临床试验方案设计中主要疗效指标及试验时间的考虑要素

新药上市前,需要进行临床试验,以便对药物的疗效、安全性及风险效益比作出评价。科学合理的临床试验方案是评价的基础;在制定试验方案时,必须考虑到一些重要因素。为此,本文对主要疗效指标和试验时间这2个重要因素进行阐述。

一项随机、序贯、开放性的对比索拉非尼-舒尼替尼与舒尼替尼-索拉非尼治疗转移性肾细胞癌的疗效和安全性的研究

为了前瞻性评估多酶抑制剂的使用顺序,对比索拉非尼-舒尼替尼（So-Su）与舒尼替尼-索拉非尼（Su-So）两种治疗方案对转移性肾细胞癌患者的疗效,一项多中心、随机、开放性的三期临床研究在未接受全身性治疗的转移性肾细胞癌患者中进行,并依据Memorial Sloan Kettering肿瘤中心的风险评分对患者进行分层（有利的或者居中的）。

20mg多西环素片剂联合局部外用0.75%甲硝唑洗剂治疗酒渣鼻疗效的随机、双盲、安慰剂对照试验

Background: Subantimicrobial doses of doxycycline may improve outcomes in rosacea when combined with topical metronidazole and used as maintenance monotherapy. Objective: The purpose of this study was to evaluate the safety and efficacy of doxycycline hyclate 20 mg (subantimicrob- ial dose doxycycline) administered twice daily as an adjunct to metronidazole 0.75% topical lotion in the treatment of rosacea. Methods: Patients received subantimicrobial doses of doxycycline twice daily plus metronidazole (n=20) or placebo plus metronidazole (n=20) for 12 weeks. Subantimicrobial- dose doxycycline or placebo monotherapy continued for 4 weeks. The primary efficacy measure was change from baseline in total inflammatory lesions at weeks 2 and 16. Results: Total inflammatory lesions were reduced significantly (P =.048) by week 4 and by all subsequent visits in the subantimicrobial- dose doxycycline/metronidazole group compared with placebo/metronidazole. Changes from baseline increased over time and were maintained during subantimicrobial- dose doxycycline monotherapy. Conclusion: Adjunctive use of subantimicrobial dose doxycycline significantly reduced the clinical signs of rosacea compared with metronidazole alone and may be useful maintenance monotherapy.

药物临床试验中疗效指标的选择

本文参考国内外药品注册相关法规、技术要求和指导原则,根据20多年新药审评经验和对技术标准及指导原则的深入理解,对新药临床试验中疗效指标概念和与疗效指标选择密切相关的几种疗效指标类型进行了分析和说明。对药物临床试验中主要疗效指标的特点以及主要疗效指标和次要疗效指标选择的基本原则进行了梳理和归纳。对疗效指标选择时需要考虑的问题进行了详细的概括和总结。对使用几种常见类型疗效指标进行疗效评价时需要注意的事项和问题进行了认真的分析和讨论。

利凡斯明治疗与帕金森病相关的痴呆

BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson s disease. We investigated the effects of the dual c holinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild to moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson s disease were randomly assigned to receive pl acebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy varia bles were the scores for the cognitive subscale of the Alzheimer s Disease Ass essment Scale (ADAS cog) and Alzheimer s Disease Cooperative Study Clinici an s Global Impression of Change (ADCS CGIC). Secondary clinical outcomes we re the scores for the Alzheimer s Disease Cooperative Study Activities of Da ily Living, the 10 item Neuropsychiatric Inventory, the Mini Mental State Ex amination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock Drawing test. RESULTS: A total of 541 patients w ere enrolled, and 410 completed the study. The outcomes were better among patien ts treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reporte d in trials of rivastigmine for Alzheimer s disease. Rivastig mine treated patients had a mean improvement of 2.1 points in the score for the 70 point A DAS cog, from a baseline score of 23.8, as compared with a 0.7 point worseni ng in the placebo group, from a baseline score of 24.3 (P < 0.001). Clinically m eaningful improvements in the scores for the ADCS CGIC were observed in 19.8 p ercent of patients in the rivastigmine group and 14.5 percent of those in the pl acebo group, and clinically meaningful worsening was observed in 13.0 percent an d 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respec t to all secondary efficacy variables. The most frequent adverse events were nau sea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 perce nt of those in the placebo group, P < 0.001), vomiting (16.6 and 1.7 percent, P < 0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo con trolled study, rivastigmine was associated with moderate improvements in dementi a associated with Parkinson s disease but also with higher rates of nausea, vo miting, and tremor.

氢溴酸加兰他敏治疗慢性疲劳综合征的一项随机对照试验

Context: There is no established pharmacological treatment for the core sympto ms of chronic fatigue syndrome CORE JOURNALS IN CLINICAL NEUROLOGY CORE VIEW (CF S). Galantamine hydrobromide, an acetyl cholesterone inhibitor, has pharmacologi cal properties that might benefit patients with CFS. Objective: To compare the e fficacy and tolerability of galantamine hydrobromide in patients with CFS. Desig n, Setting, and Patients: Randomized, double blind trial conducted June 1997 th rough July 1999 at 35 outpatient centers in the United Kingdom(n=17), United Sta tes (n=14), the Netherlands (n=2), Sweden (n=1), and Belgium (n=1) involving 434 patients with a clinical diagnosis of CFS (modified US Centers for Disease Cont rol and Prevention criteria). Interventions: A total of 89 patients were randoml y assigned to receive 2.5 mg of galantamine hydrobromide; 86 patients, 5.0 mg; 9 1 patients, 7.5 mg; and,86 patients, 10 mg (these patients received medicine in the tablet form 3 times per day); a total of 82 patients received matching place bo tablets 3 times per day. Main Outcome Measures: The primary efficacy variable was the global change on the Clinician Global Impression Scale after 4, 8, 12, and 16 weeks of treatment. Secondary outcomes were changes in core symptoms of CFS on the Chalder Fatigue Rating Scale, the Fibromyalgia Impact Q uestionnaire, and the Pittsburgh Sleep Quality Index; changes in quality of life on the Nottingham Health Profile; and assessment of plasma free cortisol level s and cognitive performance on a computer based battery of tests. Results: Afte r 16 weeks, there were no statistically significant differences between any of t he galantamine or placebo groups in clinical condition on the Clinician Global I mpression Scale, or for any of the secondary end points. Exploratory regression analysis failed to detect any consistent prognostic factor that might have influ enced the primary or any secondary outcome measures. Conclusion: This trial did not demonstrate any benefit of galantamine over placebo in the treatment of pati ents with CFS.

分析一次性使用血压传感器的应用有效性与安全性

分析临床上使用一次性使用血压传感器的价值。方法 在2022年1月~2022年8月,株洲市二医院选择76例血压监测患者,并按照随机方法将其分为观察组和对照组各38例,比较两组主要疗效指标、次要疗效指标以及应用安全性。结果 两组气管插管后即刻、麻醉诱导前、静脉注射麻醉后即刻中心静脉压及动脉压监测后未发现其存在一定差异性,为P>0.05。且在安全性能方面的对比也未彰显出明显差异性,为P>0.05。结论 一次性使用血压传感器应用后存在较高的安全性和有效性,实际应用价值较高,适合广泛推广。

桂昆风湿合剂联合甲氨蝶呤治疗类风湿关节炎的临床研究

目的:评价桂昆风湿合剂联合甲氨蝶呤治疗寒湿痹阻型类风湿关节炎(Rheumatoid Arthritis,RA)的有效性及安全性。方法:2017年1月1日至2018年12月1日在中山市中医院肾病风湿科门诊及病房确诊的RA(寒湿痹阻型)患者62例,随机分为桂昆风湿合剂联合甲氨蝶呤治疗组(观察组),甲氨蝶呤治疗组(对照组),每组各31例患者,疗程为24周。主要疗效评价指标为:C反应蛋白计算的28关节疾病活动指数(disease activity score 28 C-reactive protein,DAS28-CRP)、ACR20、ACR50、关节超声评分、中医证候评分,次要疗效评价指标:ACR70、健康评估问卷(health assessment questionnaire,HAQ)、视觉模拟评分(visual analogue scale,VAS)、晨僵时间,实验室指标包括血沉(erythrocyte sedimentation rate,ESR)、C反应蛋白(C-reactive protein,CRP)、类风湿因子(Rheumatoid factor,RF)、抗环瓜氨酸肽抗体(Anti-cyclic citrullinated peptide antibody,抗CCP)。评价血常规、肝肾功能等指标及治疗过程中的不良反应。结果:两组患者在年龄、性别、病程及初始DAS28-CRP及VAS评分、HAQ、ESR、CRP、RF、抗CCP、关节超声评分等方面无差异。两组共脱落2例,其中观察组失访1例,对照组失访1例。24周时,观察组DAS28-CRP改善总有效率明显高于对照组;12周、24周时观察组ACR20、ACR50、ACR70达标率均明显高于对照组;12周、24周时,观察组的ESR、RF均显著低于对照组;治疗24周时观察组的VAS评分及HAQ评分分别为1.47±0.97、0.23±0.43,对照组分别为2.00±1.05、0.53±0.68;24周时观察组中医症候总有效率96.67%,较对照组80.00%明显改善;24周时,观察组关节彩超评分中的关节渗出评分、滑膜炎症评分及滑膜层血流信号评分均显著低于对照组。不良反应发生例次两组比较无差异。结论:桂昆风湿合剂联合甲氨蝶呤能提高RA患者的ACR20、ACR50、ACR70达标率,在炎症的控制、中医证候的改善及减少关节渗出、滑膜炎症、滑膜层血流信号等方面优于单用甲氨蝶呤,具有较好的临床应用前景。