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Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial

Summary 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... Full description

Journal Title: The Lancet (British edition) 2017, Vol.389 (10084), p.2117-2127
Main Author: Fellström, Bengt C, Prof
Other Authors: Barratt, Jonathan, FRCP , Cook, Heather, PhD , Coppo, Rosanna, MD , Feehally, John, Prof , de Fijter, Johan W, Prof , Floege, Jürgen, Prof , Hetzel, Gerd, Prof , Jardine, Alan G, Prof , Locatelli, Francesco, FRCP , Maes, Bart D, Prof , Mercer, Alex, PhD , Ortiz, Fernanda, PhD , Praga, Manuel, Prof , Sørensen, Søren S, Prof , Tesar, Vladimir, Prof , Del Vecchio, Lucia, MD
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 0140-6736
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title: Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial
format: Article
creator:
  • Fellström, Bengt C, Prof
  • Barratt, Jonathan, FRCP
  • Cook, Heather, PhD
  • Coppo, Rosanna, MD
  • Feehally, John, Prof
  • de Fijter, Johan W, Prof
  • Floege, Jürgen, Prof
  • Hetzel, Gerd, Prof
  • Jardine, Alan G, Prof
  • Locatelli, Francesco, FRCP
  • Maes, Bart D, Prof
  • Mercer, Alex, PhD
  • Ortiz, Fernanda, PhD
  • Praga, Manuel, Prof
  • Sørensen, Søren S, Prof
  • Tesar, Vladimir, Prof
  • Del Vecchio, Lucia, MD
subjects:
  • 3121 Internal medicine
  • Abridged Index Medicus
  • Added value
  • Adult
  • Adults
  • Albumin
  • Algorithms
  • Analysis
  • Angiotensin
  • Antibodies
  • Antigen-antibody complexes
  • Appendix
  • Attenuation
  • Biocompatibility
  • Biopsy
  • Budesonide
  • Budesonide - administration & dosage
  • Care and treatment
  • Cell activation
  • Cell proliferation
  • Chronic kidney failure
  • Circulation
  • Clinical Medicine
  • Clinical trials
  • Collection
  • Committees
  • Complications
  • Constrictions
  • Corticoids
  • Corticosteroids
  • Creatinine
  • Diabetes mellitus
  • Diagnosis
  • Diet
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug delivery
  • Drug Delivery Systems
  • Drug dosages
  • Drug therapy
  • Drugs
  • End-stage renal disease
  • Enzyme inhibitors
  • Evidence-based medicine
  • Excretion
  • Female
  • Filtration
  • Gastrointestinal tract
  • Glomerular Filtration Rate
  • Glomerulonephritis
  • Glomerulonephritis, IGA - drug therapy
  • Glomerulonephritis, IGA - pathology
  • Glucocorticoids - administration & dosage
  • Health risks
  • Humans
  • Hypertension
  • IgA nephropathy
  • Ileum
  • Immune system
  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulins
  • Immunosuppression
  • Inflammation
  • Inhibitors
  • Internal Medicine
  • Intestine
  • Kidney diseases
  • Kidney transplantation
  • Kidneys
  • Klinisk medicin
  • Lymphocytes
  • Lymphocytes B
  • Male
  • Medical and Health Sciences
  • Medical treatment
  • Medicin och hälsovetenskap
  • Metabolism
  • Middle Aged
  • Mucosal immunity
  • Nephritis
  • Nephrology
  • Optimization
  • Osteoporosis
  • Pathogenesis
  • Peptidyl-dipeptidase A
  • Pharmacokinetics
  • Pharmacology
  • Proteins
  • Proteinuria
  • Randomization
  • Reduction
  • Renal function
  • Renin
  • Risk factors
  • Risk management
  • Risk reduction
  • Safety
  • Steroids
  • Stimulation
  • Thromboembolism
  • Thrombosis
  • Titration
  • Treatment Outcome
  • Urine
  • Urologi och njurmedicin
  • Urology and Nephrology
ispartof: The Lancet (British edition), 2017, Vol.389 (10084), p.2117-2127
description: Summary 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 4
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
  • 1474-547X
url: Link


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titleTargeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial
sourceAlma/SFX Local Collection
creatorFellström, Bengt C, Prof ; Barratt, Jonathan, FRCP ; Cook, Heather, PhD ; Coppo, Rosanna, MD ; Feehally, John, Prof ; de Fijter, Johan W, Prof ; Floege, Jürgen, Prof ; Hetzel, Gerd, Prof ; Jardine, Alan G, Prof ; Locatelli, Francesco, FRCP ; Maes, Bart D, Prof ; Mercer, Alex, PhD ; Ortiz, Fernanda, PhD ; Praga, Manuel, Prof ; Sørensen, Søren S, Prof ; Tesar, Vladimir, Prof ; Del Vecchio, Lucia, MD
creatorcontribFellström, Bengt C, Prof ; Barratt, Jonathan, FRCP ; Cook, Heather, PhD ; Coppo, Rosanna, MD ; Feehally, John, Prof ; de Fijter, Johan W, Prof ; Floege, Jürgen, Prof ; Hetzel, Gerd, Prof ; Jardine, Alan G, Prof ; Locatelli, Francesco, FRCP ; Maes, Bart D, Prof ; Mercer, Alex, PhD ; Ortiz, Fernanda, PhD ; Praga, Manuel, Prof ; Sørensen, Søren S, Prof ; Tesar, Vladimir, Prof ; Del Vecchio, Lucia, MD ; NEFIGAN Trial Investigators
descriptionSummary 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.
identifier
0ISSN: 0140-6736
1ISSN: 1474-547X
2EISSN: 1474-547X
3DOI: 10.1016/S0140-6736(17)30550-0
4PMID: 28363480
languageeng
publisherEngland: Elsevier Ltd
subject3121 Internal medicine ; Abridged Index Medicus ; Added value ; Adult ; Adults ; Albumin ; Algorithms ; Analysis ; Angiotensin ; Antibodies ; Antigen-antibody complexes ; Appendix ; Attenuation ; Biocompatibility ; Biopsy ; Budesonide ; Budesonide - administration & dosage ; Care and treatment ; Cell activation ; Cell proliferation ; Chronic kidney failure ; Circulation ; Clinical Medicine ; Clinical trials ; Collection ; Committees ; Complications ; Constrictions ; Corticoids ; Corticosteroids ; Creatinine ; Diabetes mellitus ; Diagnosis ; Diet ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug delivery ; Drug Delivery Systems ; Drug dosages ; Drug therapy ; Drugs ; End-stage renal disease ; Enzyme inhibitors ; Evidence-based medicine ; Excretion ; Female ; Filtration ; Gastrointestinal tract ; Glomerular Filtration Rate ; Glomerulonephritis ; Glomerulonephritis, IGA - drug therapy ; Glomerulonephritis, IGA - pathology ; Glucocorticoids - administration & dosage ; Health risks ; Humans ; Hypertension ; IgA nephropathy ; Ileum ; Immune system ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulins ; Immunosuppression ; Inflammation ; Inhibitors ; Internal Medicine ; Intestine ; Kidney diseases ; Kidney transplantation ; Kidneys ; Klinisk medicin ; Lymphocytes ; Lymphocytes B ; Male ; Medical and Health Sciences ; Medical treatment ; Medicin och hälsovetenskap ; Metabolism ; Middle Aged ; Mucosal immunity ; Nephritis ; Nephrology ; Optimization ; Osteoporosis ; Pathogenesis ; Peptidyl-dipeptidase A ; Pharmacokinetics ; Pharmacology ; Proteins ; Proteinuria ; Randomization ; Reduction ; Renal function ; Renin ; Risk factors ; Risk management ; Risk reduction ; Safety ; Steroids ; Stimulation ; Thromboembolism ; Thrombosis ; Titration ; Treatment Outcome ; Urine ; Urologi och njurmedicin ; Urology and Nephrology
ispartofThe Lancet (British edition), 2017, Vol.389 (10084), p.2117-2127
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0Fellström, Bengt C, Prof
1Barratt, Jonathan, FRCP
2Cook, Heather, PhD
3Coppo, Rosanna, MD
4Feehally, John, Prof
5de Fijter, Johan W, Prof
6Floege, Jürgen, Prof
7Hetzel, Gerd, Prof
8Jardine, Alan G, Prof
9Locatelli, Francesco, FRCP
10Maes, Bart D, Prof
11Mercer, Alex, PhD
12Ortiz, Fernanda, PhD
13Praga, Manuel, Prof
14Sørensen, Søren S, Prof
15Tesar, Vladimir, Prof
16Del Vecchio, Lucia, MD
17NEFIGAN Trial Investigators
title
0Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial
1The Lancet (British edition)
addtitleLancet
descriptionSummary 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.
subject
03121 Internal medicine
1Abridged Index Medicus
2Added value
3Adult
4Adults
5Albumin
6Algorithms
7Analysis
8Angiotensin
9Antibodies
10Antigen-antibody complexes
11Appendix
12Attenuation
13Biocompatibility
14Biopsy
15Budesonide
16Budesonide - administration & dosage
17Care and treatment
18Cell activation
19Cell proliferation
20Chronic kidney failure
21Circulation
22Clinical Medicine
23Clinical trials
24Collection
25Committees
26Complications
27Constrictions
28Corticoids
29Corticosteroids
30Creatinine
31Diabetes mellitus
32Diagnosis
33Diet
34Dose-Response Relationship, Drug
35Double-Blind Method
36Drug delivery
37Drug Delivery Systems
38Drug dosages
39Drug therapy
40Drugs
41End-stage renal disease
42Enzyme inhibitors
43Evidence-based medicine
44Excretion
45Female
46Filtration
47Gastrointestinal tract
48Glomerular Filtration Rate
49Glomerulonephritis
50Glomerulonephritis, IGA - drug therapy
51Glomerulonephritis, IGA - pathology
52Glucocorticoids - administration & dosage
53Health risks
54Humans
55Hypertension
56IgA nephropathy
57Ileum
58Immune system
59Immunoglobulin A
60Immunoglobulin G
61Immunoglobulins
62Immunosuppression
63Inflammation
64Inhibitors
65Internal Medicine
66Intestine
67Kidney diseases
68Kidney transplantation
69Kidneys
70Klinisk medicin
71Lymphocytes
72Lymphocytes B
73Male
74Medical and Health Sciences
75Medical treatment
76Medicin och hälsovetenskap
77Metabolism
78Middle Aged
79Mucosal immunity
80Nephritis
81Nephrology
82Optimization
83Osteoporosis
84Pathogenesis
85Peptidyl-dipeptidase A
86Pharmacokinetics
87Pharmacology
88Proteins
89Proteinuria
90Randomization
91Reduction
92Renal function
93Renin
94Risk factors
95Risk management
96Risk reduction
97Safety
98Steroids
99Stimulation
100Thromboembolism
101Thrombosis
102Titration
103Treatment Outcome
104Urine
105Urologi och njurmedicin
106Urology and Nephrology
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1Barratt, Jonathan, FRCP
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6Floege, Jürgen, Prof
7Hetzel, Gerd, Prof
8Jardine, Alan G, Prof
9Locatelli, Francesco, FRCP
10Maes, Bart D, Prof
11Mercer, Alex, PhD
12Ortiz, Fernanda, PhD
13Praga, Manuel, Prof
14Sørensen, Søren S, Prof
15Tesar, Vladimir, Prof
16Del Vecchio, Lucia, MD
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creationdate2017
titleTargeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial
authorFellström, Bengt C, Prof ; Barratt, Jonathan, FRCP ; Cook, Heather, PhD ; Coppo, Rosanna, MD ; Feehally, John, Prof ; de Fijter, Johan W, Prof ; Floege, Jürgen, Prof ; Hetzel, Gerd, Prof ; Jardine, Alan G, Prof ; Locatelli, Francesco, FRCP ; Maes, Bart D, Prof ; Mercer, Alex, PhD ; Ortiz, Fernanda, PhD ; Praga, Manuel, Prof ; Sørensen, Søren S, Prof ; Tesar, Vladimir, Prof ; Del Vecchio, Lucia, MD
facets
frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-1886t-957ed98a9bdaf9c71fa245cf54d7fbbfaa4a345ee05bb7fc1e48be03b0dc03d43
rsrctypearticles
prefilterarticles
languageeng
creationdate2017
topic
03121 Internal medicine
1Abridged Index Medicus
2Added value
3Adult
4Adults
5Albumin
6Algorithms
7Analysis
8Angiotensin
9Antibodies
10Antigen-antibody complexes
11Appendix
12Attenuation
13Biocompatibility
14Biopsy
15Budesonide
16Budesonide - administration & dosage
17Care and treatment
18Cell activation
19Cell proliferation
20Chronic kidney failure
21Circulation
22Clinical Medicine
23Clinical trials
24Collection
25Committees
26Complications
27Constrictions
28Corticoids
29Corticosteroids
30Creatinine
31Diabetes mellitus
32Diagnosis
33Diet
34Dose-Response Relationship, Drug
35Double-Blind Method
36Drug delivery
37Drug Delivery Systems
38Drug dosages
39Drug therapy
40Drugs
41End-stage renal disease
42Enzyme inhibitors
43Evidence-based medicine
44Excretion
45Female
46Filtration
47Gastrointestinal tract
48Glomerular Filtration Rate
49Glomerulonephritis
50Glomerulonephritis, IGA - drug therapy
51Glomerulonephritis, IGA - pathology
52Glucocorticoids - administration & dosage
53Health risks
54Humans
55Hypertension
56IgA nephropathy
57Ileum
58Immune system
59Immunoglobulin A
60Immunoglobulin G
61Immunoglobulins
62Immunosuppression
63Inflammation
64Inhibitors
65Internal Medicine
66Intestine
67Kidney diseases
68Kidney transplantation
69Kidneys
70Klinisk medicin
71Lymphocytes
72Lymphocytes B
73Male
74Medical and Health Sciences
75Medical treatment
76Medicin och hälsovetenskap
77Metabolism
78Middle Aged
79Mucosal immunity
80Nephritis
81Nephrology
82Optimization
83Osteoporosis
84Pathogenesis
85Peptidyl-dipeptidase A
86Pharmacokinetics
87Pharmacology
88Proteins
89Proteinuria
90Randomization
91Reduction
92Renal function
93Renin
94Risk factors
95Risk management
96Risk reduction
97Safety
98Steroids
99Stimulation
100Thromboembolism
101Thrombosis
102Titration
103Treatment Outcome
104Urine
105Urologi och njurmedicin
106Urology and Nephrology
toplevel
0peer_reviewed
1online_resources
creatorcontrib
0Fellström, Bengt C, Prof
1Barratt, Jonathan, FRCP
2Cook, Heather, PhD
3Coppo, Rosanna, MD
4Feehally, John, Prof
5de Fijter, Johan W, Prof
6Floege, Jürgen, Prof
7Hetzel, Gerd, Prof
8Jardine, Alan G, Prof
9Locatelli, Francesco, FRCP
10Maes, Bart D, Prof
11Mercer, Alex, PhD
12Ortiz, Fernanda, PhD
13Praga, Manuel, Prof
14Sørensen, Søren S, Prof
15Tesar, Vladimir, Prof
16Del Vecchio, Lucia, MD
17NEFIGAN Trial Investigators
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1MEDLINE
2MEDLINE (Ovid)
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8Academic OneFile (A&I only)
9News PRO
10Pharma and Biotech Premium PRO
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67Biological Science Database
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76OpenAIRE (Open Access)
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79SwePub Articles
jtitleThe Lancet (British edition)
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Fellström, Bengt C, Prof
1Barratt, Jonathan, FRCP
2Cook, Heather, PhD
3Coppo, Rosanna, MD
4Feehally, John, Prof
5de Fijter, Johan W, Prof
6Floege, Jürgen, Prof
7Hetzel, Gerd, Prof
8Jardine, Alan G, Prof
9Locatelli, Francesco, FRCP
10Maes, Bart D, Prof
11Mercer, Alex, PhD
12Ortiz, Fernanda, PhD
13Praga, Manuel, Prof
14Sørensen, Søren S, Prof
15Tesar, Vladimir, Prof
16Del Vecchio, Lucia, MD
aucorpNEFIGAN Trial Investigators
formatjournal
genrearticle
ristypeJOUR
atitleTargeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial
jtitleThe Lancet (British edition)
addtitleLancet
date2017
risdate2017
volume389
issue10084
spage2117
epage2127
pages2117-2127
issn
00140-6736
11474-547X
eissn1474-547X
abstractSummary 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.
copEngland
pubElsevier Ltd
pmid28363480
doi10.1016/S0140-6736(17)30550-0
orcididhttps://orcid.org/0000-0001-5815-9370
oafree_for_read