Oral cysteamine as an adjunct treatment in cystic fibrosis pulmonary exacerbations: An exploratory randomized clinical trial.

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.
Clinical Trial Registration: NCT03000348; www.clinicaltrials.gov.
Competing Interests: The authors have read the journal's policy and have the following competing interests: Deborah A O’Neil (DO) is the CEO, CSO, and shareholder of the trial sponsor NovaBiotics Ltd. Douglas J Fraser-Pitt (DFP) is a Principal Scientist and salaried employee of the trial sponsor NovaBiotics Ltd. Emma Lovie (EL) is a research scientist and Jennifer Robertson (JR) is a laboratory manager/research scientist; Both are salaried employees of the trial sponsor NovaBiotics Ltd. Graham Devereux (GD) received support from NovaBiotics Ltd to attend the 2018 NACFC. Danielle Wrolstad (DW) reports personal fees through her employer (Precision Medicine Group) from NovaBiotics Ltd, during the study. Rose Franco (RF), Stephen J Bourke (SB), Benjamin T Kopp (BK) and Ryan Dougherty (RD) report grant from NovaBiotics Ltd during the conduct of the study. SB & BK report grants from Vertex outside the submitted work. DFP and DO are authors of patent; WO2016198842A1, IL256162D0 - An amino thiol for use in the treatment of an infection caused by the bacterium mycobacterium spp. DO is also author of the following patents; US9364491B2 (and other territories) - Antimicrobial compositions with cysteamine/A composition comprising an antibiotic and a dispersant; WO2016046524A1 - Use of cysteamine in treating infections caused by yeasts/moulds; US9782423B2 (and other territories) - Antibiotic compositions comprising an antibiotic agent and cysteamine; US9339525B2 (and other territories) - Inhibition of biofilm organisms; and US20190175501A1 pending (and other territories) - Microparticles comprising a sulphur-containing compound. (JR, EL, DFP, and DO) are involved in the development of cysteamine bitartrate as a therapy for cystic fibrosis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.