by the site PI. Though the majority of the study is performed within a clinical encounter, all NTM-PD diagnoses and study withdrawals must be approved by the site PI. At the completion of the study, a copy of the CRF data is provided to the site to be retained at the participants CD Center. Data is collected and kept in Medidata Solutions, Inc. (Medidata) Rave and managed by the TDNCC. The Medidata Rave EDC system is designed to be US Code of Federal Regulations (CFR) 21 Part 11 compliant, with a robust audit trail system and electronic signature capabilities.

The TDNCC is responsible for data processing and analyses, in accordance with procedural documentation and an a priori statistical analytic plan (SAP). Database lock will occur once quality assurance procedures have been completed. All procedures for the handling and analysis of data is conducted using good computing practices for the handling and analysis of data for clinical trials.

4. Outcome measures

All analyses for PREDICT will be based on the group of participants who provide consent and enroll into study. The following demographic and clinical characteristics will be reported: age, sex, race, ethnicity, CFTR genotype, CF-related comorbidities, bacterial and fungal co-pathogens, and NTM history. Additionally, summaries at time of enrollment will include NTM species and subspecies, historic and baseline pulmonary function (ppFEV₁) and anthropometric measures (height, weight and BMI). Change in ppFEV₁, BMI and pulmonary exacerbations will be tracked at each visit, along with available NTM culture results, radiographic changes, and CFQ-R

The primary endpoint is the proportion of participants meeting the diagnosis of NTM-PD. Participants meeting NTM-PD diagnosis criteria will be compared to those without NTM-PD. The secondary endpoints are comparison of demographics, clinical and microbiologic features, and clinical outcomes over time (ppFEV₁, growth parameters, CFQ-R) between the two cohorts. Other secondary endpoints are adherence to PREDICT protocol, number of respiratory cultures per participant per year, withdrawals and major deviations from protocol, time between enrollment and NTM-PD diagnosis, incidence and prevalence of NTM species/subspecies by geographical region, proportion of eligible NTM positive individuals with CF enrolling in PREDICT by site, and proportion of PREDICT participants with NTM-PD diagnosis who enroll in the PATIENCE trial. Adherence to protocol will be summarized for each measure (withdrawals, number of cultures/year, and major deviations from protocol) and on a composite basis. Major deviations from protocol will include (but not limited to) the following events: not treating common respiratory pathogens and initiation of treatment before NTM-PD diagnosis criteria are met.

5. Statistics

Continuous variables will be summarized and compared via covariate adjusted longitudinal regression methods; graphical as well as model-based summaries of lung function, growth parameters (height, weight, BMI) and CFQ-R will be assessed by NTM-PD diagnosis. The proportion of participants who meet the NTM-PD diagnosis will also be estimated and compared using Fisher’s exact test or via logistic regression using generalized estimating equations (GEE). Time to event analyses will be analyzed using Kaplan-Meier estimates and Cox Proportional Hazards models with all events evaluated from time of enrollment for PREDICT. A lasso logistic regression model will be used to identify clinical factors most associated with NTM disease. For each site, the proportion of eligible NTM positive participants enrolling into PREDICT will be estimated from the CFF patient registry. Sensitivity analyses utilizing alternate event start dates will be incorporated. All estimates will include two-sided 95% confidence intervals.

6. Discussion

The PREDICT protocol is designed to standardize the diagnosis and collect relevant data associated with the presence of NTM-PD in people with NTM positive cultures to both improve clinical care and to build a framework for future therapeutic trials. The diagnosis of NTM-PD is especially challenging, as there are no pathognomonic markers, radiographic findings, or clinical symptoms that can distinguish NTM-PD from other infections or CF-related comorbidities. In the setting of >1 NTM positive culture, the diagnosis often depends on establishing that an individual is experiencing a more accelerated clinical decline than what would be typically attributed to underlying progression of CF. In practice, this requires that the management of all other co-infections and co-morbidities be optimized in order to rule-out more common and easily treated conditions. In pwCF with excellent control of all aspects of their disease, the emergence of NTM-PD is often quite apparent to both patient and provider. However, in many cases, treatment of CF may not be optimal and when standard therapies are reintroduced the signs or symptoms attributed to NTM may resolve. In our experience, the majority of pwCF with intermittent positive NTM cultures do not meet a definition for NTM-PD over an extended timeframe; however, the fact that treatment is not always necessary can unintentionally delay the decision to treat in individuals with NTM-PD(3).

Currently, expert opinion emphasizes the avoidance of treatment of apparently indolent NTM infections. Treatment is challenging with a substantial occurrence of side-effects and drug toxicity as recommendations call for 3 to 4 active antibiotics for a minimum of one year after conversion to consistently negative sputum cultures (16). In the absence of a clear clinical syndrome, it is unlikely that pwCF will experience a benefit from therapy, although some may argue that eradication of the pathogen is a worthwhile goal (22, 23). The decision to treat has become even more challenging since CFTR modulator therapy was approved for the vast majority of adults in the U.S. with CF in late 2019 and children in 2021. CFTR modulation is now standard of care for up to 90% of pwCF in the U.S. Of particular interest are the exceptional outcomes from two CFTR modulators currently in clinical use: ivacaftor in pwCF with CFTR gating mutations (24, 25), and the triple combination elexacaftor, tezacaftor and ivacaftor (E/T/I) in pwCF who are either homozygous (26) or heterozygous for the F508del CFTR variant (27). Therapy of these mutations with the corresponding CFTR modulators has resulted in marked improvement in lung function, body mass index, quality of life, and rate of pulmonary exacerbations. In analysis of registry data and small case series, there are reports of individuals who appear to have cleared NTM, based on airway culture results (28, 29), as well as preliminary analysis for this study (30). In some pwCF, the extent of improvement in clinical symptoms, combined with resolution of many radiographic findings associated with infection potentially could mask the signs and symptoms of NTM-PD, and potentially delay treatment until the disease is relatively fulminant. As the PREDICT trial has been ongoing since 2013, the longitudinal study design allows for comparison before and after CFTR modulator therapy within subjects, and between subjects who are receiving or not receiving CFTR modulator therapy (30). It is likely that different diagnostic criteria will be needed for pwCF receiving CFTR modulator therapy, and the current trial is well-positioned to explore that possibility.

Cultures from the airway are the “gold standard” for screening, disease classification, and assessing treatment response; however, in the CF population they suffer from particularly low sensitivity due to required decontamination procedures (31). Historically, sputum production was a hallmark of CF, however, reduction in sputum production is a nearly universal benefit of CFTR modulator therapy, and many pwCF receiving CFTR modulator therapy expectorate mucus infrequently or only during pulmonary exacerbations. This is particularly true in children and adults with relatively mild lung disease. Thus, there is intense interest in identifying more sensitive markers of NTM infection and disease. With the collection of urine, blood, sputum research samples concomitantly with NTM cultures, HRCT and clinical assessments, a variety of metabolic and molecular markers are under investigation with the potential to monitor different aspects of NTM infection and treatment response (TABLE 3). For each, formal validation trials are needed, as well as a better appreciation for the appropriate application, alone and in combination with orthogonal markers and standard cultures.

TABLE 3:

ANCILARY TRIALS AND STUDIES LINKED TO PREDICT

Clinical Trial or Research Study	Sample/cohort	Sponsor	Ref
Healthcare Associated Links in Transmission of NTM in Patients with CF (NCT04024423, NCT05686837)	NTM isolates	CFF (GROSS19Q0) (GROSSY5)	(9, 13, 32)
Protocol for Bacteriophage Treatment of Mycobacteria abscessus through An Investigational New Drug Application	NTM isolates, blood, urine, sputum, clinical data in a participant with NTM-PD	FDA (IND 26902)	(33, 34)
A Phase 1b, Multi-center Study of IV Gallium Nitrate in Patients with Cystic Fibrosis who are Colonized with Nontuberculous Mycobacteria (ABATE Trial)(NCT04294043)	NTM isolates, participants with indolent infection	FDA (R01FD-R-6848) CFF
Prospective Longitudinal Assessment of Culture-Independent Molecular Airway Markers of Nontuberculous Mycobacteria	Sputum, NTM isolates, clinical data	NIH (HL146228)	(35, 36)
Improving NTM Disease Diagnosis Through Use of a Novel High-Resolution Chest CT Score	HRCT scans, clinical data	CFF (MARTIN22K0, MARTIN20Y5)
Prospective Evaluation of Markers of NTM and Host Response in Saliva	Saliva, clinical data	CFF (NICK21KO)	(31)
Population Genomics of NTM in Cystic Fibrosis Care Centers, United States	NTM isolates, culture and clinical data	NIH (AI125726) CFF (NICK15R0)	(4, 5, 37)
Prospective Algorithm for Treatment of NTM in Cystic Fibrosis (PATIENCE)(NCT02419989)	Participants with NTM-PD	CFF (NICK17K0)
PrOSpecTive STandardized Assessment of MycobacterioPhage (POSTSTAMP) Trial	Participants with treatment refractory NTM-PD	CFF (NICK23A0)

7. Trial status

Registration information is available at ClinicalTrials.gov (Identifier: NCT02073409). Recruitment began in December 2013. The study protocol has been revised on 5 occasions to simplify aspects of data collection and to accommodate changes in clinical care imposed by the COVID-19 pandemic and widespread adoption of CFTR modulator therapy. The anticipated completion date is 2025, but enrollment may be extended based on interim data analysis. All results will be available on ClinicalTrials.gov, conference presentations and peer-reviewed publications. The deidentified datasets and statistical codes will be available from the corresponding author for qualified investigators at the completion of the trial, as is the full protocol. A number of ancillary trials are linked to collection of isolates, HRCT, samples, and data from the PREDICT trial (TABLE 3).

Highlights.

• The CF population is at high risk for infections by nontuberculous mycobacteria

• Identifying those with NTM disease who will benefit from treatment is challenging

• A standardized approach to establishing the NTM disease diagnosis is needed

• A prospective multicenter observational study design is described

List of abbreviations

NTM:

Nontuberculous mycobacteria

CF:

cystic fibrosis

PREDICT:

prospective evaluation of nontuberculous mycobacteria disease in cystic fibrosis

MAC:

M. avium complex

NTM-PD:

NTM pulmonary disease

WGS:

whole genome sequencing

pwCF:

people with CF

CFF:

US Cystic Fibrosis Foundation

ECFS:

European Cystic Fibrosis Society

CFF PR:

CFF Patient Registry

BMI:

Body Mass Index

ppFEV1:

percent predicted forced expiratory volume in 1 second

CFQ-R:

Cystic Fibrosis Questionnaire-Revised

PATIENCE:

Prospective Evaluation of a Standardized Approach to treatment of Nontuberculous Mycobacteria Disease in Cystic Fibrosis

TDNCC:

therapeutics development Network coordinating center

SAP:

Statistical Analysis Plan

GEE:

generalized estimating equations

LAM:

Lipoarabinomannan

CFTR:

CF transmembrane-conductance regulator

Appendix: Investigators of the Cystic Fibrosis NTM Consortium

G. Marty Solomon, MD, University of Alabama Birmingham, Alabama, United States

Thomas G. Keens, MD, Children’s Hospital of Los Angeles Los Angeles, California, United States

Douglas J. Conrad, MD, University of California San Diego San Diego, California, United States

Silvia Delgado Villalta, MD, University of Florida Gainesville, Florida, United States

Manu Jain, MD, Northwestern University Chicago, Illinois, United States

Keira A. Cohen, MD and Noah Lechtzin, MD, Johns Hopkins University Baltimore, Maryland, United States

Rebecca E. Cagnina, MD, Boston Children’s Hospital, Brigham & Women’s Hospital Boston, Massachusetts, United States

Lindsay J. Caverly, MD, University of Michigan Ann Arbor, Michigan, United States

Brian P. O’Sullivan, MD, Dartmouth Hitchcock Medical Center Lebanon, New Hampshire, United States

Emily DiMango, MD, Columbia University New York, New York, United States

Jennifer L. Goralski, MD and Charles R. Esther, MD, University of North Carolina at Chapel Hill Chapel Hill, North Carolina, United States

Karen S. McCoy, MD, Nationwide Children’s Hospital Columbus, Ohio, United States

Joseph M. Pilewski, MD, University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, United States

Raksha Jain, MD, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States

Zachary L. Weintraub, MD, University of Vermont Medical Center Burlington, Vermont, United States

Ronald L. Gibson, MD, Children’s Hospital Seattle, Washington, United States

Moira L. Aitken, MD, University of Washington, Seattle, Washington, United States

Matthias Salathe, MD, University of Kansas Medical Center, Kansas City, Kansas, United States

Charles S. Haworth, MD, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom

Kenneth N. Olivier, MD, National Institutes of Health, Bethesda, Maryland, United States

Michael P. Boyle, MD and Bruce C. Marshall, MD, Cystic Fibrosis Foundation, Bethesda, Maryland, United States.