A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis.
BACKGROUND
Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB(4)-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B(4) (LTB(4))-receptor antagonist BIIL 284 BS in CF patients.


METHODS
CF patients aged ≥6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV(1) and incidence of pulmonary exacerbation.


RESULTS
After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38).


CONCLUSIONS
While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events.
Rainbow Babies & Children's Hospital, Cleveland, OH, USA; Case Western Reserve University, Cleveland, OH, USA. Electronic address: michael.konstan@UHhospitals.org.
M W
MW
Konstan
Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
G
G
Döring
Seattle Children's Hospital, Seattle, WA, USA.
S L
SL
Heltshe
Research Institute of the McGill University Health Centre, Montreal Children's Hospital, Montreal, QC, Canada.
L C
LC
Lands
Case Western Reserve University, Cleveland, OH, USA.
K A
KA
Hilliard
Boehringer Ingelheim, USA.
P
P
Koker
Boehringer Ingelheim, USA.
S
S
Bhattacharya
Boehringer Ingelheim, Germany.
A
A
Staab
Boehringer Ingelheim, Canada.
A
A
Hamilton
D000293:Adolescent; D000328:Adult; D000578:Amidines / Q000008:administration & dosage / Q000009:adverse effects; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000503:physiopathology; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012129:Respiratory Function Tests / Q000379:methods; D018570:Risk Assessment; D013183:Sputum / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
D000578:Amidines; D000893:Anti-Inflammatory Agents; D002219:Carbamates; D018102:Receptors, Leukotriene B4; C424425:amelubant
Anti-inflammatory therapy; Clinical trial; Cystic fibrosis; Leukotriene B(4) receptor antagonist; Lung disease