Preclinical models of disease have suggested that targeting microRNA-21 may slow the decline in kidney function in individuals with Alport syndrome. The objective of this study was to investigate the effects of the anti-microRNA-21 oligonucleotide, lademirsen, on rate of estimated glomerular filtration rate (eGFR) decline in adults with Alport syndrome at risk of rapid disease progression. 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 Alport syndrome, eGFR >35 to <90 mL/min/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. Following a planned interim analysis (after 24 of 43 randomized participants completed the Week 48 study visit or discontinued prior to Week 48), the trial was terminated for futility. Forty-three adults with Alport syndrome (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 (TEAEs), 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 TEAEs. The least-squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was -5 (-8.7, -1.1) and -5 (-10.2, 0.8) mL/min/1.73 m2/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 Weeks 24 or 48. While anti-microRNA-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 Alport syndrome at risk of rapidly progressive disease was observed.