Atrasentan in Patients with IgA Nephropathy.

Journal

The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562

Informations de publication

Date de publication:
25 Oct 2024
Historique:
medline: 26 10 2024
pubmed: 26 10 2024
entrez: 26 10 2024
Statut: aheadofprint

Résumé

Patients with IgA nephropathy and severe proteinuria have a high lifetime risk of kidney failure. The efficacy and safety of the selective endothelin type A receptor antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are incompletely understood. We are conducting a phase 3, multinational, double-blind, randomized, controlled trial involving adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m A total of 340 patients were recruited into the main stratum. Among the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit, the geometric mean percentage change in the urinary protein-to-creatinine ratio relative to baseline was significantly greater with atrasentan (-38.1%) than with placebo (-3.1%), with a geometric mean between-group difference of -36.1 percentage points (95% confidence interval, -44.6 to -26.4; P<0.001). The percentage of patients with adverse events did not differ substantially between the two groups. Fluid retention was reported by 19 of 169 patients (11.2%) in the atrasentan group and in 14 of 170 (8.2%) in the placebo group but did not lead to discontinuation of the trial regimen. No apparent cases of cardiac failure or severe edema occurred. In this prespecified interim analysis, atrasentan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Novartis; ALIGN ClinicalTrials.gov number, NCT04573478.).

Sections du résumé

BACKGROUND BACKGROUND
Patients with IgA nephropathy and severe proteinuria have a high lifetime risk of kidney failure. The efficacy and safety of the selective endothelin type A receptor antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are incompletely understood.
METHODS METHODS
We are conducting a phase 3, multinational, double-blind, randomized, controlled trial involving adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m
RESULTS RESULTS
A total of 340 patients were recruited into the main stratum. Among the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit, the geometric mean percentage change in the urinary protein-to-creatinine ratio relative to baseline was significantly greater with atrasentan (-38.1%) than with placebo (-3.1%), with a geometric mean between-group difference of -36.1 percentage points (95% confidence interval, -44.6 to -26.4; P<0.001). The percentage of patients with adverse events did not differ substantially between the two groups. Fluid retention was reported by 19 of 169 patients (11.2%) in the atrasentan group and in 14 of 170 (8.2%) in the placebo group but did not lead to discontinuation of the trial regimen. No apparent cases of cardiac failure or severe edema occurred.
CONCLUSIONS CONCLUSIONS
In this prespecified interim analysis, atrasentan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Novartis; ALIGN ClinicalTrials.gov number, NCT04573478.).

Identifiants

DOI: 10.1056/NEJMoa2409415 PMID: 39460694
pubmed: 39460694
doi: 10.1056/NEJMoa2409415
doi:

Banques de données

ClinicalTrials.gov
['NCT04573478']

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Massachusetts Medical Society.

Auteurs

Hiddo J L Heerspink (HJL)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Meg Jardine (M)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Donald E Kohan (DE)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Richard A Lafayette (RA)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Adeera Levin (A)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Adrian Liew (A)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Hong Zhang (H)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Amit Lodha (A)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Todd Gray (T)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Yi Wang (Y)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Ronny Renfurm (R)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Jonathan Barratt (J)

From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).

Classifications MeSH