title: Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.
abstract: BACKGROUND
  IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035.
  
  
  RESULTS
  Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59-0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53-0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58-1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later).
  
  
  CONCLUSIONS
  TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation.
  
  
  BACKGROUND
  Pharmalink AB.
authors.affiliation: Uppsala University Hospital, Uppsala, Sweden. Electronic address: bengt.fellstrom@medsci.uu.se.
authors.forename: Bengt C
authors.initials: BC
authors.lastname: Fellström
authors.affiliation: University of Leicester, Leicester, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barratt
authors.affiliation: PharmaLogic Consulting AB, Stockholm, Sweden.
authors.forename: Heather
authors.initials: H
authors.lastname: Cook
authors.affiliation: Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Coppo
authors.affiliation: University of Leicester, Leicester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Feehally
authors.affiliation: Leiden University Medical Center, Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
authors.affiliation: RWTH University Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: HeinrichHeine-University, DaVita Renal Center, Düsseldorf, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hetzel
authors.affiliation: University of Glasgow, Glasgow, UK.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Jardine
authors.affiliation: Ospedale A Manzoni, Lecco, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: AZ Delta, Roeselare, Belgium.
authors.forename: Bart D
authors.initials: BD
authors.lastname: Maes
authors.affiliation: Pharmalink AB, Stockholm, Sweden.
authors.forename: Alex
authors.initials: A
authors.lastname: Mercer
authors.affiliation: Helsinki University Hospital, Helsinki, Finland.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ortiz
authors.affiliation: Complutense University, Investigation Institute Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Praga
authors.affiliation: Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Søren S
authors.initials: SS
authors.lastname: Sørensen
authors.affiliation: Charles University, Prague, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tesar
authors.affiliation: Ospedale A Manzoni, Lecco, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Del Vecchio
mesh_terms: D000328:Adult; D019819:Budesonide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016503:Drug Delivery Systems; D005260:Female; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA / Q000188:drug therapy* / Q000473:pathology; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D019819:Budesonide