title: A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies.
abstract: tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Various potentially confounding factors are discussed.
authors.affiliation: Department of Molecular Pharmacology, Stanford CCSR Building, Stanford, CA 94305-5174, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Ilynn B
authors.initials: IB
authors.lastname: Nepomuceno
authors.forename: Anna H
authors.initials: AH
authors.lastname: Messner
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Moran
authors.forename: Eric P
authors.initials: EP
authors.lastname: Batson
authors.forename: Sue
authors.initials: S
authors.lastname: Dimiceli
authors.forename: Byron W
authors.initials: BW
authors.lastname: Brown
authors.forename: Julie K
authors.initials: JK
authors.lastname: Desch
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Norbash
authors.forename: Carol K
authors.initials: CK
authors.lastname: Conrad
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wine
authors.forename: Barrie J
authors.initials: BJ
authors.lastname: Carter
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Reynolds
authors.forename: Richard B
authors.initials: RB
authors.lastname: Moss
authors.forename: Phyllis
authors.initials: P
authors.lastname: Gardner
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007322:Instillation, Drug; D016753:Interleukin-10 / Q000032:analysis; D008297:Male; D008443:Maxillary Sinus / Q000276:immunology / Q000382:microbiology; D015523:Maxillary Sinusitis / Q000235:genetics / Q000601:surgery / Q000628:therapy; D017817:Nasal Lavage Fluid / Q000166:cytology / Q000382:microbiology; D055502:Secondary Prevention; D013997:Time Factors
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016753:Interleukin-10