Clinical Drug Investigation最新文献

Background: Pembrolizumab shows effectiveness in treating metastatic non-small cell lung cancer (metNSCLC), with a subgroup of patients experiencing long-term survival (LTS) benefits. The existence of a LTS subgroup may influence the cost-effectiveness of pembrolizumab monotherapy compared with platinum-based chemotherapy. This study aims to assess the potential implications of such a subgroup on the cost-effectiveness for patients with non-squamous metNSCLC and PD-L1 ≥ 50% who are ineligible for targeted therapies.

Methods: This study used a decision analytic model based on Dutch real-world data (2008-2014). Two strategies were simulated: (1) a chemotherapy strategy: patients receive chemotherapy in the first-, second-, and third-line; and (2) a pembrolizumab strategy: patients receive first-line pembrolizumab followed by chemotherapy for those progressing to second- and third-lines. The pembrolizumab strategy is evaluated with and without the assumption that there is a LTS subgroup. The LTS subgroup is assumed to be free from metNSCLC-related progression after treatment. Costs (2022 €), including drug costs, other direct medical costs, family costs, and healthcare costs in life years gained, are considered from first-line treatment to death. Effects are measured in quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) is assessed using an €80,000/QALY threshold. Threshold analyses are performed on the size and mortality rate of the LTS subgroup and on the price of pembrolizumab.

Results: QALYs per patient were 0.65 for chemotherapy, 1.24 for pembrolizumab without LTS, and 3.52 for pembrolizumab with LTS. Average costs per patient were €58,800 for chemotherapy, €154,600 for pembrolizumab without LTS, and €178,600 for pembrolizumab with LTS. Pembrolizumab without LTS was not cost-effective compared with chemotherapy (ICER €167,600/QALY), but pembrolizumab with LTS (30% of simulated population) was cost effective (ICER of €43,100/QALY). Threshold analyses showed that a LTS subgroup size of at least 10% or halving the price of pembrolizumab was needed for pembrolizumab to be cost-effective.

Conclusions: Pembrolizumab is a cost-effective first-line treatment for patients with metNSCLC and PD-L1 ≥ 50% in the Netherlands when at least 10% of patients are long-term survivors. Without long-term survivors, this treatment is not cost-effective. Therefore, it is crucial to consider long-term survivors in assessing the cost-effectiveness of immunotherapy in metNSCLC.

Background and objective: This phase III study conducted in 22 centres in Poland assessed the efficacy equivalence of candidate tocilizumab biosimilar, CT-P47, and European Union-approved reference tocilizumab (r-TCZ) in rheumatoid arthritis. We report 1-year data, including switching from r-TCZ to CT-P47.

Methods: This active-controlled, double-blind, multicentre trial randomised (1:1) adults (aged 18-75 years) with moderate-to-severe rheumatoid arthritis diagnosed for ≥ 24 weeks and treated with methotrextate for ≥ 12 weeks before the first study drug administration, to receive CT-P47 or r-TCZ every 4 weeks (8 mg/kg, intravenous) up to week 20. At week 24, those on CT-P47 continued maintenance treatment; those on r-TCZ were re-randomised (1:1) to continue r-TCZ (r-TCZ maintenance) or to switch to CT-P47 (CT-P47 switched) until week 48 (Treatment Period 2). After week 48, patients were followed up until week 52 (end of study). Efficacy, pharmacokinetics, safety and immunogenicity were evaluated.

Results: In Treatment Period 2, 225 patients continued CT-P47 maintenance, 109 continued r‑TCZ maintenance and 110 switched to CT-P47. During Treatment Period 2, efficacy findings were comparable between groups. At week 52, the mean change from baseline in Disease Activity Score in 28 joints-erythrocyte sedimentation rate was - 4.279, - 4.231 and - 4.376 in the CT-P47 maintenance, r-TCZ maintenance and CT-P47 switched groups, respectively. Joint damage progression over 1 year was minimal in all groups. Drug serum concentrations were relatively consistent throughout Treatment Period 2. The safety profile and antidrug antibody-positive conversion rate (< 5% in each group) were similar between groups.

Conclusions: Week 52 results show maintained efficacy after switching from r-TCZ to CT-P47, and comparable efficacy, pharmacokinetics, safety and immunogenicity of CT-P47 versus r-TCZ over 1 year of treatment.

Clinical trial registration: NCT05489224, 24 July 2022.

Objective: The RENOTORCH trial found that toripalimab plus axitinib extended progression-free and overall survival in patients with advanced renal cell carcinoma (RCC), though its financial burden may limit widespread use. This study aimed to assess the cost-effectiveness of toripalimab plus axitinib compared with sunitinib monotherapy as a first-line therapy for patients with previously untreated or intermediate- or poor-risk advanced RCC from a US third-party payer perspective.

Methods: A three-state partitioned survival model (progression-free, progression, death) was utilized, with clinical outcomes obtained from the RENOTORCH trial. Progression-free survival (PFS) and overall survival (OS) were modeled using various parametric functions over a 5-year horizon, applying a 3% annual discount rate. Costs of treatments, administration, monitoring, and management of grade 3/4 adverse events (≥ 5% occurrence) were sourced from Micromedex® and Centers for Medicare & Medicaid Services (CMS) databases. Life years (LY), quality-adjusted life years (QALY), and incremental costs per LY and QALY were estimated. One-way and probabilistic sensitivity analyses were conducted. Subgroup analyses for intermediate- and poor-risk patients, as classified by the International Metastatic RCC Database Consortium (IMDC) criteria, were performed using similar methods.

Results: Toripalimab plus axitinib increased total costs by $332,359, gained 0.68 LY and 0.36 QALY compared with sunitinib, resulting in incremental costs of $489,747 per LY and $923,962 per QALY. One-way sensitivity analysis showed that the incremental cost per QALY was most sensitive to changes in toripalimab plus axitinib's cost. At a $150,000 willingness-to-pay threshold, probabilistic sensitivity analysis showed a nearly 0% probability of toripalimab plus axitinib being cost-effective. Similarly, toripalimab plus axitinib was still not cost-effective for intermediate- and poor-risk patients.

Conclusions: Compared with sunitinib monotherapy, our study suggested that toripalimab plus axitinib was not cost-effective for patients with advanced renal cell carcinoma from a US third-party payer perspective. Further analyses are warranted when more data are available. Despite benefits across different risk groups, toripalimab plus axitinib was not cost-effective for intermediate- and poor-risk patients.

Background and objective: Access to direct oral anticoagulants (DOACs) in sub-Saharan Africa is limited due to prohibitive upfront costs, making warfarin the standard of care for many patients, especially those relying on public-sector healthcare. This study evaluated the cost-effectiveness of using the DOAC, rivaroxaban, compared to warfarin for treating venous thromboembolism (VTE), a cardiovascular disorder caused by blood clots in the veins, in western Kenya.

Methods: We developed a discrete-time individual state-transition Markov model to simulate a VTE patient's quality-adjusted life-years (QALYs) and annual treatment costs under a rivaroxaban or warfarin therapy strategy. Transition state probabilities were derived from real-world event-rate data observed in patients treated with rivaroxaban (n = 160) or warfarin (n = 116) for VTE at Moi Teaching and Referral Hospital in western Kenya. Base-case parameter values were obtained from cohort event rates, local costs, and literature-derived utility values. Cost-effectiveness was assessed over a 1-year time horizon using an incremental cost-effectiveness ratio (ICER) threshold of (US)$6020.40 per QALY gained (equivalent to three times Kenya's 2021 per capita GDP). Deterministic and probabilistic sensitivity analyses were conducted to assess parameter and model uncertainty.

Results: After 12 months, total mean treatment costs per patient were $216.00 and $173.00 using warfarin and rivaroxaban, respectively. In the base-case analysis, rivaroxaban therapy resulted in an additional 0.023 QALYs per patient compared to warfarin, with an ICER of $- 1862.00 per QALY gained. Based on probabilistic sensitivity analysis with Monte Carlo simulation, when costs, utility values, and event rates were varied, rivaroxaban was cost-effective compared to warfarin in 84.1% of all simulations at a willingness-to-pay threshold of $6020.40 per QALY. One-way sensitivity analyses and scenario analyses were stable with rivaroxaban therapy, resulting in fewer costs and higher QALYs.

Conclusions: In this study, rivaroxaban is a clinically and economically superior alternative to warfarin. This research may catalyze further discussions with policymakers and industry partners to scale up the appropriate use of rivaroxaban in resource-constrained settings.

Background: Patients with infective endocarditis can develop various renal diseases, including infective endocarditis-associated glomerulonephritis. Antibiotics are essential for eradicating the infection. However, the prognosis for renal function remains poor. This systematic review examines the role of immunosuppressants in managing infective endocarditis-associated glomerulonephritis (GN).

Methods: A comprehensive search was performed across four databases: PubMed, Scopus, MedLine, and Web of Science up to April 2024. We included studies that investigated patients with any type of GN due to infective endocarditis (IE) who were treated with immunosuppressants. Data extraction was conducted using a standardized sheet, and study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal tool.

Results: The review incorporated 55 studies encompassing 84 cases, 65 of whom were male. The median age was 46.5 years. A total of 30 cases required kidney replacement therapy. Following immunosuppressive therapy, clinical improvement of IE was observed in 54 cases, while 9 patients experienced worsening conditions, 3 patients had no clinical change, and data were unavailable in 18 cases. Renal outcomes showed improvement in 67 patients, with 9 cases showing worsening conditions, 3 patients showing no change, 3 experiencing partial or residual impairment, and renal outcome was unavailable in 2 cases. A total of ten patients died, primarily owing to sepsis or infection-related complications (five cases), congestive or global heart failure (three cases), and renal failure with associated metabolic complications (two cases). Additional treatments included plasma exchange, with nine cases receiving plasmapheresis/plasma exchange. Of these, eight patients showed marked renal function improvement, and one patient showed partial improvement. Three patients also received intravenous immunoglobulin.

Conclusions: Immunosuppressive therapy led to renal function improvement in the majority of cases, suggesting its potential benefit in managing infective endocarditis-associated glomerulonephritis. However, variability in response and significant mortality highlight the need for individualized treatment strategies and further research to optimize management.

Background and objectives: Cannabinoid treatments are commonly used for sleep conditions, but the direct sedating effects of daytime treatment consumption and indirect effects on night-time sleep are unclear. This study measures the direct effects of low-dose cannabinoid treatments on daytime sleepiness and potential indirect night-time sleep effects in healthy adult, novice cannabis users.

Methods: Using a double-blind, randomised, placebo-controlled cross-over design, participants were orally administered a standardised dose of 1 mL oil containing THC:CBD ratios of either 1:1, 1:16 or a placebo over five weekly in-lab visits. Daytime sleepiness was measured at 40, 135 and 265 min post-dosing using the Karolinska Sleepiness Scale (KSS). Indirect night-time sleep effects on total sleep time (TST), sleep-onset latency (SOL), and number of awakenings after onset were measured using daily wrist-actigraphy and sleep-diary entries during the 7-day washout period between treatments.

Results: Final analyses (N = 20) showed subjective sleepiness (KSS score) significantly increased (mean difference = 1.9, SE 0.25) from 40 min to 265 min post-treatment (p < 0.001). No significant differences were observed between treatments for KSS. Indirect sleep measures (TST, SOL, number of awakenings) showed no differences between treatments or over time (all p > 0.05).

Conclusion: Daytime consumption of low-dose cannabinoid oils did not induce direct sleepiness or indirect night-time effects post-dosing among adults. Future studies would benefit from exploring pharmacokinetics and the possibility of treatment amplification of daytime fatigue, mood and cognitive changes to assist the development of therapeutic guidelines for safe daytime medical cannabis use.

Anctr trial registration number: ACTRN12622001539729, 13 December 2022, prospectively registered.