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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


Fraser-Pitt, Douglas (2020), 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, Dryad, Dataset,


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.


Trial design: 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.

Participants, eligibility criteria, and settings: 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 >40kg, and had an FEV1 >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, NCT03000348 (registered 22nd December 2016). All participants provided written informed consent.

Interventions: 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.

Outcomes: 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.

Sample size/power considerations: 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

Interim analyses and stopping guidelines: Not applicable.

Randomization: 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.

Blinding: Participants and trial staff were blinded to study treatment allocation. 

Statistical analysis: 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.

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