Clinical Drug Investigation最新文献

The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.

AVT04 (Uzpruvo^®) is a biosimilar of the reference anti-interleukin (IL)-12 and IL-23 monoclonal antibody ustekinumab. It is approved in the EU for plaque psoriasis, paediatric plaque psoriasis, psoriatic arthritis and Crohn's disease as per the reference product. AVT04 has similar physicochemical characteristics to those of reference ustekinumab, and the pharmacokinetic similarity of the agents has been shown in healthy volunteers and patients with moderate to severe chronic plaque psoriasis. AVT04 demonstrated clinical efficacy similar to that of reference ustekinumab in patients with moderate to severe chronic plaque psoriasis, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of AVT04 were similar to those of reference ustekinumab, and switching from reference ustekinumab to AVT04 had no impact on efficacy, safety or immunogenicity. The role of reference ustekinumab in the management of inflammatory diseases is well established and AVT04 provides an effective biosimilar alternative for patients requiring ustekinumab therapy.

Background: Although selective serotonin reuptake inhibitors (SSRIs) are usually considered safe to use in patients with Parkinson's disease (PD), there are mixed data about their effectiveness, and only a few investigations have led to a total improvement of depressive symptoms in patients with PD.

Objectives: We aimed to conduct a comprehensive systematic review and meta-analysis of all studies that investigated the effectiveness of SSRIs in treating depression in the context of PD.

Methods: From its commencement to June 2024, the databases of MEDLINE via PubMed, Scopus, Embase, and Google Scholar were electronically searched for the relevant papers. All full-text journal articles assessing the effectiveness of SSRIs in treating depression in patients with PD were included. The tool developed by the Cochrane Collaboration was utilized to evaluate the bias risk. Data were analyzed utilizing a pair-wise comparison meta-analysis using the standardized mean difference.

Results: A total of 19 articles and 22 separate interventions were included. We found that SSRI treatment attenuated depression in patients with PD (1.242 standardized mean difference, 95% confidence interval 0.956, 1.529, p < 0.001). The general heterogeneity of the studies was medium (ϰ² = 72.818, T² = 0.317, df = 21, I² = 71.15%, p < 0.001). The funnel plot was reasonably symmetrical. However, three studies were trimmed to the left of the mean. Begg's test (p = 0.080), Egger's test (p = 0.121), and funnel plot showed no significant risk of publication bias. The meta-regression showed that the treatment effect increased as a function of paroxetine treatment duration (slope p = 0.001) but decreased as a function of sertraline treatment duration (slope p = 0.019).

Conclusions: There are few controlled antidepressant trials on the PD population, even though patients with PD frequently experience depression and use antidepressants. Clinical studies that are larger and better structured are needed in the future to determine if antidepressants are useful for treating patients with PD with depression.

Background and objective: Trastuzumab targets human epidermal growth factor receptor 2 (HER2) receptors and is indicated for treating HER2-positive metastatic breast cancer. BP02, a recombinant IgG1 kappa humanized monoclonal antibody, is being developed as a trastuzumab biosimilar. The objective of this study was to evaluate the equivalence of BP02 with reference trastuzumab (RT: Herceptin^®-EU) in patients with HER2-positive metastatic breast cancer.

Methods: This double-blinded, 1:1 randomized, parallel-group, active-controlled, phase III equivalence trial recruited women aged 18-75 years with histologically/cytologically confirmed HER2- positive, locally recurrent or metastatic breast cancer with systemic metastasis, from 59 sites in India. Patients were randomly allocated 1:1 stratified by estrogen receptor/progesterone receptor status to receive BP02/RT (8-mg/kg loading dose on day 1-cycle 1, 6 mg/kg on day 1-cycles 2-8, of each 3-week cycle) combined with docetaxel (75 mg/m² on day 1-cycles 1-8) [induction phase]. Participants with complete or partial response, or stable disease at the end of the induction phase continued the study drug until disease progression/treatment discontinuation [maintenance phase]. The primary efficacy endpoint was the objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Results: Between 23 September, 2020 and 16 September, 2022, 690 patients were recruited (n = 345 each to BP02/RT). At the end of the induction phase (intent-to-treat population), a similar proportion of patients achieved an objective response rate with BP02 (n = 231 [67.0%], 95% confidence interval [CI] 62.0, 71.9) and RT (n = 238 [69.0%], 95% CI 64.1, 73.9). The 95% CI of risk difference (-2.03, 95% CI -9.15, 5.09) and 90% CI of risk ratio (0.97, 90% CI 0.89, 1.06) were within equivalence margins of ± 13% and (0.80, 1.25), respectively. Treatment-emergent adverse events leading to treatment withdrawal were reported in 2.9% and 3.2% patients with BP02 and RT, respectively.

Conclusions: BP02 showed an equivalent efficacy and similar safety profile to RT at the end of 24 weeks.

Clinical trial registration: CTRI Number: CTRI/2020/04/024456.

Background and objective: Cytomegalovirus (CMV) is a common opportunistic infection after allogenic hematopoietic stem cell transplantation (allo-HSCT). Letermovir, an inhibitor of CMV DNA terminase, is approved for CMV prophylaxis in allo-HSCT patients. We report the final results of post-marketing surveillance of letermovir in Japan.

Methods: The case report forms were drafted in part by the Japanese Data Center for Hematopoietic Cell Transplantation using data elements in the Transplant Registry Unified Management Program and sent to individual HSCT centers to decrease the burden of reporting. Hematopoietic stem cell transplantation patients who received letermovir between May 2018 and May 2022 were registered. Data collected included physician-assessed adverse events/adverse drug reactions and clinical effectiveness (development of CMV disease, CMV antigen status, and use of preemptive therapy).

Results: A total of 821 HSCT patients were included in the safety analyses. Adverse drug reactions occurred in 11.33% of patients, with serious adverse drug reactions in 3.05%. The five most common adverse drug reactions were nausea (1.58%), renal impairment (1.46%), and acute graft versus host disease, CMV test positive, and hepatic function abnormal (0.61% each). A total of 670 patients were eligible for effectiveness analyses. Among these patients, 16.57% and 28.66% required preemptive therapy through week 14 and week 48, respectively. In addition, relatively few patients developed CMV disease throughout the follow-up period (1.34% at week 14 and 3.85% at week 48).

Conclusions: This final analysis of post-marketing surveillance with up to 48 weeks follow-up period in Japan provides further evidence supporting the safety profile and effectiveness of letermovir for CMV prophylaxis in patients undergoing allo-HSCT in real-world settings.

Background: CAVE is a single arm, Phase 2 trial, that demonstrated anti-tumor activity of cetuximab rechallenge plus avelumab in patients with RAS wild type (wt) metastatic colorectal cancer (mCRC).

Objective: We conducted a post hoc analysis to identify potential radiomic biomarkers for patients with CRC liver metastasis (LM).

Patients and methods: Patients with LM that could be measured by enhanced contrast phase computed tomography (CT) imaging at baseline and at first response evaluation were included. Multiple texture parameters were extracted with the LifeX Software. Delta-texture (D-TA) variations were calculated by comparing data at baseline and after treatment.

Results: Overall, 55/77 patients (71%) had LM; 39 met the inclusion criteria for the current analysis. The D-TA parameters that significantly correlated at univariate analysis with median progression-free survival (mPFS) were Entropy^Histogram (p = 0.021), Homogeneity^GLCM (p < 0.001) and Dissimilarity ^GLCM (p = 0.002). At multivariate analysis, only Homogeneity^GLCM resulted significant for PFS (p = 0.001). Patients (19/39, 48.7%) with reduction of Homogeneity^GLCM experienced better mPFS (4.6 vs 2.9 months; HR 0.45; 95% CI 0.23-0.88; p = 0.021) and median overall survival (mOS) (17.3 vs 6.8 months; HR 0.40, 95% CI 0.21-0.80; p = 0.010). A trend to better mPFS, was also observed in patients with RAS/BRAF wt circulating tumor DNA and reduction of Homogeneity^GLCM. Overall survival was significantly better in this subgroup of patients with low Homogeneity^GLCM: mOS was 17.8 (95% CI 15.5-20.2) versus 6.8 months (95% CI 3.6-10.0) (HR 0.34, 95% CI 0.14-0.81; p = 0.016).

Conclusion: Reduction in the D-TA parameter Homogeneity^GLCM by radiomic analysis correlates with improved outcomes in patients with LM receiving cetuximab rechallenge plus avelumab therapy. Larger prospective studies are needed to validate and confirm these findings.

Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia.

Background: Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I-II cervical sprains. The combination of thiamine + pyridoxine + cyanocobalamin vitamins has been used, alone and in combination with NSAIDs, for pain and inflammation in musculoskeletal disorders.

Objective: The objective of this study was to demonstrate the analgesic synergy of dexketoprofen, and the combination of vitamins thiamine + pyridoxine + cyanocobalamin in a fixed-dose combination (FDC) for the treatment of acute pain caused by grade I-II cervical sprains.

Methods: We conducted a multicentre, prospective, randomized, double-blind, phase IIIb clinical study comparing two treatment groups: (1) dexketoprofen 25 mg/vitamin B (thiamine 100 mg, pyridoxine 50 mg and cyanocobalamin 0.50 mg) in an FDC (two or more active ingredients combined in a single dosage form) versus (2) dexketoprofen 25 mg monotherapy (single drug to treat a particular disease), one capsule or tablet orally, every 8 h for 7 days. Final mean, average change, and percentage change in pain perception (measured using a visual analogue scale [VAS]) were compared with baseline between groups. A p value < 0.05 was considered statistically significant. Analyses were conducted using SPSS software, v.29.0.

Results: A statistically significant reduction in pain intensity was observed from the third day of treatment with the FDC compared with monotherapy (- 3.1 ± - 1.5 and - 2.6 ± - 1.1 cm, respectively) measured using the VAS (p = 0.011). Regarding the degree of disability, using the Northwick Park Neck Pain Questionnaire (NPQ), statistical difference was observed for the final measurement (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p = 0.028). A lower proportion of adverse events was reported when using the FDC.

Conclusions: The FDC of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins demonstrated superior efficacy and a better safety profile compared with dexketoprofen monotherapy for pain treatment in patients with grade I-II cervical sprains.

Clinical trials registration: NCT05001555, registered 29 July 2021 ( https://clinicaltrials.gov/study/NCT05001555 ).

BACKGROUND AND OBJECTIVE: Intravenous immunoglobulin (IVIG) is a prominent therapeutic agent for Kawasaki disease (KD) that significantly reduces the incidence of coronary artery anomalies. Various methodologies, including machine learning, have been employed to develop IVIG non-responder prediction models; however, their validation and reproducibility remain unverified. This study aimed to develop a predictive scoring system for identifying IVIG nonresponders and rigorously test the accuracy and reliability of this system. METHODS: The study included an exposure group of 228 IVIG non-responders and a control group of 997 IVIG responders. Subsequently, a predictive machine learning model was constructed. The Shizuoka score, including variables such as the "initial treatment date" (cutoff: < 4 days), sodium level (cutoff: < 133 mEq/L), total bilirubin level (cutoff: ≥ 0.5 mg/dL), and neutrophil-to-lymphocyte ratio (cutoff: ≥ 2.6), was established. Patients meeting two or more of these criteria were grouped as high-risk IVIG non-responders. Using the Shizuoka score to stratify IVIG responders, propensity score matching was used to analyze 85 patients each for IVIG and IVIG-added prednisolone treatment in the high-risk group. In the IVIG plus prednisolone group, the IVIG non-responder count significantly decreased (p < 0.001), with an odds ratio of 0.192 (95% confidence interval 0.078-0.441). CONCLUSIONS: Intravenous immunoglobulin non-responders were predicted using machine learning models and validated using propensity score matching. The initiation of initial IVIG-added prednisolone treatment in the high-risk group identified by the Shizuoka score, crafted using machine learning models, appears useful for predicting IVIG non-responders.

Background: In the panorama of therapeutic strategies for inflammatory bowel diseases, oral upadacitinib stands out for its potential to improve short-term and long-term patient outcomes.

Objective: This meta-analysis aspires to collate and assess the available evidence regarding the efficacy and safety of upadacitinib in managing moderate-to-severe Crohn's disease and ulcerative colitis.

Methods: A meta-analysis was conducted using studies sourced from MEDLINE/PubMed, Cochrane Library, Scopus, and Embase, published from January 2010 to March 2024. Peer-reviewed articles that reported data on the effects of upadacitinib in adult patients with Crohn's disease and ulcerative colitis were included based on established inclusion and exclusion criteria.

Results: Eight studies, encompassing a total of 2818 patients treated with upadacitinib, were included. In primary outcomes, for patients with Crohn's disease who were using upadacitinib, the weighted pooled clinical remission rate was found to be 45.8% (95% confidence interval [CI] 0.39-0.52), while for patients with ulcerative colitis who were using upadacitinib, the rate was 25.4% (95% CI 0.17-0.36). The pooled clinical response rate for Crohn's disease was 53.6% (95% CI 0.50-0.57), and for ulcerative colitis it was 72.6% (95% CI 0.69-0.76). The pooled serious adverse event rate was 6.0% (95% CI 0.07-0.09).

Conclusions: Upadacitinib demonstrates significant efficacy in achieving clinical remission and response in patients with moderate-to-severe Crohn's disease and ulcerative colitis, as shown by clinical remission rates of 44.9% and 36.0%, respectively. The treatment also maintains a favorable safety profile with a serious adverse event rate of 7.8%, making it an effective option for those resistant or intolerant to traditional immunosuppressants or tumor necrosis factor antagonists.