Graham Devereux1, Danielle Wrolstad2, Stephen J Bourke3, Cori L Daines4, Simon Doe3, Ryan Dougherty5, Rose Franco6, Alastair Innes7, Benjamin T Kopp8, Jorge Lascano9, Daniel Layish10, Gordon MacGregor11, Lorna Murray12, Daniel Peckham13, Vincenzina Lucidi14, Emma Lovie15, Jennifer Robertson15, Douglas J Fraser-Pitt15, Deborah A O'Neil15. 1. Liverpool School of Tropical Medicine, Liverpool, United Kingdom. 2. Precision for Medicine, Oncology and Rare Disease, Carlsbad, CA, United States of America. 3. Royal Victoria Infirmary, Newcastle, United Kingdom. 4. Banner University of Arizona Medical Center, Tucson, Arizona, United States of America. 5. San Francisco Critical Care Medical Group California Pacific Medical Center, San Francisco, United States of America. 6. The Medical College of Wisconsin/Froedtert Hospital, Milwaukee, Wisconsin, United States of America. 7. Western General Hospital, Edinburgh, United Kingdom. 8. Nationwide Children's Hospital, Columbus, OH, United States of America. 9. University of Florida, Gainesville, Florida, United States of America. 10. Central Florida Pulmonary Group, Orlando, Florida, United States of America. 11. Queen Elizabeth University Hospital, Glasgow, United Kingdom. 12. Raigmore Hospital, Inverness, United Kingdom. 13. St James's University Hospital, Leeds, United Kingdom. 14. Ospedale Padiatrico Bambino Gesu Centro Fibrosi Cistica, Rome, Italy. 15. NovaBiotics Ltd, Aberdeen, United Kingdom.
Abstract
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 includedaminoglycoside 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.
RCT Entities:
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.
Authors: Alexandra L Quittner; Avani C Modi; Claire Wainwright; Kelly Otto; Jean Kirihara; A Bruce Montgomery Journal: Chest Date: 2009-05-15 Impact factor: 9.410
Authors: Ranjan Dohil; Betty L Cabrera; Jon A Gangoiti; Bruce A Barshop; Patrice Rioux Journal: Fundam Clin Pharmacol Date: 2012-10-31 Impact factor: 2.748
Authors: Frederick W Woodley; Emrah Gecili; Rhonda D Szczesniak; Chandra L Shrestha; Christopher J Nemastil; Benjamin T Kopp; Don Hayes Journal: Respir Med Date: 2021-11-23 Impact factor: 3.415