Clinical Drug Investigation最新文献

Rapid treatment of prolonged convulsive seizures (PCS), preferably within the first few minutes after onset in most patients, is important to prevent progression to life-threatening status epilepticus (SE) and its associated complications. In community settings, benzodiazepine rescue medication for PCS is often administered by non-medical caregivers to achieve timely seizure control. Until recently, rectally administered diazepam was the only treatment approved by the European Medicines Agency (EMA) for PCS in adults. However, an oromucosal midazolam formulation, which has been approved by the EMA for PCS treatment in paediatric patients for over a decade, has now also received such approval for use in adults. The aim of this narrative review is to describe the role of midazolam oromucosal solution in the management of PCS in adults in community settings in Europe. The approval of midazolam oromucosal solution was supported by pharmacokinetic modelling studies, which extrapolated the efficacy of oromucosal midazolam to adults through exposure matching, alongside European clinical studies where oromucosal midazolam was used as an off-label treatment, thereby demonstrating its effectiveness for treating PCS and SE in adults and paediatric patients. With this approval, adult patients across Europe now have access to an alternative to rectal diazepam that is easy to administer, socially acceptable, and pharmacokinetically appropriate. The increased willingness of caregivers to administer rescue medication by the oromucosal compared with the rectal route should encourage its appropriate use, thus potentially improving outcomes for adults with PCS in Europe.

Mitomycin intravesical solution (ZUSDURI^TM), a hydrogel formulation of the DNA synthesis inhibitor mitomycin, has been developed by UroGen Pharma, Inc. for the treatment of low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC) via intravesical instillation. In June 2025, mitomycin intravesical solution was approved for the treatment of recurrent LG-IR-NMIBC in the USA. This article summarizes the milestones in the development of mitomycin intravesical solution leading to this first approval for LG-IR-NMIBC.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) involving hepatocyte destruction, inflammation, and typically pericellular fibrosis, potentially progressing to cirrhosis. Resmetirom, a T3 analogue and an oral agonist of thyroid hormone receptor-β(THR-β), represents a significant advancement in targeted drug therapy for MASH as the first US Food and Drug Administration (FDA)-approved treatment. Clinical trials have shown that resmetirom effectively improves MASH markers, reduces liver fat content, and exhibits high selectivity for THR-β, which is predominantly expressed in the liver. Despite promising research data, challenges remain in the treatment of MASH with resmetirom, including adverse reactions and limited efficacy in some patients. This article reviews the discovery, mechanisms, and clinical evaluation of resmetirom in detail, and discusses the challenges encountered in MASH precision therapy.

Aim: This study was conducted to examine disproportionality, times to onset, incidence rates, and outcomes of trastuzumab deruxtecan-associated pulmonary adverse events (AEs) using the Japanese Adverse Drug Event Report database.

Methods: We analyzed data for the period from April 2004 to December 2024. Data on pulmonary AEs were extracted, and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs).

Results: Of the 3,221,393 reports analyzed, we identified 1561 reports of AEs associated with trastuzumab deruxtecan, including 505 pulmonary AEs. Only 474 reports were identified as signal-positive: interstitial lung disease, pulmonary toxicity, pneumonitis, and Pneumocystis jirovecii pneumonia. Among these, interstitial lung disease was the most frequently reported (26.6%) and included several fatal cases. Histograms of median times to onset for the four detected pulmonary AE signals showed that AEs occurred at a median of 7-27.5 days after trastuzumab deruxtecan administration. Weibull distributions showed that interstitial lung disease occurred early after administration (early failure type), but pulmonary toxicity occurred constantly throughout the exposure period (random failure type).

Conclusions: We focused on pulmonary AEs associated with trastuzumab deruxtecan as postmarketing AEs. Serious outcomes can arise after trastuzumab deruxtecan administration. Patients should be monitored for signs of onset of these AEs not only at the start of administration but also over an extended period.

Background: Mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease that predominantly affects mucosae. Treatments for MMP often lack robust evidence and may be poorly tolerated, especially in elderly patients.

Objective: This scoping review aims to provide an overview of MMP outcome measurement of the last two decades by mapping and listing all previously reported outcomes and outcome measurement instruments (OMIs).

Design: A large scoping review was performed in scientific databases and trial registries (MEDLINE, Embase, CINAHL, PsycINFO, Cochrane CENTRAL, Web of Science, the International Clinical Trials Registry Platform and Clinicaltrials.gov) covering January 2002 to December 2023. Clinical trials, prospective cohort studies, and systematic reviews were included, while retrospective studies were excluded.

Results: Thirty-nine studies met the inclusion criteria, including 20 prospective cohort studies, 13 systematic reviews, and 6 clinical trials. A total of 285 outcomes were extracted verbatim and categorized into 29 domains and 9 overarching areas. The most commonly reported outcome areas were related to clinical response, safety, and resource use. The majority were investigator-reported outcomes (85%), with only 8% being patient-reported. Various OMIs (n = 14) were employed, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI) score and tools for assessing ocular impairment and quality of life. Reported outcomes and OMIs are very diverse due to the heterogeneity in the presentation of MMP.

Conclusions: The standardized use of consensus-based outcome definitions and high-quality instruments that consider the patient perspective is expected to increase the efficacy of future MMP research and can be achieved by consensus-based selection of outcomes and critical appraisal of the measurement properties of OMIs.

Background: Patients with early-stage non-small-cell lung cancer (eNSCLC) often experience disease recurrence after surgery and adjuvant chemotherapy, leading to a substantial clinical and economic burden. The introduction of immunotherapy such as atezolizumab in the adjuvant setting may offer both clinical benefits and healthcare cost reductions by preventing disease progression.

Objectives: This analysis aimed to estimate the economic impact of prevented recurrences by measuring the costs avoided in the Italian population potentially eligible for adjuvant atezolizumab.

Methods: A cost-consequence analysis was developed using a published model, adapted to the Italian context, to estimate the number of recurrences per year from 2023 to 2033, comparing scenarios 'with' and 'without' atezolizumab. Epidemiological and clinical input was obtained from published literature, clinical trials, and local market research. Direct healthcare costs were sourced from an Italian real-world study. The Italian national health system (NHS) perspective was considered, and a deterministic one-way sensitivity analysis was performed to evaluate the uncertainty over the main parameters.

Results: Over the period considered, 2582 patients with stage II-IIIA eNSCLC (7th edition of the TNM [tumour, node, metastases] classification) after resection and chemotherapy were estimated annually. Of these, 720 (27.9%) were potentially eligible to receive atezolizumab according to the approved indication. Overall, the model estimated 2556 recurrences for the eligible patients, which generated an economic burden of €11.02 million yearly. The introduction of atezolizumab could avoid 720 recurrences (111 locoregional and 609 metastatic), resulting in a direct healthcare cost reduction of €3.11 million annually from the perspective of the Italian NHS. One-way sensitivity analysis showed moderate base-case changes, especially due to drug costs in the metastatic settings.

Conclusions: Recurrences are common among patients with eNSCLC and are associated with a remarkable increase in total direct costs. It appears that adjuvant atezolizumab would prevent a relevant number of events, with potential savings in recurrence-related costs from the perspective of the NHS in Italy.

Background and objectives: In clinical practice, granulocyte colony-stimulating factor (G-CSF) is often used to lower infection risk and avoid poor outcomes from chemotherapy dose reduction or delay. Efbemalenograstim alfa (also known as F-627) is a non-pegylated but long-acting (once-per-cycle) recombinant human granulocyte colony-stimulating factor (rhG-CSF) compared with pegfilgrastim. This study was designed to obtain pharmacokinetic (PK)/pharmacodynamic (PD), safety, and tolerability data for F-627 in healthy Chinese participants.

Methods: This was a single-center, open-label phase I clinical study involving 24 healthy Chinese volunteers (sex ratio = 1:1). All the participants were administered a single subcutaneous injection of 20 mg F-627 into the abdomen.

Results: In this study, 15 (62.5%) participants reported 28 treatment-related adverse events. PK/PD data showed that after a single 20 mg subcutaneous (SC) F-627 abdominal injection in healthy Chinese participants, serum concentrations peaked at 36 h post dose, while the absolute neutrophil count (ANC) peaked at 96 h. After peaking, F-627 serum levels decreased rapidly to low concentrations by 120 h, while ANC declined gradually to near baseline by day 15. Similar trends in serum concentration and ANC kinetics were seen between sex.

Conclusions: This phase I study showed that 20 mg F-627 was well tolerated and exhibited a favorable safety profile in a healthy Chinese population. The PK and PD data correlated well and were consistent across sex.

Trial registration: This trial was registered at the Chinese Clinical Trial Registry (chictr.org.cn) on 10 September 2024 (registration ID: ChiCTR2400089548).

Background and objectives: Neutropenia is the most severe hematologic toxicity of myelosuppressive chemotherapy. The objective of this study was to evaluate the safety and efficacy of efbemalenograstim alfa versus filgrastim for neutropenia support in patients with breast cancer receiving myelosuppressive chemotherapy and find the recommended dose for phase III clinical trials.

Methods: This was an open-label, dose-finding, active-controlled, phase II study. In total, 138 patients with postoperative breast cancer received up to four cycles of epirubicin 100 mg/m² + cyclophosphamide 600 mg/m² (EC) chemotherapy. Patients were randomized in a 1:1:1 ratio to efbemalenograstim alfa (10 mg/dose or 20 mg/dose) or filgrastim group. Duration and incidence rate of moderate or severe neutropenia, depth of absolute neutrophil count (ANC) nadir, time to ANC recovery post nadir, and safety information were evaluated.

Results: The mean duration of moderate and severe neutropenia in cycle 1 was 0.8, 0.6, and 0.8 days for the 10 mg/dose efbemalenograstim alfa, 20 mg/dose efbemalenograstim alfa, and filgrastim groups, respectively. The incidence rate of moderate and severe neutropenia in cycle 1 was lower in 20 mg/dose efbemalenograstim alfa (25.5%) than that in 10 mg/dose efbemalenograstim alfa (35.1%) and filgrastim (38.5%), and no significant differences were observed for the two doses of efbemalenograstim alfa with filgrastim (p = 0.815; p = 0.246, respectively). The ANC nadir occurred between days 9 and 10 in cycle 1, and the median ANC nadir in the 20 mg/dose efbemalenograstim alfa group was higher than that in the 10 mg/dose efbemalenograstim alfa and filgrastim groups (2.2 × 10⁹/L versus 1.7 × 10⁹/L and 1.4 × 10⁹/L, respectively). The time to ANC recovery post nadir in the 20 mg/dose efbemalenograstim alfa group was shorter, but no significant differences were observed for the two doses of efbemalenograstim alfa with filgrastim (0.8 and 1.7 versus 1.2 days, respectively). Efbemalenograstim alfa exhibited similar safety profile to filgrastim. No febrile neutropenia occurred. The incidence rates of common adverse reactions related to the study drugs, such as back pain and bone pain, were lower in the efbemalenograstim alfa groups than that in the filgrastim group (10.3% and 8.0% versus 24.4%).

Conclusions: The efficacy and safety of efbemalenograstim alfa are comparable to those of filgrastim in treating chemotherapy-induced neutropenia in patients with breast cancer receiving EC chemotherapy. Efbemalenograstim alfa at a dose of 20 mg is the recommended dose for phase III clinical trials.

Trial registration: ClinicalTrials.gov: NCT02521441, on 13 August 2015.

Introduction: Mitral regurgitation (MR) is the second most common valve disease in Europe with an increasing prevalence, causing a significant healthcare burden and impacting quality of life. Despite its clinical importance, real-world data on MR burden are limited.

Objectives: This study aimed to estimate MR prevalence, describe patient profiles, and assess healthcare resource utilization and related costs, stratified by degenerative (DMR) and functional (FMR) aetiologies, using real-world data from Italy.

Methods: A retrospective study using Italy's Hospital Discharge Records was conducted including patients discharged in 2018 with a diagnosis of MR. The cohort was stratified into degenerative (DMR) and functional MR (FMR) based on comorbidities and clinical criteria. Patients were followed for 12 months to assess interventions received, including surgical (SMVr) and transcatheter mitral valve repair (TMVr), as well as length of stay, in-hospital mortality, and associated costs.

Results: In 2018, 5816 patients who met the eligibility criteria were hospitalised with MR (83.6% DMR, 16.4% FMR). Among DMR patients, 44.2% underwent isolated valve repair (89.7% SMVr, 10.3% TMVr), while 29.1% of FMR patients received repair (59.6% SMVr, 40.4% TMVr). TMVr patients were older (DMR: 41.6%, FMR: 42.9% aged ≥75 years) and had more comorbidities. Untreated patients had higher 1-year in-hospital mortality (DMR: 4.7%, FMR: 8.5%) compared to treated groups and the highest reintervention rate at 1 year (DMR: 19.9%, FMR: 13.3%). Re-intervention rates were lower in DMR (SMVr: 0.4%, TMVr: 0%) versus FMR (SMVr: 0.6%, TMVr: 0.9%). The cost differences between interventions were negligible, primarily reflecting the different DRG tariffs applied for each intervention type.

Conclusions: Untreated MR is associated with worse clinical outcomes and higher long-term resource use. These findings support early intervention strategies and highlight the need to improve access to care, especially for high-risk populations. Further studies are warranted to explore outpatient care and address treatment disparities.

Background and objectives: There is an important need for the development of neuroprotective therapeutic agents that could be combined to reperfusion strategies in acute ischemic stroke to improve patient prognosis. OTR4132 is a polymer of glucose engineered to mimic heparan sulfates (HS), which demonstrated neuroprotective effects in animal models. The aim of this study was to assess the safety of OTR4132 and to identify the highest, and well-tolerated, single dose of OTR4132 in patients with anterior circulation acute ischemic stroke who underwent endovascular thrombectomy (EVT).

Methods: The MaTRISS study is a multi-center, first-in-man, open-label, dose-escalation study. OTR4132 was administered intra-arterially immediately after EVT recanalization. Dose levels were determined on the basis of preclinical studies. Six doses (from 0.2 to 2.5 mg) were planned to be administered in groups of at least three patients. Each dose escalation was authorized by the data safety monitoring board (DSMB) after reviewing all clinical, biological, and radiological data from a dose group up to 7 days post-administration. Key inclusion criteria were an acute ischemic stroke in the anterior circulation territory and endovascular thrombectomy performed with recanalization (thrombolysis in cerebral infarction [TICI] score of 2b-3) confirmed by angiography. The primary endpoint was the rate of investigational treatment-related severe adverse events occurring from baseline to 7 days after injection. All other safety and efficacy endpoints were exploratory and included all serious and non-serious adverse events, stroke lesion volumes, National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Modified Barthel Index (BI), and Montreal Cognitive Assessment (MoCA) from baseline up to 3 months.

Results: In total, 19 patients were recruited from three centers in France between March 2022 and March 2024 and six different doses of OTR4132 were tested (in n patients): 0.2 mg (3), 0.5 mg (3), 1 mg (3), 1.5 mg (6), 2 mg (3), and 2.5 mg (1). No adverse drug events and no changes in vital signs or laboratory parameters were observed up to 3 months following administration, regardless of administered doses. Four patients presented at least one serious adverse event. None was considered linked to the investigational treatment on the basis of investigator and DSMB assessment. One patient died of intracranial hemorrhagic transformation at 24 h and the causality link between OTR4132 administration and death remained unknown.

Conclusions: The highest tolerated dose of OTR4132 was the highest dose administered (i.e., 2.5 mg). These safety results need to be confirmed in a larger multicenter randomized placebo-controlled clinical trial. The trial was first registered in clinicaltrials.gov on 5 September 2019 (NCT04083001).