Gale, Daniel P;
Gross, Oliver;
Wang, Fang;
Esteban de la Rosa, Rafael Jose;
Hall, Matthew;
Sayer, John A;
Appel, Gerald;
... Ding, Jie; + view all
(2024)
A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome.
Clinical Journal of the American Society of Nephrology (CJASN)
, 19
(8)
pp. 995-1004.
10.2215/CJN.0000000000000458.
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Abstract
Background : Preclinical models of disease have suggested that targeting microRNA-21 (miRNA-21) may slow the decline in kidney function in individuals with Alport syndrome (AS). The objective of this study was to investigate the effects of the anti–miRNA-21 oligonucleotide, lademirsen, on rate of eGFR decline in adults with AS at risk of rapid disease progression. // Methods : This study was a phase 2 trial of lademirsen, with a randomized, double-blind, placebo-controlled period followed by an open-label period. Adults with AS, eGFR >35 to <90 ml/min per 1.73 m2, and evidence of rapidly progressive kidney dysfunction were randomized 2:1 to lademirsen 110 mg subcutaneously once weekly or placebo for 48 weeks. After a planned interim analysis (after 24 of 43 randomized participants completed the week 48 study visit or discontinued before week 48), the trial was terminated for futility. // Results : Forty-three adults with AS (26 men, 17 women) participated (mean age 34 years), and 28 (lademirsen: n=19; placebo: n=9) completed 48 weeks of double-blind treatment. All participants in both groups developed treatment-emergent adverse events, mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period and one participant in the open-label period, owing to treatment-emergent adverse events. The least squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was −5 (−8.7 to −1.1) and −5 (−10.2 to 0.8) ml/min per 1.73 m2 per year, respectively. No significant differences between groups were identified in eGFR at any timepoint or in proportion of participants with prespecified reductions in eGFR at week 24 or 48. // Conclusions : While anti–miRNA-21 therapy with lademirsen was generally well-tolerated with an acceptable safety profile, no meaningful improvement in rate of kidney function decline in adults with AS at risk of rapidly progressive disease was observed. // Clinical Trial registration number: NCT02855268.
| Type: | Article |
|---|---|
| Title: | A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.2215/CJN.0000000000000458 |
| Publisher version: | http://dx.doi.org/10.2215/cjn.0000000000000458 |
| Language: | English |
| Additional information: | This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), https://creativecommons.org/licenses/by-nc-nd/4.0/, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
| Keywords: | Alport syndrome |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10196184 |
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