Impact of acute antibiotic therapy on the pulmonary exacerbation endpoint in cystic fibrosis clinical trials

Nicole Mayer-Hamblett, Lisa Saiman, Larry C. Lands, Michael Anstead, Margaret Rosenfeld, Margaret Kloster, Leigh Fisher, Felix Ratjen

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background: In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use. Methods: A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed. Results: 40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥. 2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p=0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p. <. 0.0001] as compared to a 50% reduction not accounting for PIT [p=0.003]). Conclusion: PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies.

Original languageEnglish
Pages (from-to)99-105
Number of pages7
JournalContemporary Clinical Trials
Issue number1
StatePublished - Sep 2013

Bibliographical note

Funding Information:
Funding: This research was supported by the CF Foundation Therapeutics and a research grant from Novartis Pharmaceuticals . The funding sources had no role in the study design, analysis, interpretation of results, decision to publish, or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Funding Information:
Disclosures: Dr. Hamblett has received research grant funding from the Cystic Fibrosis Foundation Therapeutics, the National Institutes of Health, Novartis, and Vertex Pharmaceuticals. Dr. Saiman has received a grant from Gilead Pharmaceuticals and served on scientific advisory boards for Insmed, Novartis, Gilead, and Vertex. She also serves on a steering committee for Insmed. Dr. Lands has received funds to travel to advisory board meetings for Novartis but these activities do not relate to the topic of this manuscript. Dr. Anstead has received grant money from the Cystic Fibrosis Foundation Therapeutics, Vertex Pharmaceuticals, Kalobios Pharmaceuticals, and MPEX Pharmaceuticals. He has also received honoraria for speaking on behalf of Vertex Pharmaceuticals and Gilead Pharmaceuticals. Dr. Rosenfeld has received served as a consultant to Genentech and has received a grant from Genentech but none of these activities relate to the topic of this manuscript. She receives funding for her active research from the NIH and the Cystic Fibrosis Foundation. Ms. Kloster declares no conflicts of interest. Ms. Fisher declares no conflicts of interest. Dr Ratjen has received funding from the Canadian Institutes of Health Research, US National Institutes of Health, Cystic Fibrosis Foundation, and Cystic Fibrosis Canada. He also acts as a consultant for Bayer, Genentech, Novartis, Talecris, and Vertex.


  • Antibiotic therapy
  • Cystic fibrosis
  • Pulmonary exacerbation definitions
  • Sample size
  • Study design

ASJC Scopus subject areas

  • Pharmacology (medical)


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