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In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a lower rate of total worsening heart failure events and death from cardiovascular causes than placebo.

In this double-blind trial, patients with stage 1 to 4 chronic kidney disease and type 2 diabetes were randomly assigned to receive finerenone or placebo. Finerenone treatment was superior with regard to the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.

Anti-malarial artemisinin-based combination therapies (ACTs) might be losing efficacy in east Africa, with the spread of artemisinin partial resistance and reduced partner drug activity. Our trial aimed to measure the efficacies of artemether–lumefantrine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, and artesunate–pyronaridine in three sites in Uganda. This randomised, open-label, phase 4 clinical trial was carried out at three sites in the Agago, Arua, and Busia districts of Uganda. Children aged 6 months to 10 years with uncomplicated Plasmodium falciparum malaria were randomly assigned to receive either artemether–lumefantrine (20 mg artemether; 120 mg lumefantrine; twice a day for 3 days) in all sites or dihydroartemisinin–piperaquine (40 mg dihydroartemisinin and 320 mg piperaquine, once a day for 3 days) in Agago, artesunate–amodiaquine (25 mg artesunate and 67·5 mg amodiaquine for children <9 kg or 50 mg artesunate and 135 mg amodiaquine for children ≥9 kg, once a day for 3 days) in Busia; and artesunate–pyronaridine (60 mg artesunate and 180 mg pyronaridine for children >15 kg or 20 mg artesunate and 60 mg pyronaridine for children <15 kg, once a day for 3 days) in Arua, with follow-up to 42 days. Participants were not blinded to group assignments; however, investigators and those assessing outcome were masked. The primary outcome was parasitaemia, assessed by microscopy, either uncorrected or PCR-corrected to distinguish recrudescence from new infection. All participants who received the treatment per protocol and were not lost to follow-up were included in the primary outcome. All participants who were randomly allocated to treatment groups were included in the safety analyses. This study is registered with the Pan African Clinical Trials Registry, number PACTR202301796134887, and is complete. Between Nov 7, 2022, and March 24, 2023, 808 participants (437 [54%] female) were enrolled and assigned to treatment groups; 15 (2%) were lost to follow-up and 793 (98%) completed follow-up. The uncorrected adequate clinical and parasitological response for artemether–lumefantrine was 87 (51·8%; 95% CI 44·0–59·5) of 168 participants in Arua, 88 (51·8%; 44·0–59·4) of 170 and Busia, and 131 (79·4%; 72·3–85·1) of 165 in Agago. This response for artemether–lumefantrine was lower than that of the other ACTs at all sites: 97 (98·0%; 92·2–99·6) of 99 for dihydroartemisinin–piperaquine in Agago, 95 (99·0%; 93·5–99·9) of 96 for artesunate–amodiaquine in Busia, and 73 (73·7%; 63·8–81·8) of 99 for artesunate–pyronaridine in Arua. PCR-corrected 28-day efficacies were 88 (81·5%; 72·6–88·1) of 108 for artemether–lumefantrine and 95 (100%; 95·2–100·0) of 95 for artesunate–amodiaquine in Busia; 131 (97·0%; 92·1–99·0) of 135 for artemether–lumefantrine and 97 (100%; 95·3–100·0) of 97 for dihydroartemisinin–piperaquine in Agago; and 87 (82·1%; 73·2–88·6) of 106 for artemether–lumefantrine and 73 (92·4%; 83·6–96·9) of 79 for artesunate–pyronaridine in Arua. All regimens were well tolerated. The most common adverse events were upper respiratory tract infection, diarrhoea, and anaemia. None of the reported adverse events were attributed to the study drugs. There were two serious adverse events, both cases of severe malaria in Arua, one in each of the treatment groups. Parasite clearance half-lives were prolonged with parasites carrying the PfK13 Cys469Tyr (median 4·2 h; IQR 3·4–4·9) and Ala675Val (4·9 h; 3·4–5·7) mutations compared with wild-type parasites (2·8 h; 2·3–3·6; p<0·0001). Artemether–lumefantrine was associated with a higher risk of recurrent malaria than other antimalarial combinations tested, and K13 mutations were associated with delayed parasite clearance. Changes in first-line therapy for uncomplicated malaria must be considered in response to suboptimal efficacy of artemether–lumefantrine. US President's Malaria Initiative, US Agency for International Development, through the Uganda Malaria Reduction Activity and the National Institutes of Health (AI075045 and AI117001). For the Swahili translation of the abstract see Supplementary Materials section.

Background. Ceftriaxone is the foundation of currently recommended gonorrhea treatment. There is an urgent need for backup treatment options for patients with cephalosporin allergy or infections due to suspected cephalosporin-resistant Neisseria gonorrhoeae. We evaluated the efficacy and tolerability of 2 combinations of existing non-cephalosporin antimicrobials for treatment of patients with urogenital gonorrhea. Methods. We conducted a randomized, multisite, open-label, noncomparative trial in 5 outpatient sexually transmitted disease clinic sites in Alabama, California, Maryland, and Pennsylvania. Patients aged 15–60 years diagnosed with uncomplicated urogenital gonorrhea were randomly assigned to either gentamicin 240 mg intramuscularly plus azithromycin 2 g orally, or gemifloxacin 320 mg orally plus azithromycin 2 g orally. The primary outcome was microbiological cure of urogenital infections (negative follow-up culture) at 10–17 days after treatment among 401 participants in the per protocol population. Results. Microbiological cure was achieved by 100% (lower 1-sided exact 95% confidence interval [CI] bound, 98.5%) of 202 evaluable participants receiving gentamicin/azithromycin, and 99.5% (lower 1-sided exact 95% CI bound, 97.6%) of 199 evaluable participants receiving gemifloxacin/azithromycin. Gentamicin/azithromycin cured 10 of 10 pharyngeal infections and 1 of 1 rectal infection; gemifloxacin/azithromycin cured 15 of 15 pharyngeal and 5 of 5 rectal infections. Gastrointestinal adverse events were common in both arms. Conclusions. Gentamicin/azithromycin and gemifloxacin/azithromycin were highly effective for treatment of urogenital gonorrhea. Gastrointestinal adverse events may limit routine use. These non-cephalosporin-based regimens may be useful alternative options for patients who cannot be treated with cephalosporin antimicrobials. Additional treatment options for gonorrhea are needed. Clinical Trials Registration. NCT00926796.

Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25–20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025–0.167mmol/L) compared with the placebo group (−0.075mmol/L); no patients developed hyperkalemia. When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

Finerenone is a novel nonsteroidal mineralocorticoid receptor (MR) antagonist (MRA) with unique pharmacological properties that offer potent and selective blockade of the MR with a more favorable side effect profile than spironolactone and eplerenone. In a large phase III clinical trial involving 13,026 patients with type 2 diabetes mellitus and a broad spectrum of chronic kidney disease, finerenone provoked a substantial placebo-subtracted reduction in the risk of hospitalization for heart failure (HF). These preliminary clinical trial data, along with the ongoing uncertainty about the safety and efficacy of MR antagonism in patients with HF and higher levels of ejection fraction have provided the rationale for the design of the FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure) trial. In this multicenter, double-blind, randomized, phase III trial involving 6001 patients with HF and mildly reduced or preserved ejection fraction, finerenone was superior to placebo in improving the primary composite outcome of total (first and recurrent) worsening HF events and death from cardiovascular causes. This benefit was similar in magnitude in patients receiving and in patients not receiving background treatment with a sodium-glucose co-transporter type 2 inhibitor, suggesting a potential additive benefit with combination therapy. We explore the emerging role of the nonsteroidal MRA finerenone as a new therapeutic opportunity to improve the risk of adverse cardiovascular outcomes in patients with HF and mildly reduced or preserved ejection fraction. We discuss preliminary clinical trial data and provide a critical evaluation of the main results of the FINEARTS-HF trial.

Define the effect of finerenone on kidney function within the overall FIDELITY Asian subpopulation. This FIDELITY pooled subanalysis assessed the following outcomes in the Asian subpopulation: chronic estimated glomerular filtration rate (eGFR) slope, urine albumin-to-creatinine ratio (UACR) from baseline to month 4, time to UACR regression, and safety. In total, 2858 (22.0 %) participants included in FIDELITY were Asian. Chronic eGFR slope was reduced with finerenone compared with placebo in the Asian subpopulation; least-squares mean between-group difference was 1.08 mL/min/1.73 m2 (95 % confidence interval 0.53–1.63; p = 0.0002). Greater reductions in chronic eGFR slope were also observed for finerenone compared with placebo when analyzed according to baseline UACR. Finerenone treatment reduced UACR from baseline to month 4 by 34 %. This treatment effect was seen regardless of baseline eGFR, systolic blood pressure, glycated hemoglobin, body mass index, sodium-glucose co-transporter-2 inhibitor use, and glucagon-like peptide-1 receptor agonist use. Regression from high to normal albuminuria was seen in 39.5 % of all Asian participants treated with finerenone versus 14.8 % receiving placebo. Treatment-emergent adverse events were similar between finerenone and placebo, and hyperkalemia was manageable. Finerenone slows eGFR decline and lowers UACR in Asian participants with chronic kidney disease and type 2 diabetes. Trial registration number: FIDELIO-DKD (NCT02540993); FIGARO-DKD (NCT02545049). [Display omitted] •Finerenone treatment reduced chronic eGFR slope in the FIDELITY Asian population•Finerenone treatment also reduced UACR from baseline to month 4 by 34 %•Albuminuria regression was seen in 39.5 % of finerenone-treated Asian participants•Overall, treatment-emergent AEs were similar between finerenone and placebo

A novel oral combination of the long‐acting antimalarials pyronaridine (PYR) and piperaquine (PQP) has potential for malaria chemoprevention. This single‐center randomized, double‐blind, placebo‐controlled study assessed the effects of PYR and PQP alone and when co‐administered on Fridericia‐corrected QT interval (QTcF). Between February 14, 2022, and May 31, 2022, thirty‐seven healthy black adults of African sub‐Saharan origin were enrolled and randomized to PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8) or double placebo (n = 6) administered once daily (fasted) for 3 days at doses approved for malaria treatment. Triplicate digitalized electrocardiogram (ECG) recordings and pharmacokinetic samples were taken at matched timepoints. Concentration–response analysis was performed for QTcF changes from baseline (ΔQTcF), and the impact of PYR, PQP, and PYR + PQP administration on placebo‐corrected ΔQTcF (ΔΔQTcF) was assessed. The final qualified and validated concentration–QTc model included a linear component for PYR and an Emax component for PQP. The maximum predicted effect on ΔΔQTcF on day 3 was +4.94 msec (90% CI 0.338, 9.54) with PYR + placebo, +19.2 msec (14.6, 23.8) with PQP + placebo, and + 23.1 msec (18.5, 27.6) with PYR + PQP. As expected, PQP increased ΔΔQTcF above the regulatory threshold of concern (+10 msec), whereas PYR did not. The small additional increase in ΔΔQTcF with PYR + PQP coadministration was explained mainly by an increase in PQP Cmax (1.4‐fold) versus monotherapy. In healthy adults, PYR + PQP coadministration does not appear to increase significantly the effect of PQP on ΔΔQTcF versus PQP administered alone. However, further studies are needed in malaria patients to confirm these findings in the target population. Trial Registration: ClinicalTrials.gov identifier: NCT05160363; EudraCT number: 2021‐005698‐21

Background The mechanisms underlying cardiorenal benefits of finerenone remain unclear. This mechanistic trial aimed to evaluate the effects of finerenone on vascular stiffness, as assessed using the cardio-ankle vascular index (CAVI), and cardiorenal biomarkers in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). Methods Eligible patients with T2D and CKD (estimated glomerular filtration rate [eGFR], 25 to < 90 mL/min/1.73 m 2 ; urinary albumin-to-creatinine ratio [UACR], 30 to < 3500 mg/g Cr) were randomly allocated to receive either dose-adjusted finerenone or matching placebo. The primary endpoint was the change in CAVI at week 24. The key secondary endpoint was the proportional change in UACR from baseline over 24 weeks. As an exploratory analysis, changes in circulating proteins were measured by using the Olink® Target 96 Cardiovascular III and Inflammation panels. Results This investigator-initiated, multicentre, prospective, two-arm parallel, placebo-controlled, double-blind, randomised clinical trial was conducted at 13 sites in Japan. Among 102 patients randomised, 101 (66.3% men; median age, 73 years; eGFR, 56.2 mL/min/1.73 m 2 ; and UACR, 193.8 mg/g Cr) were analysed. Changes in CAVI at week 24 were − 0.023 (95% confidence interval [CI], − 0.299 to 0.254) for finerenone and 0.011 (95% CI, − 0.245 to 0.267) for placebo. The group difference was − 0.057 (95% CI, − 0.428 to 0.314; P  = 0.760). Compared with placebo, finerenone led to a 29% reduction in UACR levels at weeks 12 (group ratio 0.706 [95% CI, 0.504 to 0.989; P  = 0.043]) and 24 (0.709 [95% CI, 0.506 to 0.994; P  = 0.046]). Finerenone also resulted in an early and sustained eGFR decline over 24 weeks, without increasing levels of urinary biomarkers of acute tubular injury. Finerenone, compared with placebo, was associated with nominal changes in the expression of 11 proteins among the 181 circulating proteins tested. Conclusions Finerenone did not affect changes in vascular stiffness but led to a significant and sustained reduction in albuminuria in patients with T2D and CKD. The clinical benefits of finerenone may result from lowering intraglomerular pressure rather than from its effect on vascular stiffness. Registration ClinicalTrial.gov (NCT05887817) and Japan Registry of Clinical Trials (jRCTs021230011). Graphical abstract This mechanistic clinical trial involving patients with T2D and CKD found that 24-week finerenone therapy did not significantly reduce CAVI from baseline compared with placebo (−0.057; 95% CI, −0.428 to 0.314), led to a 29% reduction (group ratio [finerenone vs. placebo] of 0.71) in UACR levels, and was associated with nominal changes in 11 circulating proteins (six upregulated and five downregulated) over 24 weeks. CAVI, cardio-ankle vascular index; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine ratio.

New therapies to treat malaria are needed. In this report, in which the authors studied 1271 patients from Asia and Africa, pyronaridine–artesunate was found to be noninferior to mefloquine plus artesunate in the treatment of uncomplicated Plasmodium falciparum malaria. Artemisinin-based combination therapy is critical for the effective treatment and control of Plasmodium falciparum malaria. 1 – 4 However, reports from the Cambodian–Thai border indicate the emergence of artemisinin tolerance or resistance in P. falciparum . 2 – 8 Pyronaridine–artesunate is a fixed-dose, artemisinin-based combination therapy that is being developed for the treatment of uncomplicated P. falciparum and P. vivax malaria. 9 – 11 In phase 2 and 3 clinical trials, a fixed-dose, 3:1 ratio of pyronaridine to artesunate has shown high efficacy in the treatment of falciparum malaria, with cure rates on day 28 of more than 98% (corrected for reinfection with the use of . . .