NEJM original articles

Background. Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, provided significantly better renal responses than placebo in a phase 2 trial involving patients with lupus nephritis receiving standard therapy.

Methods. In a phase 3, randomized, controlled trial, we assigned adults with biopsy-proven active lupus nephritis in a 1:1 ratio to receive obinutuzumab in one of two dose schedules (1000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 50) or placebo. All patients received standard therapy with mycophenolate mofetil, along with oral prednisone at a target dose of 7.5 mg per day by week 12 and 5 mg per day by week 24. The primary end point was a complete renal response at week 76, defined by a urinary protein-to-creatinine ratio of less than 0.5 (with protein and creatinine both measured in milligrams), an estimated glomerular filtration rate of at least 85% of the baseline value, and no intercurrent event (i.e., rescue therapy, treatment failure, death, or early trial withdrawal). Key secondary end points at week 76 included a complete renal response with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event.

Results. A total of 271 patients underwent randomization; 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 2.0 to 24.8; P = 0.02). A complete renal response at week 76 with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 was observed in more patients in the obinutuzumab group than in the placebo group (42.7% vs. 30.9%; adjusted difference, 11.9 percentage points; 95% CI, 0.6 to 23.2; P = 0.04), and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event was more common with obinutuzumab than with placebo (55.5% vs. 41.9%; adjusted difference, 13.7 percentage points; 95% CI, 2.0 to 25.4; P = 0.02). No unexpected safety signals were identified. More serious adverse events, mainly infections and events related to coronavirus disease 2019, occurred with obinutuzumab than with placebo.

Conclusions. Among adults with active lupus nephritis, obinutuzumab plus standard therapy was more efficacious than standard therapy alone in providing a complete renal response. (Funded by F. Hoffmann-La Roche; REGENCY ClinicalTrials.gov number, NCT04221477.).

Background. Tecovirimat is available for the treatment of mpox (formerly known as monkeypox) in Europe and the United States, on the basis of findings from efficacy studies in animals and safety evaluations in healthy humans. Evidence from randomized, controlled trials of safety and efficacy in patients with mpox is lacking.

Methods. We conducted a double-blind, randomized, placebo-controlled trial of tecovirimat in patients with mpox in the Democratic Republic of Congo (DRC). Patients with at least one mpox skin lesion and positive polymerase-chain-reaction results for clade I MPXV were assigned in a 1:1 ratio to receive tecovirimat or placebo. All patients received supportive care. The primary end point was resolution of mpox lesions, measured in number of days after randomization. Safety was also assessed.

Results. From October 7, 2022, through July 9, 2024, a total of 597 patients underwent randomization - 295 to receive tecovirimat and 302 to receive placebo. The median time from randomization to lesion resolution was 7 days with tecovirimat and 8 days with placebo; the competing-risks hazard ratio for lesion resolution was 1.13 (95% confidence interval [CI], 0.97 to 1.31; P = 0.14). Results were similar whether patients began the trial regimen within 7 days after the reported onset of symptoms (competing-risks hazard ratio, 1.16; 95% CI, 0.98 to 1.37) or more than 7 days after onset (competing-risks hazard ratio, 1.00; 95% CI, 0.71 to 1.40). Overall mortality was 1.7%, which was lower than the case fatality rate of 4.6% reported in the DRC in 2023. At 14 days, the percentages of patients who had blood, lesion, and oropharyngeal samples negative for MPXV by PCR were similar in the two groups. Adverse events occurred in 72.9% of the patients in the tecovirimat group and 70.5% of those in the placebo group, and serious adverse events were reported in 5.1% and 5.0%, respectively.

Conclusions. Tecovirimat did not reduce the number of days to lesion resolution in patients with mpox caused by clade I MPXV. No safety concerns were identified. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM007 ClinicalTrials.gov number, NCT05559099.).

Background. Pulmonary-vein isolation is an effective treatment for paroxysmal atrial fibrillation. Pulsed field ablation (PFA) is a nonthermal ablation method with few adverse effects beyond the myocardium. Data are lacking on outcomes after PFA as compared with cryoballoon ablation as assessed with continuous rhythm monitoring.

Methods. In this randomized noninferiority trial in Switzerland, we randomly assigned patients with symptomatic paroxysmal atrial fibrillation in a 1:1 ratio to undergo PFA or cryoablation. All the patients received an implantable cardiac monitor to detect atrial tachyarrhythmias. The primary end point was the first recurrence of an atrial tachyarrhythmia between day 91 and day 365 after ablation. We assessed noninferiority using a margin of 20 percentage points for the difference in the cumulative incidence of recurrence. The safety end point was a composite of procedure-related complications.

Results. A total of 105 patients were assigned to undergo PFA, and 105 were assigned to undergo cryoablation. A recurrence of atrial tachyarrhythmia was observed between day 91 and day 365 in 39 patients in the PFA group and in 53 patients in the cryoablation group (Kaplan-Meier cumulative incidence, 37.1% and 50.7%, respectively; between-group difference, -13.6 percentage points; 95% confidence interval, -26.9 to -0.3; P<0.001 for noninferiority, P = 0.046 for superiority). The safety end point occurred in 1 patient (1.0%) with PFA and in 2 patients (1.9%) with cryoablation.

Conclusions. Among patients with symptomatic paroxysmal atrial fibrillation, PFA was noninferior to cryoballoon ablation with respect to the incidence of a first recurrence of atrial tachyarrhythmia, as assessed by continuous rhythm monitoring. (Funded by Inselspital and others; SINGLE SHOT CHAMPION ClinicalTrials.gov number, NCT05534581.).

Background. Treatment with fidanacogene elaparvovec, a recombinant adeno-associated virus (AAV) vector developed for the treatment of hemophilia B, led to sustained expression of the high-activity factor IX variant (FIX-R338L, or FIX-Padua) in a phase 1-2a study. The long-term safety and efficacy of this treatment are not known.

Methods. In a 12-month study, 15 participants with severe or moderately severe hemophilia B (factor IX coagulant activity, ≤2% of the normal value) received fidanacogene elaparvovec at a dose of 5×10¹¹ vector genomes (vg) per kilogram of body weight; thereafter, participants could enroll in a 5-year follow-up study. Safety end points included adverse events and changes in laboratory measures. Efficacy end points included the annualized rate of treated bleeding events (annualized bleeding rate) and factor IX activity.

Results. A total of 14 participants provided consent and completed at least 3 years of follow-up (median, 5.5; range 3 to 6); participation was ongoing among 8 at the data cutoff. None of the participants reported treatment-related adverse events after year 1. Throughout follow-up, nine serious adverse events were noted in 4 participants; none were thrombotic or treatment-related. No factor IX inhibitors were detected. Throughout follow-up, mean factor IX activity was in the mild hemophilia range; the mean annualized bleeding rate was less than 1, and 10 participants had no treated bleeding episodes. Surveillance liver ultrasounds obtained from year 1 onward showed no evidence of cancer but showed steatosis in 4 participants who had weight gain and elevated aminotransferase levels (maximum alanine aminotransferase level, 77 U per liter). One participant with a history of hepatitis C, hepatitis B, human immunodeficiency virus infection, and an elevated body-mass index had progression of underlying advanced liver fibrosis. A total of 13 surgical procedures were performed in 8 participants; exogenous factor IX was administered for 10 procedures, and no associated unexpected bleeding complications occurred.

Conclusions. Fidanacogene elaparvovec was associated with no or only low-grade adverse effects over a period of 3 to 6 years. Efficacy was maintained in the long term at 5×10¹¹ vg per kilogram, one of the lowest intravenous doses of AAV used for any indication. (Funded by Pfizer; ClinicalTrials.gov number, NCT03307980.).