DOI: 10.5061/dryad.c59zw3r5d
title: CARE-CF-1 Clinical trial data: An exploratory, randomized, double-blind, placebo-controlled 6-arm clinical trial examining cysteamine as an adjunct therapy for the treatment of pulmonary exacerbations of cystic fibrosis

description: Background: Emerging data suggests a possible role for cysteamine as an
 adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that
 continue to be a major clinical challenge. There are no studies
 investigating the use of cysteamine in pulmonary exacerbations of CF. This
 exploratory randomized clinical trial was conducted to answer the
 question: In future pivotal trials of cysteamine as an adjunct treatment
 in pulmonary exacerbations of CF, which candidate cysteamine dosing
 regimens should be tested and which are the most appropriate, clinically
 meaningful outcome measures to employ as endpoints? Methods and findings:
 Multicentre double-blind randomized clinical trial. Adults experiencing a
 pulmonary exacerbation of CF being treated with standard care that
 included aminoglycoside therapy were randomized equally to a concomitant
 14-day course of placebo, or one of 5 dosing regimens of cysteamine.
 Outcomes were recorded on days 0, 7, 14 and 21 and included sputum
 bacterial load and the patient reported outcome measures (PROMs): Chronic
 Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis
 Questionnaire–Revised (CFQ-R); FEV1, blood leukocyte count, and
 inflammatory markers. Eighty nine participants in fifteen US and EU
 centres were randomized, 78 completed the 14-day treatment period.
 Cysteamine had no significant effect on sputum bacterial load, however
 technical difficulties limited interpretation. The most consistent
 findings were for cysteamine 450mg twice daily that had effects additional
 to that observed with placebo, with improved symptoms, CRISS additional
 9.85 points (95% CI 0.02, 19.7) p=0.05, reduced blood leukocyte count by
 2.46x109 /l (95% CI 0.11, 4.80), p=0.041 and reduced CRP by geometric mean
 2.57 nmol/l (95% CI 0.15, 0.99), p=0.049. Conclusion: In this exploratory
 study cysteamine appeared to be safe and well-tolerated. Future pivotal
 trials investigating the utility of cysteamine in pulmonary exacerbations
 of CF need to include the cysteamine 450mg doses and CRISS and blood
 leukocyte count as outcome measures.
description: <em>Trial design:</em> This was a parallel-group,
 randomised placebo controlled trial with a 1:1:1:1:1:1 allocation ratio
  comparing the addition of 5 differing cysteamine dosing regimens or
 placebo to the standard treatment of adults with CF experiencing a
 pulmonary exacerbation. <em>Participants,
 eligibility criteria, and settings:</em> Participants were recruited
 from 15 CF centres in the UK, EU and USA between 12th January 2017 and
 21st March 2018. Participants were aged ≥18 years with an established
 diagnosis of CF lung disease, chronic infection with Gram-negative
 organisms, experiencing a new CF pulmonary exacerbation requiring
 treatment that included an aminoglycoside antibiotic, weighed
 &gt;40kg, and had an FEV1 &gt;30% predicted in the previous 6
 months. The diagnosis of CF lung disease with Gram-negative infection was
 established from clinical records. Exacerbations were confirmed by ≥4
 defining symptoms as described by Fuchs.19 Exclusion criteria included
 hypersensitivity to cysteamine, excipients or penicillamine, and
 transplant recipients. Participants were recruited by clinic staff and the
 treatment setting for pulmonary exacerbation was as per local practice for
 each centre (a mix of inpatient and community therapy).
 The trial sponsor was NovaBiotics and the trial was approved by
 each site’s Institutional Review Board. Trial registrations FDA IND
 127409, EudraCT 2015-004986-99, www.clinicaltrials.gov NCT03000348
 (registered 22nd December 2016). All participants provided written
 informed consent. <em>Interventions:</em>
 Cysteamine (as mercaptamine bitartrate) in 150mg hard gel capsules for
 oral administration was supplied by Recordati Industria Chimica e
 Farmaceutica S.p.A. Milan, Italy. Placebo comprised the excipients in
 identical capsules and in order to maintain double-blinding, were packaged
 in ‘smell-masked’ blister packs to mirror the odour of the treatment
 capsules. Participants were randomly assigned to one of six treatment
 groups in equal ratio: placebo, cysteamine 150mg three times daily,
 cysteamine 450mg once daily, cysteamine 300mg three times daily,
 cysteamine 450mg twice daily and cysteamine 450mg three times daily.
 Dosing schedules were based on those for cystinosis and the findings of a
 previous trial18 and are outlined in Figure 1. Cysteamine doses were
 either administered in oral 450mg boluses or an equivalent total oral
 daily dose three times a day, to investigate the relative contributions of
 peak concentrations and total daily dose to any therapeutic effect, i.e.
 450mg once daily, 150mg three times daily, and 450mg twice daily, 300mg
 three times daily. The treatment period with antibiotics was 14 days and
 each participant took 3 study capsules (non-cysteamine capsules made up
 with placebo), 3 times a day for 14 days.
 <em>Outcomes:</em> Outcome data were collected by
 face-to-face assessments at recruitment/baseline (day 0), 7, 14 and 21
 days. Participants ceasing trial medication were encouraged to attend
 remaining scheduled assessments. Sputum samples were
 obtained at each assessment and the following sputum based outcomes were
 quantified in central laboratories: a). Gram-negative bacterial load
 expressed as colony-forming units (CFU) per ml, b). sputum interleukin
 (IL)-8, c). sputum neutrophil elastase (NE), and d) sputum cysteamine (day
 14 only). The PROMs administered at each assessment: Cystic Fibrosis
 Respiratory Symptom Domain-Chronic Respiratory Infection Symptom Score
 (CFRSD-CRISS),20,21 the Cystic Fibrosis Questionnaire– Revised (CFQ-R),22
 and the Jarad & Sequeiros Symptom Score (JSSS).23 Venous blood
 samples were obtained at each assessment and the following outcomes were
 quantified in central laboratories: a). haematology including leukocyte
 count b). biochemistry, c). C-reactive protein (CRP), and d) blood
 cysteamine (day 14 only). Additional outcomes collected at each assessment
 visit were FEV1 percent predicted, weight, routine urinalysis, , adverse
 events (AE)/reactions, serious adverse events (SAE)/reactions, and
 adherence. <em>Sample size/power
 considerations: </em>The sample size of approximately 120 patients
 with pulmonary exacerbations of CF with 20 patients in each group was
 selected empirically without a formal statistical assumption. The sample
 size selection was considered to be appropriate for an exploratory study
 to determine the optimal dose and regimen based on evidence of efficacy
 and acceptable safety and tolerability profile as well as establish point
 estimates and variability for efficacy endpoints for future evaluation. At
 the time the study was being designed there was a lack of published PROM
 data from observational studies and interventional trials of exacerbations
 of CF. With a sample size of 20 patients in each group the study had 80%
 power to detect a 1.2 log reduction over placebo of sputum Gram-negative
 bacterial load, assuming a 5% withdrawal rate, a standard deviation of
 1.31, based on a two-sided, two-sample t-test at the 5% level of
 significance.24 This estimated standard deviation is that reported for a
 2-week study of CF patients with Pseudomonas aeruginosa who were treated
 during exacerbations with 2 weeks of intravenous tobramycin.25
 <em>Interim analyses and stopping
 guidelines: </em>Not applicable.
 <em>Randomization: </em>Randomization in 1:1:1:1:1:1
 allocation to the six test groups was achieved via a web-based
 computer-generated program, verified for accuracy using strict quality
 control procedures. Randomization was centralized and each site was
 assigned blocks of six treatments in the randomization scheme.
 <em>Blinding: </em>Participants and trial staff were
 blinded to study treatment allocation. 
 <em>Statistical analysis: </em>All analyses were
 governed by a Statistical Analysis Plan. The intention to treat (ITT)
 analysis included all participants who had taken at least one dose of
 trial drug. A per-protocol analysis performed as a sensitivity analysis
 comprised all participants whose baseline sputum cultured Gram-negative
 organisms and who completed the 14-day treatment period without protocol
 violations. The primary outcome of change in sputum
 Gram-negative bacterial load  from Baseline (Day 0) to Day 14  was
 compared between randomized groups using all available data without
 imputation in a linear mixed model for repeated measures (MMRM) with an
 unstructured covariance matrix, factors for treatment group (6 levels:
 placebo, 450mg once daily (QD), 150mg three times daily (TID), 450mg twice
 daily (BID), 300mg TID, and 450TID), assessment (2 levels: Day 7 and 14),
 and assessment by treatment group interaction and the baseline value as a
 continuous covariate. Exploratory ANCOVA modelling was performed to assess
 the influence of select baseline factors on the change from baseline at
 day 14. We did not adjust for centre as an effect because 11 of the 15
 sites recruited less than 10 participants each, such that there were often
 only one or two participants within each treatment group at each site.
 With such low numbers within each treatment group at each site we
 anticipated that inclusion of ‘centre’ would result in convergence issues
 as well as complexities with interpretability and exploratory analyses
 confirmed that this was indeed the case. A 5% two-sided significance level
 was used throughout and no adjustment for multiple comparisons was
 performed because of the exploratory nature of the study. Secondary
 outcomes were similarly analysed. Examination of the residuals (eg, Q-Q
 and density plots, residual plots, variance of residuals within groups,
 sensitivity to outliers) for the MMRM and ANCOVA models confirmed that the
 necessary normality assumptions were not contravened. Analyses were
 performed using Base SAS®, v9.4. SAS Institute Inc.
description: Read me file lists each of the data files uploaded with a short
 descriptions and notes on what is included.