C.H. Goss

Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations

The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

Patient-reported respiratory symptoms in cystic fibrosis

BACKGROUND Cystic fibrosis (CF) specific patient-derived and reported symptom tools are critical steps toward evaluating the outcomes of new therapies for CF. METHODS We conducted 25 in-depth qualitative interviews using the Day Reconstruction Method and 9 cognitive interviews at two CF programs, the University of Washington and Seattle Childrens Hospital and Regional Medical Center. The interviews were audio-recorded and transcribed, and then coded and analyzed for themes relating to pulmonary symptoms and related psychosocial impacts. RESULTS Six pulmonary symptoms were identified as central to CF: cough, sputum production, wheeze, chest tightness, difficulty breathing/shortness of breath, and fever. Emotional impacts included frustration, sadness/depression, irritability, worry, difficulty sleeping; while activity impacts included time spent sitting or lying down, reduction of usual activities, and missing school or work. In all, 8 symptom items, 4 emotional impacts items, and 4 activity impacts were selected for inclusion on a new daily diary. We also assessed triggers for seeking care. CONCLUSIONS Using a qualitative inductive methodology, we have obtained patient centered data regarding pulmonary symptoms and burdens and have created a novel patient reported outcome measure for CF. Future studies will assess the validity of the instruments.

Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis

BACKGROUND Given the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols. METHODS Response parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored. RESULTS The most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening. CONCLUSIONS Results from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

WS02.1 Efficacy of a protocol for eradication of newly acquired MRSA: Results of the STAR-too trial

Objectives The ST aph A ureus R esistance – t reat o r o bserve trial (STAR-too) evaluates microbiologic effectiveness of an eradication protocol (Rx) compared to observation (Obs.) in subjects with newly + MRSA cultures. The study was stopped early by the Data Monitoring Committee (DMC) due to efficacy. Methods Subjects were eligible if they were: within the first 6 months of their first MRSA positive culture, age 4–45 years, and had not received MRSA active antibiotics 4 weeks prior. Due to poor enrollment, the protocol was amended to allow patients with a recent + MRSA clinical isolate but negative at screening. The eradication protocol was: oral trimethoprim-sulfamethoxazole (or minocycline) plus rifampin and chlorhexidine mouthwash for two weeks, nasal mupirocin and chlorhexidine body wipes for five days, and environmental decontamination for 21 days. The primary endpoint was MRSA culture status at day 28. Results Among 42 patients (45% female, mean age 12.3±6.8 years, baseline FEV 1 % predicted 98.7±18.7) randomized at the time of the DMC review, 39 had evaluable culture results. Seventeen (81%) were MRSA negative in the Rx arm and 4 (22%) in the Obs. arm at day 28 (diff.: 59%, 95% CI: 28–76%). Among 27 MRSA positive at screening, 8 (67%) were MRSA neg. in the Rx arm compared to 2 (13%) in the Obs. arm (diff.: 53%, 95% CI: 16–75%) at day 28. Exacerbation rate up to day 28 was reduced in the Rx arm vs. Obs. arm [rate ratio 0.40 (0.08, 1.52)]. Conclusion This MRSA eradication protocol for newly acquired MRSA demonstrated microbiologic efficacy with a large treatment effect. No safety concerns were raised. Final primary efficacy data will be presented. CFF TDN. Funding: CFF.

Initial development and pilot testing of observer-reported outcomes (ObsROs) for children with cystic fibrosis ages 0–11 years

PURPOSE Patient-reported outcomes are important clinical trial endpoints. Young children may not be able to reliably report on how they feel or function, so observer-reported outcomes (ObsROs) may be more appropriate for them. The purpose of this study was to develop and pilot field test electronic parent-reported observational instruments for children with cystic fibrosis (CF) 0-6 and 7-11years of age. METHODS We performed concept elicitation interviews with parents of children with CF ≤11years of age to elicit the respiratory signs they could observe at baseline and during an acute respiratory illness. The resulting instruments were refined based on interviews with parents and clinicians. We conducted a pilot field test to evaluate test-retest reliability and the ability of items to distinguish well and sick periods. RESULTS The instruments consist of 17 items assessing respiratory signs and observable CF-related impacts. Test-retest reliability was acceptable for both age groups but discrimination was low for ages 7-11, likely reflecting less direct observation of older children by their parents. CONCLUSIONS An ObsRO for children with CF ages 0-6 appears promising, while self-report may be more appropriate for children >6years of age. Next steps for the 0-6year old instrument will be utilizing it as an exploratory endpoint in clinical trials to enable item reduction, scale development, and further reliability and validity testing. Ultimately, this ObsRO could be a promising endpoint for early intervention trials in young children with CF.

189 Standardized treatment of pulmonary exacerbation (STOP) study: Symptomatic treatment response

Objectives Pulmonary exacerbations (PEx) are common in patients with CF, but there are few studies evaluating symptomatic resolution with intravenous (IV) antibiotics. Careful delineation of symptomatic response could provide an important tool to future studies. Methods STOP is an observational study projected to enroll over 200 participants over 12 years old who are admitted to the hospital for treatment of a PEx. The CF Respiratory Symptom Diary-Chronic Respiratory Infection Symptom Scale (CFRSD-CRISS) was given to participants daily during the 28-day study. The CFRSD-CRISS is a validated unidimensional scale based on 8 items, with a total score ranging 0–100 (higher score indicates greater symptom severity). Prior analyses have suggested the responder criteria is 11.0 points. Results 204 patients (56% female) have entered the study. 112 subjects had completed diaries at admission, at end of treatment, and at day 28. The mean CFRSD-CRISS of these 112 patients was 48.7 (SD = 10.9) at the beginning of treatment, 21.7 (SD = 16) at the end of treatment, and 27.0 (15.5) at day 28. The mean and median time to lowest CFRSD-CRISS was 11.6 (SD = 6.1) days and 11.5 (95% CI: 10.0,13.0) days respectively. Ninety-six (85.7%) had a ≥11 point reduction at the end of treatment compared to 86 (76.8%) subjects by day 28 of the study. Conclusion While the study is still ongoing, clear treatment responses have been noted in the CFRSD-CRISS. A high percentage of these patients had experienced a clinically meaningful improvement in the CFRSD-CRISS by the end of treatment and to a lesser degree by day 28. Final analysis data will be presented. We thank the CFFT TDN. Funding: CFF.

188 Standardized treatment of pulmonary exacerbations (STOP) study: Clinical presentations of pulmonary exacerbations

Objectives Pulmonary exacerbations (PEx) are common in patients with CF, but there is no standard definition. Our objective was to describe the phenotypes of PExs treated with IV antibiotics in adults and adolescents with CF. Methods STOP is an observational study at 10 US CF centers that will enroll over 200 participants ≥12 years of age admitted to the hospital for treatment of PEx, determined at the discretion of the treating physician. Demographic and clinical data are collected at the time of enrollment. Results After 12 months of enrollment, 204 patients (56% female) have entered the study. The mean age is 27.2 years (SD 9.8) with a range of 12.1–74.9 years. There are 27 (15%) patients 1 is 52% predicted (range 16–108%; SD 22). FEV1 fell >10% from best in the 6 months prior in 45%. Among 173 patients with available physician assessment, the duration of symptoms prior to admission was 21 days in 33%. 46% had failed outpatient antibiotics prior to admission and 43% had received IV antibiotics in the 6 months prior to admission. Signs and symptoms present at admission included chest pain (24%), hemoptysis (11%), and wheezing (17%). Conclusion Most patients enrolled in the study are adults, but there is a goal to include up to 30% pediatric patients. Most patients have had symptoms for more than one week before admission, and nearly half had first been treated as an outpatient with oral antibiotics. These are only preliminary data and results may change as numbers increase. Enrollment will be completed in January, 2015. Funded by CFFT TDN.

WS07.1 Standardized treatment of pulmonary exacerbations (STOP) study: Treatment goals for pulmonary exacerbations

Objectives Pulmonary exacerbations (PEx) are common in individuals with CF, but there are no standard treatment recommendations. STOP collects information to define the primary endpoint for studies of treatment of PEx, and to access the feasibility for future trials to use the CF Foundation Patient Registry (CFFPR) for data capture. Methods STOP is an observational pilot study using the CFFPR and projected to enroll over 200 patients (age >12 years) at 10 sites admitted to the hospital for PEx treatment. A survey of admitting physicians was performed to ascertain treatment goals and physician willingness to enroll the patient in hypothetical interventional trials. Results After 12 months, 204 patients (56% female) have entered the study, with a mean age of 27.2±9.2 years and 53% homozygous F508del. The primary objective of treatment was recovery of lung function (53%) and improvement of symptoms (45%). The mean lung function recovery goal (target FEV1 – admission FEV1) was 13.7% predicted (range: 0–65.7%). For CF centers with a treatment protocol, the average planned treatment duration was 13.9±1.6 days. A majority of physicians were willing to enroll their patients in a trial of differing durations [10 days (71%) and 14 days (87%)], specified antibiotics (86%), and other treatments (83%), but less so for treatment of 7 days (30%). Conclusion The primary goals for treatment of PEx are recovery of lung function, targeting almost 14% recovery, and symptom improvement. Most sites express willingness to enroll patients into interventional trials of treatments. Early experience suggests the CFFPR can be used successfully for clinical trials. Supported by CFFT.