PMID- 28363480
OWN - NLM
STAT- MEDLINE
DCOM- 20180925
LR  - 20180925
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 389
IP  - 10084
DP  - 2017 May 27
TI  - Targeted-release budesonide versus placebo in patients with IgA nephropathy
      (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.
PG  - 2117-2127
LID - S0140-6736(17)30550-0 [pii]
LID - 10.1016/S0140-6736(17)30550-0 [doi]
AB  - 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Pharmalink AB.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Fellstrom, Bengt C
AU  - Fellstrom BC
AD  - Uppsala University Hospital, Uppsala, Sweden. Electronic address:
      bengt.fellstrom@medsci.uu.se.
FAU - Barratt, Jonathan
AU  - Barratt J
AD  - University of Leicester, Leicester, UK.
FAU - Cook, Heather
AU  - Cook H
AD  - PharmaLogic Consulting AB, Stockholm, Sweden.
FAU - Coppo, Rosanna
AU  - Coppo R
AD  - Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy.
FAU - Feehally, John
AU  - Feehally J
AD  - University of Leicester, Leicester, UK.
FAU - de Fijter, Johan W
AU  - de Fijter JW
AD  - Leiden University Medical Center, Netherlands.
FAU - Floege, Jurgen
AU  - Floege J
AD  - RWTH University Aachen, Germany.
FAU - Hetzel, Gerd
AU  - Hetzel G
AD  - HeinrichHeine-University, DaVita Renal Center, Dusseldorf, Germany.
FAU - Jardine, Alan G
AU  - Jardine AG
AD  - University of Glasgow, Glasgow, UK.
FAU - Locatelli, Francesco
AU  - Locatelli F
AD  - Ospedale A Manzoni, Lecco, Italy.
FAU - Maes, Bart D
AU  - Maes BD
AD  - AZ Delta, Roeselare, Belgium.
FAU - Mercer, Alex
AU  - Mercer A
AD  - Pharmalink AB, Stockholm, Sweden.
FAU - Ortiz, Fernanda
AU  - Ortiz F
AD  - Helsinki University Hospital, Helsinki, Finland.
FAU - Praga, Manuel
AU  - Praga M
AD  - Complutense University, Investigation Institute Hospital 12 de Octubre, Madrid,
      Spain.
FAU - Sorensen, Soren S
AU  - Sorensen SS
AD  - Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark.
FAU - Tesar, Vladimir
AU  - Tesar V
AD  - Charles University, Prague, Czech Republic.
FAU - Del Vecchio, Lucia
AU  - Del Vecchio L
AD  - Ospedale A Manzoni, Lecco, Italy.
CN  - NEFIGAN Trial Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT01738035
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20170328
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Glucocorticoids)
RN  - 51333-22-3 (Budesonide)
SB  - AIM
SB  - IM
CIN - Nat Rev Nephrol. 2017 Jul;13(7):390-392. PMID: 28529338
CIN - Lancet. 2017 Dec 16;390(10113):2625. PMID: 29256403
MH  - Adult
MH  - Budesonide/*administration & dosage
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Delivery Systems
MH  - Female
MH  - Glomerular Filtration Rate
MH  - Glomerulonephritis, IGA/*drug therapy/pathology
MH  - Glucocorticoids/*administration & dosage
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Treatment Outcome
EDAT- 2017/04/02 06:00
MHDA- 2018/09/27 06:00
CRDT- 2017/04/02 06:00
PHST- 2016/06/22 00:00 [received]
PHST- 2016/11/21 00:00 [revised]
PHST- 2016/12/09 00:00 [accepted]
PHST- 2017/04/02 06:00 [pubmed]
PHST- 2018/09/27 06:00 [medline]
PHST- 2017/04/02 06:00 [entrez]
AID - S0140-6736(17)30550-0 [pii]
AID - 10.1016/S0140-6736(17)30550-0 [doi]
PST - ppublish
SO  - Lancet. 2017 May 27;389(10084):2117-2127. doi: 10.1016/S0140-6736(17)30550-0.
      Epub 2017 Mar 28.