Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial.
BACKGROUND
Ivacaftor has shown a clinical benefit in patients with cystic fibrosis who have the G551D-CFTR mutation and reduced lung function. Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV1) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV1 >90% predicted.


METHODS
This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV1 >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI. The study is registered at ClinicalTrials.gov, NCT01262352.


RESULTS
Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group). Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor. No deaths occurred during study period.


CONCLUSIONS
In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in LCI. LCI might be a more sensitive alternative to FEV1 in detecting response to intervention in these patients with mild lung disease.


BACKGROUND
Vertex Pharmaceuticals Incorporated.
Paediatric Respiratory Medicine, Royal Brompton Hospital and Dept of Gene Therapy, Imperial College London, England, UK. Electronic address: j.c.davies@imperial.ac.uk.
Jane
J
Davies
University of Edinburgh, Edinburgh, Scotland, UK.
Helen
H
Sheridan
Bristol Adult Cystic Fibrosis Centre, University Hospitals Bristol, Bristol, England, UK.
Nicholas
N
Bell
Royal Hospital for Sick Children, NHS, Lothian, Edinburgh, Scotland, UK.
Steve
S
Cunningham
Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA.
Stephanie D
SD
Davis
Centre for Infection and Immunity, Queen's University, Belfast, Northern Ireland, UK.
J Stuart
JS
Elborn
Center for Excellence in Pulmonary Biology, Stanford University, Palo Alto, CA, USA.
Carlos E
CE
Milla
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Timothy D
TD
Starner
The Antonio J and Janet Palumbo Cystic Fibrosis Center, University of Pittsburgh, Pittsburgh, PA, USA.
Daniel J
DJ
Weiner
Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA.
Po-Shun
PS
Lee
Division of Respiratory Medicine, Department of Paediatrics, Physiology and Experimental Medicine, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Felix
F
Ratjen
D000293:Adolescent; D000328:Adult; D000627:Aminophenols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D018592:Cross-Over Studies; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D009079:Mucociliary Clearance / Q000187:drug effects; D009154:Mutation; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D019141:Respiratory System Agents / Q000009:adverse effects / Q000627:therapeutic use*; D013147:Spirometry; D055815:Young Adult
D000627:Aminophenols; D015363:Quinolones; D019141:Respiratory System Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor