NEJM original articles

Background. Adjunctive glucocorticoids may reduce mortality among patients with severe community-acquired pneumonia (CAP) in well-resourced settings. Whether these drugs are beneficial in low-resource settings with limited diagnostic and treatment facilities is unclear.

Methods. In this pragmatic, open-label, randomized, controlled trial conducted in 18 public hospitals in Kenya, we assigned adult patients who had received a diagnosis of CAP and who did not have a clear indication for glucocorticoids to receive either standard care for CAP or oral low-dose glucocorticoids for 10 days in addition to standard care. The primary outcome was death from any cause at 30 days after enrollment.

Results. A total of 2180 patients underwent randomization (1089 assigned to the glucocorticoid group and 1091 to the standard-care group). The median age of the patients was 53 years (interquartile range, 38 to 72); 46% were women. At day 30, deaths were reported in 530 patients (24.3%): 246 patients (22.6%) in the glucocorticoid group and 284 patients (26.0%) in the standard-care group (hazard ratio, 0.84; 95% confidence interval, 0.73 to 0.97; P = 0.02). The frequencies of adverse events and serious adverse events were similar in the two trial groups. Serious adverse events that were considered to be related to glucocorticoid administration occurred in 5 patients (0.5%).

Conclusions. In patients with CAP in a low-resource setting, adjunctive glucocorticoid therapy was associated with a lower risk of death than standard care. (Funded by Wellcome Trust and others; SONIA PACTR number, PACTR202111481740832; ISRCTN number, ISRCTN36138594.).

Background. Idiopathic normal-pressure hydrocephalus is a neurologic disorder characterized by impaired gait, balance, cognition, and bladder control in older adults. The disorder is treated with shunt surgery, but the effectiveness of shunting is unclear.

Methods. We conducted a double-blind, randomized, placebo-controlled trial involving participants selected for shunt surgery on the basis of gait-velocity improvement with cerebrospinal fluid (CSF) drainage. Participants were randomly assigned to an open-shunt valve setting (opening pressure, 110 mm of water) or a placebo valve setting (opening pressure, >400 mm of water) of a noninvasively adjustable shunt. The primary outcome was the change in gait velocity 3 months after surgery. Secondary outcomes were the change at 3 months in the Tinetti scale total score (range, 0 to 28; lower scores indicate worse gait and balance), Montreal Cognitive Assessment (MoCA) score (range, 0 to 30; lower scores indicate worse cognition), and Overactive Bladder Questionnaire score (range, 0 to 100; higher scores indicate worse urinary incontinence).

Results. A total of 99 participants underwent randomization and received the assigned intervention. At 3 months, gait velocity had increased in the open-shunt group (mean [±SD] change, 0.23±0.23 m per second; assessed in 49 participants) and was unchanged in the placebo group (mean change, 0.03±0.23 m per second; assessed in 49 participants), resulting in a treatment difference of 0.21 m per second (95% confidence interval, 0.12 to 0.31; P<0.001). A significantly greater improvement in the open-shunt group than the placebo group was seen for the Tinetti scale score (mean change, 2.9 points vs. 0.5 points; P = 0.003) but not the MoCA score (1.3 points vs. 0.3 points) or the Overactive Bladder Questionnaire score (-3.3 points vs. -1.5 points). The results regarding adverse events were mixed, with more participants in the placebo group reporting falls (46% vs. 24%), an equal percentage having cerebral bleeding (2% in both groups), and more participants in the open-shunt group having subdural bleeding (12% vs. 2%) and positional headaches (59% vs. 28%).

Conclusions. Among participants with idiopathic normal-pressure hydrocephalus who had a response to temporary CSF drainage, shunting resulted in significant improvements at 3 months in gait velocity and a measure of gait and balance but not in measures of cognition or incontinence. (Funded by the National Institute of Neurological Disorders and Stroke and the Trial Innovation Network; PENS ClinicalTrials.gov number, NCT05081128.).

Background. C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (MPGN) generally result in glomerular C3 deposition and irreversible kidney damage. The efficacy and safety of pegcetacoplan, a C3 and C3b inhibitor, in persons with C3 glomerulopathy or primary immune-complex MPGN are unclear.

Methods. We conducted a phase 3, double-blind, placebo-controlled trial involving adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, including those with native kidney disease and those with disease recurrence after transplantation. Patients were randomly assigned in a 1:1 ratio to receive pegcetacoplan or placebo. The primary end point was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 as compared with baseline.

Results. A total of 124 patients underwent randomization. The change in proteinuria (as measured by the log-transformed ratio to baseline in the urinary protein-to-creatinine ratio) was significantly greater with pegcetacoplan than with placebo (geometric mean of the urinary protein-to-creatinine ratio, -67.2% [95% confidence interval {CI}, -74.9 to -57.2] vs. 2.9% [95% CI, -8.6 to 15.9]). The difference represents a relative reduction of 68.1% (95% CI, 57.3 to 76.2) as compared with placebo. In hierarchical testing of five secondary end points, significantly higher percentages of patients in the pegcetacoplan group than in the placebo group met the composite renal end-point criteria (stabilization of estimated glomerular filtration rate [eGFR] and ≥50% reduction in urinary protein-to-creatinine ratio) (49% vs. 3%) and had at least a 50% reduction in the protein-to-creatinine ratio (60% vs. 5%). Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between the two groups; subsequent end points (decrease in C3 staining and change in eGFR) were not formally tested. Pegcetacoplan was not associated with more adverse events than placebo. No serious infections from encapsulated bacteria occurred; 1 patient receiving pegcetacoplan died from coronavirus disease 2019 pneumonia. No allograft rejection or loss occurred.

Conclusions. Pegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.).