Advances in Therapy最新文献

Introduction: Fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) is approved for the treatment of asthma in Japan. Currently, data on the safety, particularly on cardiovascular (CV) risk, and effectiveness of FF/UMEC/VI in Japanese real-world clinical practice are limited.

Methods: This prospective, multicenter, post-marketing surveillance was undertaken to assess the safety and effectiveness of once-daily single-inhaler triple therapy FF/UMEC/VI (100/62.5/25 or 200/62.5/25 mcg) newly initiated in patients with asthma in Japan between July 2021 and November 2023. The observation period was 1 year after the first FF/UMEC/VI prescription or until termination or withdrawal from treatment. Safety was assessed by incidence of adverse drug reactions (ADRs) including CV events as safety specification to be checked due to risk associated with use of UMEC. Overall assessment of effectiveness (based on lung function, asthma symptoms, and proportion of patients with exacerbation events) and asthma management status was assessed by the investigator.

Results: Overall, 8.4% (24/286) of patients reported an ADR. The most common ADRs were cough and dysphonia (each 7/286). Urinary retention was reported as a serious ADR in 1 patient, and CV event palpitations were reported in 2 patients. FF/UMEC/VI treatment was deemed effective in 92.5% (260/281) of patients in the effectiveness analysis. Lung function and asthma control test results improved following initiation of FF/UMEC/VI. In the 1 year after initiation, 6.2% (11/178) of patients experienced exacerbation events, while 25.8% (46/178) of patients experienced exacerbation events prior to initiation.

Conclusion: FF/UMEC/VI was well tolerated and effective in the treatment of patients with asthma in Japan. ADRs were reported in 8.4% of patients and the incidence of CV events was low. No new safety concerns were identified.

Introduction: Mirikizumab, an anti-interleukin-23 p19 monoclonal antibody, is approved for treating adults with moderately to severely active ulcerative colitis and Crohn's disease. For ulcerative colitis maintenance therapy, mirikizumab is administered via two 1-ml subcutaneous (SC) injections. Volume and number of SC administrations can impact injection site reactions and local pain, as well as treatment compliance. We assessed the pharmacokinetic (PK) and safety comparability of an investigational one 2-ml SC injection compared with the commercially available two 1-ml SC injections.

Methods: In this phase 1 study, USA-based healthy adults were stratified by weight and randomized (1:1) to receive citrate-free 200 mg SC mirikizumab as either two 1-ml injections (each 100 mg) or one 2-ml (200 mg) injection, delivered by an autoinjector. Participants in each arm were subrandomized by injection site location (arm, abdomen, or thigh). Blood sampling and safety assessments were conducted up to 10 weeks post dose. The primary endpoint was PK, and the secondary endpoint was safety.

Results: A total of 244 participants received one injection and 240 received two injections (mean age 42.5 years; 51.0% female). Baseline characteristics were similar in both groups. Primary PK parameters fell within the bioequivalence range (geometric least-squares mean [GLSM] ratio 0.800-1.250). Observed GLSMs were consistent across injection site locations. Treatment-emergent adverse events were reported in 48 participants with one injection (19.7%) and 55 with two injections (22.9%); most were mild (62/74 events with one injection [83.8%] and 85/100 with two injections [85.0%]). No serious adverse events were reported in either group.

Conclusion: Mirikizumab 200 mg administered as one 2-ml SC injection was bioequivalent to two 1-ml injections, and most treatment-emergent adverse events were mild in both groups. In clinical practice, reducing the number of injections may improve treatment adherence.

Trial registration: ClinicalTrials.gov identifier NCT06475729.

Introduction: Achondroplasia is the most common skeletal dysplasia condition, characterized by disproportionate short stature and delayed motor development. Additional potential complications include bowed legs and hypotonia, otitis media, sleep apnea, and complications from spinal stenosis, which may impose potential burden on individuals with achondroplasia, as well as their families. No reliable, validated, and publicly available achondroplasia-specific clinical outcome assessment (COA) is currently available that can capture the experiences of children and adolescents with achondroplasia. We sought to determine whether existing COA measures have adequate concept coverage for use in clinical studies and understand the challenges for children/adolescents with achondroplasia and their parents through concept elicitation and cognitive debriefing interviews.

Methods: Children/adolescents with achondroplasia and parents of children with achondroplasia participated in combined concept elicitation and cognitive debriefing interviews. Issues raised by participants were mapped to four COA measures to evaluate their clarity, relevance, and appropriateness for use in achondroplasia studies.

Results: Eight children/adolescents (aged 11-16) and 18 parents were interviewed. The challenges most often reported by children/adolescents were feeling hot/sweaty (88%), pain (88%), balance issues or falls (75%), fatigue (63%), muscle fatigue/loose joints (63%), and speech issues (63%). Pain (83%), ear infections (78%), and feeling hot/sweaty (78%) were frequently reported by parents. Difficulty reaching things (88%), running (88%), and walking (75%) were the functional challenges most reported by children/adolescents, while parents most commonly reported difficulty reaching things (78%), toileting (63%), bathing (56%), walking (56%), running (56%), and dressing (50%). Results of response mapping indicated that the QoLISSY, PedsQL, WeeFIM, and Pain-NRS cover most of the important concepts mentioned by parents and children/adolescents.

Conclusions: The PedsQL, QoLISSY, Pain-NRS, and WeeFIM are content valid, appropriate, and relevant to include in future studies of individuals with achondroplasia.

Introduction: Pharmacological inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-established strategy for achieving substantial reductions in low-density lipoprotein cholesterol (LDL-C). Recently, novel oral PCSK9 inhibitors have emerged, providing new evidence regarding their lipid-lowering efficacy and safety.

Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. Randomized clinical trials evaluating oral PCSK9 inhibitors and reporting percentage changes in lipid parameters and/or adverse events were included. A qualitative synthesis was performed for all studies meeting predefined eligibility criteria, followed by a quantitative synthesis of studies with sufficient data for statistical pooling.

Results: Seven randomized clinical trials were included in the qualitative analysis, of which four were eligible for meta-analysis. Five oral PCSK9 inhibitors were identified. Three agents (MK-0616, AZD0780, and NNC0385-0434) contributed to the quantitative analysis, while two (DC371739 and CVI-LM001) were assessed descriptively. Compared with placebo, oral PCSK9 inhibitors significantly reduced LDL-C [mean difference (MD) - 55.7; 95% confidence interval (CI) - 59.3 to - 52.1; I² = 14%)] and apolipoprotein B (MD - 46.9; 95% CI - 54.6 to - 39.2; I² = 72.9%). They also lowered non-high-density lipoprotein cholestero (MD - 49.4; 95% CI - 57.4 to - 41.5; I² = 50.3%), triglycerides (MD - 13.2; 95% CI - 21.4 to - 5.0; I² = 0%), and lipoprotein(a) (MD - 24.9; 95% CI - 34.9 to - 15.0; I² = 77.6%). Across trials, no differences in safety outcomes were observed between oral PCSK9 inhibitors and placebo.

Conclusion: Oral PCSK9 inhibitors demonstrate lipid-lowering efficacy and safety comparable to that of currently approved injectable PCSK9 therapies. These findings support their potential as a convenient and effective alternative, although current evidence remains limited to early-phase studies.

Introduction: Urgent endoscopy should be performed in patients with cirrhosis and acute gastrointestinal bleeding (AGIB), but this approach is resource-intensive and associated with procedural risks. Therefore, its necessity has been questioned in low-risk patients. This study aims to identify low-risk patients with cirrhosis and AGIB for whom endoscopy may be unnecessary during hospitalization.

Methods: Patients with cirrhosis and AGIB who presented with melena alone were retrospectively screened from an international multicenter cohort. They were further classified according to the use of endoscopy. Logistic regression analyses were performed to explore the relationship of Child-Pugh score and hepatocellular carcinoma (HCC) with in-hospital death.

Results: Overall, 673 patients were included, of whom 202 (30.0%) did not undergo endoscopy. Child-Pugh score and HCC were significantly associated with in-hospital mortality. There was no death during hospitalization among the 304 patients with Child-Pugh score ≤ 7 and without HCC, who were stratified as a low-risk population. Among them, neither in-hospital mortality (0.0% vs. 0.0%) nor rate of 5-day failure to control bleeding (1.3% vs. 4.7%, P = 0.110) was significantly different between patients who underwent endoscopy and those who did not.

Conclusions: Patients with cirrhosis and AGIB, who present with melena alone, and have Child-Pugh score ≤ 7, but without HCC, may not require urgent endoscopy.

Trial registration: This study is a secondary analysis based on the data from our previously registered study (ClinicalTrials.gov identifier NCT04662918).

Introduction: Sickle cell disease (SCD) is characterized by vaso-occlusive crises (VOCs) that can lead to clinical complications, higher mortality, and healthcare resource use (HCRU). Lack of Canadian data poses challenges to health system planning, a gap this study intends to close. We analyzed clinical complications, mortality, and HCRU in patients with SCD with recurrent VOCs in Canada.

Methods: This retrospective cohort study identified patients with SCD with recurrent VOCs from the Institute for Clinical Evaluative Sciences (ICES) databases in Ontario, Canada from January 1, 2010, to December 31, 2021. VOCs were defined as SCD with crisis, priapism, or acute chest syndrome. Patients were matched (1:3) by age, sex, and geographic area with non-SCD individuals in the general population. Clinical complications, mortality, and HCRU were analyzed.

Results: Eight hundred fifty-nine patients with SCD with recurrent VOCs were identified and matched to 2577 controls. Mean (standard deviation [SD]) age was 22.1 (14.4) years; 50.9% were female. Mean (SD) rate of VOCs per person per year was 3.2 (4.4) in patients with recurrent VOCs. Acute and chronic complication rates were higher in patients than controls. Compared with controls, mortality was substantially higher for patients with recurrent VOCs. Mean (SD) age at death for patients with recurrent VOCs was 39.2 (17.2) years. There was significantly higher HCRU than matched controls (P < 0.0001).

Conclusion: Patients with SCD with recurrent VOCs had substantially higher rates of complications, mortality, and HCRU than controls, further highlighting the need for novel therapies to reduce VOCs and the associated burden.

Delayed union and nonunion of long bone fractures are common clinical complications, especially among patients suffering from chronic diseases like osteoporosis and diabetes. Although traditional surgical procedures are commonly applied, they are characterized by numerous problems, such as the need for secondary surgical procedures and the increased risk of complications. On the other hand, non-surgical therapy presents an attractive option since it can avoid the hazards of surgery, prevent complications, and help lower medical expenses. This practice has been gaining interest in recent times. This article will summarize the most recent developments in the non-surgical treatment field for delayed union and nonunion of long bone fractures, which will help improve clinical practice and the discipline of regenerative medicine.