CMH统计分析方法在多中心试验2×2表资料的应用

ＣＭＨ统计分析（Ｃｏｃｈｒａｎ－Ｍａｎｔｅｌ－ＨａｅｎｓｅｌＳｔａｔｉｓ－ｔｉｃｓ），是Ｍａｎｔｅｌ于１９６３年在原有ＭＨ统计分析方法（１９５９年）的基础上提出来的，Ｋｏｃｈ等统计学家于１９７８至１９８８年使之发展和完善，现在习惯称之为扩展的ＭＨ卡方...

热敏灸治疗慢性持续期哮喘多中心试验设计特点与方案优化

科学规范的设计方案是确保临床试验内在真实性的关键。以国家"十一五"科技支撑计划资助的腧穴热敏化艾灸治疗慢性持续期哮喘的优化方案研究为例,从随机化、盲法运用、对照设置、重复性等方面介绍试验设计特点,同时围绕中医临床研究优化的理念、过程和方法进一步阐述方案优化的具体措施。

国际多中心试验中的中心实验室

国际多中心临床试验中,如何避免因不同实验室的检查方法、正常值范围的差异对整体的数据造成影响?最有效的方法是将所有标本在同一实验室统一检查,中心实验室能将此变成现实。本期专栏重点介绍中心实验室的利弊,以期更好地增加试验的科学性。

医学顾问:国际多中心试验不可或缺的角色

怎样让这些差异性不影响到国际多中心试验的"一致性",使临床试验最终获得科学、严谨的数据,是一个十分重要的问题。

比较植入ICD的自发性室性心动过速患者中经验性抗心动过速起搏与电除颤的前瞻性随机多中心试验:快速性室性心律失常起搏治疗降低除颤研究(PainFREE RxⅡ)试验结果

Background-Successful antitachycardia pacing(ATP) terminates ventricular tachycardia(VT) up to 250 bpm without the need for painful shocks in implantable cardioverter-defibrillator(ICD) patients. Fast VT(FVT) >200 bpm is often treated by shock because of safety concerns, however. This prospective, randomized, multicenter trial compares the safety and utility of empirical ATP with shocks for FVT in a broad ICD population. Methods and Results-We randomized 634 ICD patients to 2 arms-standardized empirical ATP(n=313) or shock (n=321)-for initial therapy of spontaneous FVT. ICDs were programmed to detect FVT when 18 of 24 intervals were 188 to 250 bpm and 0 of the last 8 intervals were >250 bpm. Initial FVT therapy was ATP (8 pulses, 88%of FVT cycle length) or shock at 10 J above the defibrillation threshold. Syncope and arrhythmic symptoms were collected through patient diaries and interviews. In 11±3 months of follow-up, 431 episodes of FVT occurred in 98 patients, representing 32%of ventricular tachyarrhythmias and 76%of those that would be detected as ventricular fibrillation and shocked with traditional ICD programming. ATP was effective in 229 of 284 episodes in the ATP arm(81%, 72%adjusted). Acceleration, episode duration, syncope, and sudden death were similar between arms. Quality of life, measured with the SF-36, improved in patients with FVT in both arms but more so in the ATP arm. Conclusions-Compared with shocks, empirical ATP for FVT is highly effective, is equally safe, and improves quality of life. ATP may be the preferred FVT therapy in most ICD patients.

婴儿纤维性错构瘤:一项意大利多中心试验

Background: Fibrous hamartoma (FH) of infancy is a benign mesenchymal tumor, occurring as a superficial mass. Complete excision is curative. Objective and Methods: The clinical features and treatment results of 18 children with FH are described. Results: Local excision was the most common procedure. Surgery was radical in 10 patients, with microscopic residual disease in 6; all of them are alive with no evidence of disease 2 to 49 months after diagnosis. One patient, treated with a local reexcision for macroscopic residual disease (and chemotherapy for a synchronous desmoid fibromatosis) is well 83 months after diagnosis; the last patient, with a lesion of the labia majora, only underwent biopsy and is doing well, awaiting plastic surgery. Limitations: The results did not reach statistical significance due to difficulties in collecting cases. Conclusions: FH should be treated by complete excision; in our experience a nonradical excision was also able to achieve the cure. An aggressive approach should be avoided, as the overall prognosis is excellent.

超声内镜引导胰腺转移瘤的细针穿刺:一项多中心试验

Background: Metastatic lesions of the pancreas are a rare but important cause of focal pancreatic lesions. The purpose of this study is to describe the EUS features, cytologic diagnoses, and clinical impact of a cohort of patients with pancreatic metastases diagnosed by EUS-guided FNA (EUS-FNA). Methods: Over a 6-year period, in a retrospective, multicenter study, patients had the diagnosis of pancreatic metastases confirmed with EUS-FNA. All examinations were performed by one of 5 experienced endosonographers. The EUS and the clinical findings of pancreatic metastases were compared with those of a cohort with primary pancreatic malignancy. Results: Thirty-seven patients with possible metastases were identified, and 13 were excluded because of diagnostic uncertainty. The remaining 24 underwent EUS-FNA (mean passes 4.1) of a pancreatic mass without complications. Diagnoses included metastases from primary kidney (10), skin (6), lung (4), colon (2), liver (1), and stomach (1) cancer. In 4 (17%), 16 (67%), and 24 (100%) patients, EUS-FNA provided the initial diagnosis of malignancy, tumor recurrence, and pancreatic metastases, respectively. Four (17%) metastases initially were discovered by EUS after negative (n = 3) or inconclusive (n = 1) CT scans. Compared with primary cancer, pancreatic metastases were more likely to have well-defined margins (46%vs. 4%) compared with irregular (94%vs. 54%; p < 0.000 1) margins. No statistically significant difference between the two populations was noted for tumor size, echogenicity, consistency, location, lesion number, or number of FNA passes performed. Conclusions: Pancreatic metastases are an important cause of focal pancreatic lesions and may occasionally be discovered during EUS examination after previously negative or inconclusive CT. Use of immunocytochemistry, when available, may help to confirm a suspected diagnosis. These lesions are more likely to have well-defined EUS margins compared with primary pancreatic cancer.

β受体阻滞剂预防肝硬化伴临床显著性门静脉高压患者的失代偿事件(PREDESCI):一项随机、双盲、安慰剂对照、多中心试验

【据《Lancet》2019年3月报道】题:β受体阻滞剂预防肝硬化伴临床显著性门静脉高压患者的失代偿事件(PREDESCI):一项随机、双盲、安慰剂对照、多中心试验。(作者Càndid V等)肝硬化患者的临床失代偿事件与不良预后有关。临床显著性门静脉高压(CSPH)被定义为肝静脉压力梯度(HVPG)≥10 mm Hg,是肝硬化失代偿事件的显著危险因素。该研究旨在评估β受体阻滞剂在降低HVPG的同时,是否可以降低代偿期肝硬化伴CSPH患者发生失代偿事件或死亡的风险。该研究在西班牙的8家医院进行,纳入代偿期肝硬化伴CSPH且无高危静脉曲张的患者。静脉注射普萘洛尔后,所有患者均测量HVPG值,以评估急性HVPG的应答。

阿莫西林-舒巴坦钠治疗CAP多中心试验结果发布

近日，西班牙金武制药在上海发布了阿莫西林／舒巴坦钠（2：1）治疗社区获得性肺炎（CAP）多中心临床试验结果。以头孢呋辛为对照药物，在全国8家医院共316例患者入组，进行了随机、多中心临床研究，以评价阿莫西林一舒巴坦钠治疗轻中度CAP的有效性和安全性。

食管内Enteryx植入治疗GERD:扩大的多中心试验和核准后24个月的期中随访

Background: Enteryx implantation in the esophagus is an alternative therapy for patients with proton pump inhibitor (PPI) dependent GERD. Although this treatment resulted in highly significant improvement at 6 and 12 months, longer follow-up is needed to more fully assess the durability of these positive effects. Methods: An open-label, international clinical trial was conducted in 144 PPI-dependent patients with GERD with follow-up at 6 and 12 months. In addition, the durability and the safety of the treatment were assessed for 24 months in 64 patients enrolled in a postapproval study. The primary study outcome measure was usage of PPI. Secondary outcomes in the multicenter trial were GERD health-related quality of life (GERD-HRQL) symptom score and esophageal acid exposure. Results: At 12 months, PPI use was reduced ≥50%in 84%: 95%confidence interval (CI) [76%, 90%] and was eliminated in 73%: 95%CI[64%, 81%] of evaluable patients (intent-to-treat analysis 78%: 95%CI[70%, 84%] and 68%: 95%CI[60%, 76%], respectively). A GERD-HRQL ≤11 was attained in 78%: 95%CI[69%, 85%] of evaluable patients. Esophageal acid exposure (total time pH <4) was reduced by 31%: 95%CI[17%, 43%]. At 24 months, a ≥50%or greater reduction in PPI use was achieved in 72%: 95%CI[59%, 82%] and PPI use was eliminated in 67%: 95%CI[54%, 78%] of patients. Conclusions: This investigation provides evidence for sustained effectiveness and safety of implantation of Enteryx in the esophagus in PPI-dependent patients with GERD.

抗痴呆药物多中心试验

加拿大15个医疗中心正准备进行一项试验研究,750名轻度至中度的老年痴呆患者将分别在美国和加拿大参加这项抗痴呆药Linoirine的多中心试验。

单一剂量的米非司酮药物流产的多中心试验

依次应用米非司酮（mifepristone）和米索前列醇（misoprostol）的预期多中心流产试验研究的开展旨在为支持降低流产所需的米非司酮推荐剂量至200mg并允许回家服用400μg米索前列醇提供数据。所有的受试对象均停经（已确诊妊娠）不足50天、年龄18岁或18岁以上且无米非司酮应用禁忌症；受试者在注册参加试验的当天，经咨询和医学检查后，每人服用200mg米非司酮，

妊娠中期流产患者联用单硝酸异山梨酯和前列甲脂和单独使用前列甲脂的比较:一项双盲、随机、安慰剂对照的多中心试验研究

Objective: We aimed to determine whether second- trimester abortion using isosorbide mononitrate (IMN) in addition to gemeprost is more effective and reduces side effects compared with gemeprost alone. Study design: Eighty women who were age 13 to 23 weeks’ gestation were randomly assigned to receive per vaginam either IMN 40 mg (group 1, 40 women) or placebo (group 2, 40 women) in addition to gemeprost 1 mg up to 3 times daily 3 hours apart for 2 days. Analysis of variance, a χ 2 test, and a multivariate analysis were performed. Results: Of the 72 women analyzed, 68% (group 1) and 38% (group 2) underwent abortion within day 1 (P <. 05). However, group 1 was associated with more headache (18% of women) 3 hours after induction compared to group 2 (0% of women, P=.038). Conclusion: IMN in addition to gemeprost is effective for second- trimester abortion, but is associated with more headache compared with gemeprost alone.

回顾2000—2005年眼内淋巴瘤的多中心试验结果

Background:The prognosis of intraocular lymphoma(IOL)is poor,and the optimal treatment has yet to be defined.This study assesses the clinical characteristics and outcome of patients with IOL diagnosed and treated in the new millennium.Methods:Patient data in this retrospective multicentre study were compiled by standardised questionnaires sent to seven university ophthalmology departments.All cases diagnosed with primary and secondary IOL in the past 5 years not associated with HIV infection were included.Results:Twenty-two patients,11 men and women;median age 64(range 38-83)years,median Karnofsky performance status 90%(range 50-100%),were included.Nineteen patients had primary IOL(PIOL):13 a newly diagnosed disease and six an ocular relapse of primary central nervous system lymphoma(PCNSL).Three patients had secondary IOL.First-line treatment for IOL included systemic chemotherapy in 13 cases,ocular radiation in six and intraocular chemotherapy in three.Complete remission was achieved in 14/20 evaluable patients,partial remission in five and stable disease in one.All patients treated with ifosfamide(IFO)or trofosfamide(TRO)(n=8)responded.Median progression-free survival(PFS)and overall survival were 10(range 1+ to 44.5+)and 22.5(range 1+ to 49+)months,respectively.Patients with newly diagnosed PIOL and ocular relapse of PCNSL had a median PFS of 10(range 1+ to 44.5+)and 6(range 2 to 6+)months,respectively.Median PFS was 12(range 3+ to 22.5+)months after systemic and 5.5(range 1+ to 44.5+)months after local first-line therapy.Conclusions:The prognosis of PIOL is similar to that of PCNSL without ocular involvement.Systemic therapy possibly prolongs PFS as compared with local management of(P)IOL.The high response rate to monotherapy with IFO and TRO is promising.

胃内折叠缝合术的远期结果:一项美国多中心试验

Background: Endoluminal gastroplication has shown promise for the treatment of GERD in short-term studies. Until now, long-term outcome data have been lacking. Methods: A prospective, multicenter trial enrolled 85 patients with GERD to be treated with endoluminal gastroplication. Inclusion criteria were 3 or more heartburn or regurgitation episodes per week, >4.2%time in 24 hours with esophageal pH < 4, and dependency on antisecretory medications. Exclusion criteria were the presence of varices, achalasia, aperistalsis, or previous gastric resection. Patients underwent manometry, 24-hour pH monitoring, and symptom severity scoring before and after the procedure. Patient diaries were used to assess medication use and to estimate annual medication cost. Results: At 1-and 2-year follow-up, patients had significant reductions in median heartburn symptom scores (72 at baseline [interquartile range (IQR) 90-48] vs. 4 at 12 months [IQR 43-0] and 16 at 24 months [IQR 53-3.5]; p < 0.000 1 vs. baseline) and median regurgitation symptoms (2 at baseline [IQR 3-1] vs. 0 at 12 months (IQR 1-0) and 1 at 24 months [IQR 1-0]; p < 0.000 1 vs. baseline). Of all patients, 59%and 52% showed heartburn symptom resolution at 12 and 24 months, respectively (p < 0.000 1 vs. baseline). Also, 83%and 77%had regurgitation symptom resolution at 12 and 24 months, respectively (p < 0.000 1 vs. baseline). Proton pump inhibitor use also was significantly reduced at 12 and 24 months after the procedure. At 2-year follow-up, median annualized medication costs were reduced by 88%(＄1381) (p < 0.000 1). Endoluminal gastroplication significantly reduced the duration and the number of episodes of esophageal acid exposure (P< 0.000 1 vs. baseline). Only 7 patients experienced adverse events. Conclusions: Endoscopic gastroplication is safe and effective, and is associated with symptom reductions in patients with GERD for at least 24 months.

早产儿视网膜病变冷冻疗法的多中心试验—10年时的眼科学后果

目的：对参加早产儿视网膜病变冷冻疗法多中心试验（CRYO－ROP）的患儿，其患眼随机分为冷冻疗法组和对照组，治疗后10年时对结果予以评价。方法：随机分组的患儿原先有291例早产儿，体重低于1251g，一只眼或双眼发生规定阈值的早产儿视网膜病变（ROP）。双眼阈值ROP患儿（240例）被随机分为一只眼接受冷冻疗法，另只眼不用冷冻疗法。对另只眼有ROP低于阈值严重度的患儿（“不对称”组；51例），有阈值ROP的眼被随机分为冷冻疗法或不用冷冻疗法。10年后，1位不知每只眼治疗情况的测验者测患者的远、近视力，20／200或更低的视力为“不良”后果。患儿并被合格证明的眼科医生评价，这些眼科医生评定主要位于眼底后极部的ROP残余，不良后果为后部视网膜摺或更差。结果：被检查的247例患儿中，与对照眼相比，治疗眼在功能上和结构上主要后果均显示较少不良后果：远视力为44．4％对62．1％（P＜0．001），眼底状况为27．2％对47．9％（P＜0．001）。近视力结果与远视力结果相似（42．5％对61．6％；P＜0．001）全视网膜脱离继续发生于对照眼中，自51／2年时的38．6％增加至10年时的41．4％，而治疗眼保持稳定（22．0％）。以前的一个困扰亚组有较多的对照眼比治疗眼有20／40或更好的视力（在51／2年报告中）的趋向不再见于10年；接受冷冻疗法的眼被发现至少很可能与对照眼一样有20／40或更好视力。结论：术后10年时，接受冷冻疗法的眼比对照眼更少可能失明。有较高比例的有视力的对照眼比有视力的治疗眼显示有正常范围的视力，这一以前的趋向未被肯定。结果显示在有阈值ROP眼中，冷冻疗法在保存视力中的长期价值。

PEG 3350(聚乙烯二醇)与乳果糖治疗儿童功能性便秘的疗效对比:一项双盲随机对照多中心试验

Background: Recently, polyethylene glycol (PEG 3350) has been suggested as a good alternative laxative to lactulose as a treatment option in paediatric constipation. However, no large randomised controlled trials exist evaluating the efficacy of either laxative. Aims: To compare PEG 3350 (Transipeg: polyethylene glycol with electrolytes) with lactulose in paediatric constipation and evaluate clinical efficacy/side effects. Patients: One hundred patients (aged 6 months-15 years) with paediatric constipation were included in an eight week double blinded , randomised, controlled trial. Methods: After faecal disimpaction, patients < 6 years of age received PEG 3350 (2.95 g/sachet) or lactulose (6 g/sachet) while children ≥6 years started with 2 sachets/day. Primary outcome measures were: de fecation and encopresis frequency/week and successful treatment after eight weeks. Success was defined as a defecation frequency ≥3/week and encopresis ≤1 every two weeks. Secondary outcome measures were side effects after eight weeks of treatment. Results: A total of 91 patients (49 male) completed the study. A significant increase in defeca tion frequency (PEG 3350: 3 prev 7 post treatment/week; lactulose: 3 prev 6 post/week) and a significant decrease in encopresis frequency (PEG 3350: 10 prev 3 post/week; lactulose: 8 prev 3 post/week) was found in both groups (NS). However, success was significantly higher in the PEG group (56%) compared with the lactulose group (29%). PEG 3350 patients reported less abdominal pain, straining, and pain at defecation than children using lactulose. However, bad taste was reported significantly more often in the PEG group. Conclusions: PEG 3350 (0.26 (0.11) g/kg), compared with lactulose (0.66 (0.32) g/kg), provided a higher success rate with fewer side effects. PEG 3350 should be the laxative of first choice in childhood constipation.

评估短期应用克拉霉素对稳定性冠心病患者影响的随机、安慰剂对照、多中心试验:CLARICOR试验

Objective: To determine if the macrolide clarithromycin affects mortality and cardiovascular morbidity in patients with stable coronary heart disease. Design: Centrally randomised multicentre trial. All parties at all stages were blinded. Analyses were by intention to treat. Setting: Five Copenhagen University cardiology departments and a coordinating centre. Participants: 13 702 patients aged 18 to 85 years who had a discharge diagnosis of myocardial infarction or angina pectoris in 1993- 9 and alive in August 1999 were invited by letter; 4373 were randomised. Interventions: Two weeks’ treatment with clarithromycin 500 mg/day or matching placebo. Main outcome measures: Primary outcome: composite of all cause mortality, myocardial infarction, or unstable angina pectoris during three years’ follow-up. Secondary outcome: composite of cardiovascular mortality, myocardial infarction, or unstable angina pectoris. The outcomes were obtained from Danish registers and were blindly assessed by the event committee. Results: 2172 participants were randomised to clarithromycin and 2201 to placebo. We found no significant effects of clarithromycin on the primary outcome(hazard ratio 1.15, 95% confidence interval 0.99 to 1.34) or secondary outcome(1.17, 0.98 to 1.40). Mortality was significantly higher in the clarithromycin arm(1.27, 1.03 to 1.54; P=0.03) as a result of significantly higher cardiovascular mortality(1.45, 1.09 to 1.92; P=0.01). Conclusions: Short term clarithromycin in patients with stable coronary heart disease may cause significantly higher cardiovascular mortality. The long term safety of clarithromycin in patients with stable ischaemic heart disease should be examined.

多中心护理干预随机对照试验的设计与实施——以乳腺癌患者回归家庭干预为例

目的:探索多中心护理干预随机对照试验课题管理模式,为临床护理科研培训及实践提供经验。方法:严格按照临床试验管理规范,从课题的评估、计划、实施与评价4个阶段详细阐述多中心护理干预随机对照试验课题管理模式。采用患者招募率、留存率、护士参与留存率、培训依从率,评价多中心护理干预随机对照试验课题管理模式的可行性及科研培训效果。结果:患者招募率为73.3%,干预组患者留存率为96.4%,护士参与留存率为89.3%,培训依从率为78.6%。结论:回归家庭干预多中心随机对照试验的课题管理模式具有可行性,为临床护士和护理专业研究生设计和实施多中心随机对照试验提供了经验参考,同时以课题实践为导向的科研培训能够激发护士科研兴趣,提高其科研能力。