Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Remote endpoints for clinical trials in cystic fibrosis: Report from the U.S. CF foundation remote endpoints task force.

The COVID-19 pandemic necessitated a rapid shift in clinical research to perform virtual visits and remote endpoint assessments, providing a key opportunity to optimize the use of remote endpoints for clinical trials in cystic fibrosis. The use of remote endpoints could allow more diverse participation in clinical trials while minimizing participant burden but must be robustly evaluated to ensure adequate performance and feasibility. In response, the Cystic Fibrosis Foundation convened the Remote Endpoint Task Force (Supplemental Table 1), a multidisciplinary group of CF researchers with remote endpoint expertise and community members tasked to better understand the current and future use of remote endpoints for clinical research. Here, we describe the current use of remote endpoints in CF clinical research, address key unanswered questions regarding their use and feasibility, and discuss the next steps to determine clinical trial readiness.

Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

The effect of elexacaftor/tezacaftor/ivacaftor on non-pulmonary symptoms in adults with cystic fibrosis.

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator that has led to large benefits in lung function, pulmonary exacerbation rates, and respiratory symptoms. Less is known about the effect of ETI on non-pulmonary symptoms. The objective of this study was to examine the changes in patient reported outcomes after starting ETI in multiple non-pulmonary symptoms. Methods: This was a prospective cohort study of adults with CF. Participants completed questionnaires prior to starting ETI and then at weeks 2, 4, 6, 8, 10, 12, and 14 after starting ETI. They completed the following validated instruments: PROMIS Pain Intensity, PROMIS Pain Interference, FACIT Fatigue, SNOT22, PAC-SYM, PHQ8, GAD7 and Pittsburgh Sleep Quality Index. Longitudinal changes for outcomes were modelled using linear regression based on general estimating equations. Results: 22 participants enrolled who answered questionnaires before and after starting ETI. The median age was 35.3 years (IQR 11.1) and 13 (59.1%) were male. In models adjusted for age, sex, and baseline value there were significant improvements in pain interference (ß = -2.57; 95% CI -4.92, -0.23), sinus symptoms (ß = -4.50; 95% CI -7.59, -1.41), and sleep disturbance (ß = -1.90; 95% CI -2.71, -1.09) over 14 weeks after starting ETI. No symptom areas worsened over the study period. Conclusions: In this prospective study we found statistically significant improvements in three different non-pulmonary symptom areas in people with CF started on ETI. While this was a small, uncontrolled study it suggests that use of highly effective CFTR modulators can result in benefits for patients beyond pulmonary symptoms.

Telemedicine and remote monitoring in cystic fibrosis.

PURPOSE OF REVIEW: Guidelines for cystic fibrosis (CF) care recommend multidisciplinary teams see patients at least quarterly with frequent measurement of spirometry and collection of respiratory cultures. This can be burdensome for people with CF, particularly if they live far from a specialized care center. This has led to an interest in telehealth coupled with remote monitoring. We review the recent literature on these topics for people with CF. RECENT FINDINGS: The COVID-19 pandemic accelerated a move toward remote delivery of CF care and multiple recent publications have reported on the feasibility of telehealth, remote spirometry, remote collection of respiratory cultures, adherence monitoring, cough assessment, symptom monitoring and activity tracking. Useful data can be obtained and both clinicians and patients have favorable opinions about remote delivery of healthcare, though the impact on clinical outcomes is not yet known. SUMMARY: Telehealth and remote monitoring for people with CF is feasible and has grown in use, though it is too early to know how prominently these approaches will fit into routine care for CF.

COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success.

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS).Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial.Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort.Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS.

AIMS: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS. MATERIALS AND METHODS: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method. RESULTS: The full analysis set consisted of 456 patients (reldesemtiv n = 342, placebo n = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058). CONCLUSIONS: This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings. CLINICALTRIALS.GOV IDENTIFIER: NCT03160898.

MiToS and King's staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial.

OBJECTIVE: To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS. METHODS: This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King's stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage. RESULTS: The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n = 342, placebo n = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King's stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King's stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King's. CONCLUSION: This exploratory analysis showed the feasibility of MiToS and King's staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.

Prevalence and Risk Factors for Low Bone Mineral Density in Adults With Cystic Fibrosis.

Single-center studies have suggested that up to 70% of adults with cystic fibrosis (CF) have lower than expected bone mineral density (BMD), substantially higher than the 25% prevalence reported from national registries. We determined the prevalence of low BMD in CF adults at our center and assessed risk factors for low BMD. This retrospective cohort study was conducted in all CF patients ≥18 years of age who had a dual-energy X-ray absorptiometry (DXA) scan performed at the Johns Hopkins Adult Cystic Fibrosis center between 2010 and 2018. Prevalence and incidence of low BMD during the study period were determined. Poisson regression based on generalized estimating equations and robust standard errors were used to evaluate selected risk factors and risk of disease progression. A total of 234 individuals underwent an initial DXA scan. At this scan, prevalence of low BMD was 52.6% (95% confidence interval [CI] 46.0-59.1). A total of 43.6% were at risk for CF-related low BMD (AR-CFLBMD) (95% CI 37.1-50.2) and 9.0% had CF-related low BMD (CFRLBMD) (95% CI 5.6-13.4). Of the 25 with normal BMD at initial scan and a subsequent follow-up scan, 8 (32.0%) progressed to AR-CFLBMD. Of the 53 with AR-CFLBMD on initial scan and a subsequent scan, 6 (11.3%) progressed to CFLBMD, 9 (17.0%) returned to normal BMD, and 38 (71.7%) remained AR-CFLBMD. Older age (relative risk [RR] = 1.01; 95% CI 1.00-1.01) and male sex (RR = 1.32; 95% CI 1.04-1.66) were associated with increased risk of low BMD, while higher forced expiratory volume over 1 second (FEV1%) predicted (RR = 0.99; 95% CI 0.99-1.00) and body mass index (BMI; RR = 0.97; 95% CI 0.94-1.00) were associated with lower risk for low BMD. The fact that more than half of all individuals were found to have lower than expected BMD suggests that the actual prevalence may be higher than currently reported in national registries. This supports the importance of universal bone health screening of all CF adults. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Viruses to the rescue-Use of bacteriophage to treat resistant pulmonary infections.

People with cystic fibrosis (CF) are commonly infected with difficult to treat organisms, including non-tuberculous mycobacteria. Bacteriophage are viruses that lyse specific bacteria. Nick and colleagues describe the first successful treatment of a Mycobacterium abscessus lung infection with bacteriophage in an immune competent individual. This report provides important information regarding the efficacy of phage therapy and timeline of treatment response.

Indoor air pollution exposure is associated with greater morbidity in cystic fibrosis.

BACKGROUND: Exposure to higher levels of outdoor air pollution is associated with increased morbidity in individuals with cystic fibrosis. Limited information exist regarding the potential adverse effects of indoor air pollution on those with cystic fibrosis. METHODS: Individuals with cystic fibrosis who were enrolled in the Twin and Sibling Study from 2000-2013, self-reported exposure to four known sources of indoor air pollution (secondhand smoke, forced hot air, wood stove and fireplace). Change in lung function, rates of hospitalizations and pulmonary exacerbations were followed over 4 years to compare outcomes in those who were exposed to those who were not exposed. RESULTS: Of 1432 participants with data on secondhand smoke exposure, 362 (25.3%) were exposed. Of 765 individuals with data on forced hot air exposure, 491 (64.2%) were exposed. Of 1247 participants with data on wood stove exposure and 830 with data on fireplace exposure, 182 (14.6%) and 373 (44.9%) were exposed, respectively. In longitudinal analysis, pediatric individuals either exposed to secondhand smoke or to forced hot air had a 0.60% predicted/year decrease in FEV1% predicted (P=0.002) or a 0.46% predicted/year decrease in FEV1% predicted (P=0.048), respectively compared to individuals who were not exposed. Adults exposed to secondhand smoke had a 42% increased yearly risk of hospitalization compared to those who were not exposed (P=0.045). CONCLUSIONS: Our questionnaire-based data suggest that exposure to sources of indoor air pollution increase morbidity in both the pediatric and adult cystic fibrosis populations. Future studies with quantitative indoor air quality assessments are needed.

A comparison of clinic and home spirometry as longtudinal outcomes in cystic fibrosis.

BACKGROUND: The COVID-19 pandemic has accelerated the transition to telehealth, including the use of home spirometry in cystic fibrosis. Evaluating the accuracy and precision of longitudinal home spirometry is a requisite for telehealth-based research. This secondary analysis of a CF study (eICE) evaluates whether there are cross-sectional or longitudinal differences between home and clinic spirometry. METHODS: Participants age ≥14 years with ppFEV1>25 were recruited from 2011-2015, issued a home spirometer, and asked to complete spirometry efforts twice per week for one year. Clinic spirometry was collected at baseline and every three months. Cross-sectional differences between clinic spirometry and the closest home spirometry measurement were analyzed. Longitudinally, we apply 5 methods to analyze the precision of home spirometry, and differences between clinic vs. home data. RESULTS: Home spirometry is estimated to be 2.0 (95% CI: 0.3, 3.5) percentage points lower than clinic spirometry cross-sectionally. Longitudinally, the estimates of 12-month change in home spirometry varied by analysis method from -2.6 to -1.0 ppFEV1/ year, with precision markedly different. However, home spirometry change estimates were qualitatively similar to the clinic results: -3.0 ppFEV1/year (95% CI: -4.1, -1.9). CONCLUSIONS: To leverage the potential cost, feasibility and convenience of home spirometry, the differences with clinic spirometry must be acknowledged. Significantly lower ppFEV1 in home devices shows that direct comparison to clinic spirometers may induce a spurious change from baseline, and additional variability in home devices impacts statistical power. The effect of coaching, setting, and equipment must be understood to use and improve home spirometry in CF.

Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of reldesemtiv in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial.

Objective: To evaluate the possible effect of reldesemtiv, a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Methods: Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed. Cox regression analysis compared time to DME-PAP for each reldesemtiv dose with placebo. Post hoc analyses evaluated all reldesemtiv doses compared with placebo. Results: At least one DME item was prescribed and accepted by 33/114 (28.9%) of placebo patients, 19/112 (17.0%) of patients receiving reldesemtiv 150 mg bid, 24/113 (21.2%) receiving 300 mg bid, and 29/117 (24.8%) receiving 450 mg bid. The proportion of new DME-PAP was significantly lower in patients receiving reldesemtiv 150 mg bid vs placebo (17.0% vs 28.9%, p = 0.032). The hazard ratio versus placebo for accepting at least one DME item for all reldesemtiv doses combined was 0.61 (confidence interval: 0.39, 0.96, p = 0.032). 25% of placebo patients were prescribed and agreed to obtain a DME item by 84 days; this threshold was met for reldesemtiv-treated patients at 120 days. Conclusions: Results suggest ALS patients receiving reldesemtiv may have lower risk of and delayed need for DME related to impaired mobility, breathing, swallowing, or speaking; this delay is consistent with other measures indicating delay in disease progression.

Satisfaction and effectiveness of opioid pain management among adults with cystic fibrosis: A mixed methods study.

BACKGROUND: Chronic pain is common among people living with cystic fibrosis (CF) and associated with worse clinical outcomes. Despite this, little is known about how pain is managed and how opioids are used to treat pain. The purpose of this convergent mixed methods study was to examine self-reported satisfaction and effectiveness of pain management strategies among a sample of adults with CF who are prescribed opioids. METHODS: We developed an online survey querying 4 domains - demographics, pain characteristics, pain communication, and management strategies. This was distributed nationally to adults with CF (n=48) via various online platforms. We obtained quantitative and qualitative responses regarding satisfaction and effectiveness of pain management. Emerged themes from qualitative data were compared with responses from quantitative survey domains. RESULTS: Participants reported high levels of satisfaction and effectiveness with their opioid pain management plans. However, qualitative themes emerged regarding fears of addiction, experiences of feeling stigmatized by the healthcare system and ineffectiveness and inefficiency of alternative therapies for adequate pain relief. CONCLUSIONS: Adults with CF reported opioids as an important component of their current pain management plans despite risks associated with opioid use. CF-specific pain management guideline development is warranted as is further research exploring pain development.

Health care costs related to home spirometry in the eICE randomized trial.

BACKGROUND: Home spirometry with regular symptom assessment is one strategy to track lung health to intervene early in episodes of pulmonary exacerbations (PE). In a multi-center randomized controlled trial home spirometry and symptom tracking demonstrated no significant differences regarding the primary clinical endpoint, FEV1, compared to usual care, but did identify differences in healthcare utilization. We used data from the Early Intervention in Cystic Fibrosis Exacerbation (eICE) study to evaluate whether home monitoring of PE is a cost-minimizing intervention in the context of this randomized trial. METHODS: We reviewed healthcare resource utilization of all 267 eICE participants, including outpatient visits, antibiotics and hospitalizations. Prices were identified in the IBM/Watson MarketScanⓇ Commercial Claims and Encounters Databases and averaged over the 2014-2017 period. Using total healthcare utilization costs, we generated summary statistics by intervention and protocol arm (total cost, mean cost, standard deviation). We performed Welch Two Sample t-tests to determine if total costs and cost by type of utilization differed significantly between groups. RESULTS: Outpatient visit costs were significantly higher by 13% in the Early Intervention (EI) than in the usual care (UC) arm ($3,345 vs. $2,966). We found no significant differences in outpatient antibiotic, hospitalization, or total health care costs between the arms. CONCLUSIONS: Within the context of the eICE trial, outpatient visits were significantly higher in those with experimental home spirometry care, but that did not translate into statistically significant differences of overall health care costs between the two arms.

Sex differences in treatment patterns in cystic fibrosis pulmonary exacerbations.

BACKGROUND: Females with cystic fibrosis (CF) have been shown to have worse pulmonary exacerbation (PEx) related outcomes compared to males. However, it is unknown if sex differences in treatment patterns are contributing to these outcomes. Thus, we sought to explore sex differences in treatment patterns in the Standardized Treatment of Pulmonary Exacerbations (STOP) cohort. METHODS: Data for 220 participants from the STOP cohort were analyzed. Multivariable regression models were used to assess if female sex was associated with duration of treatment with IV antibiotics and inpatient length of stay. Secondary outcomes included antibiotic selection, adjunctive therapies, mean FEV1pp and CFRSD-CRISS respiratory symptom scores at the four study assessments. RESULTS: In our adjusted model, the average number of IV antibiotic treatment days was 13% higher in females compared to males (IRR 1.13, 95% CI=1.02,1.25; p=0.02). We found no sex differences in inpatient length of stay, number of IV antibiotics, antibiotic selection or initiation of adjunctive therapies. Overall, females had higher CFRSD-CRISS scores at the end of IV therapy indicating worse symptom severity (23.6 for females vs. 18.5 for males, p=0.03). CONCLUSIONS: Despite females having a longer treatment duration, our findings demonstrate that males and females are receiving similar treatments which suggest that the outcome disparities in females with CF may not be due to failure to provide the same level of care. Further research dedicated to sex differences in CF is necessary to understand why clinical outcomes differ between males and females.

The effect of oral and intravenous antimicrobials on pulmonary exacerbation recovery in cystic fibrosis.

BACKGROUND: Retrospective studies indicate that more cystic fibrosis (CF) pulmonary exacerbations (PEx) are treated with oral (PO) than with intravenous (IV) antimicrobials despite little knowledge of the relative effects of PO treatment on lung function recovery or long-term impacts on lung disease progression. Previous studies have suggested that PO treatment may be associated with slower lung function recovery compared with IV treatment. We used longitudinal home spirometry data from the eICE study (NCT01104402) to compare PO versus IV antimicrobial treatment responses for PEx diagnosed by home spirometry and symptom assessment. METHODS: Adolescent and adult eICE participants performed home spirometry twice weekly for one year. PEx were diagnosed by a protocol-defined algorithm of change in percent predicted forced expiratory volume in 1 second (ppFEV1) and/or respiratory signs and symptoms. PO- and IV-treated PEx were grouped by initial ppFEV1 drop magnitude. Group ppFEV1 treatment responses were modeled with multivariate, repeat-measure linear regression. RESULTS: Of 87 qualifying PEx from 56 participants, 62 were PO-treated and 25 were IV-treated. The average drop from best ppFEV1 to PEx start was 11.0 [95%CI: 8.5, 13.5] with similar treatment group means (p=0.72). Participants with IV-treated PEx averaged 0.72 [0.24, 1.20] ppFEV1/day greater response than those treated with PO, who experienced minimal ppFEV1 recovery. Many PO-treated participants who had <10 ppFEV1 drop from baseline tended to worsen or show no ppFEV1 improvement. DISCUSSION: These results suggest that, in this cohort, PO antimicrobial treatment of CF PEx were less effective than IVs at improving ppFEV1 during treatment.