加替沙星滴耳液Ⅰ期临床耐受性试验

目的评价健康人体对加替沙星滴耳液的耐受性。方法采用随机、双盲、安慰剂对照的单中心临床研究。52名健康受试者,男女各半,分两部分试验,均点耳后耳浴10 min。单次给药耐受性试验纳入36例,随机分为5组(6、6、8、8、8例,每组包含2例安慰剂),给药剂量分别为0.45、0.9、1.35、1.8、2.25 mg(即3、6、9、12、15滴)。连续给药耐受性试验纳入16例,随机分为2组,每组8例(每组包含2例安慰剂),给药剂量分别为1.8(12滴)、2.25 mg(15滴),3次·d-1,疗程为7 d。观察受试者用药前后生命体征、临床症状及实验室指标的变化,记录不良事件。结果 51例受试者完成试验,1例脱落。单次给药和连续给药耐受性试验中,受试者用药前后生命体征、全身症状、实验室检查均未出现有临床意义的改变。连续给药试验中有2例出现耳部不适感,考虑与试验药物肯定有关。11例实验室检查结果异常(血糖、血脂升高,血常规、尿常规、肝功能、凝血功能异常),单次给药7例,连续给药4例。所有不良事件均为轻度,考虑与试验药物可能有关,未经干预,均自行缓解。结论健康受试者耳点加替沙星滴耳液,单次用药2.25 mg·次-1以内,连续用药1.8 mg·次-1以内,每日3次,疗程7 d,可安全耐受。     

注射剂Ⅰ期临床试验关键环节探讨

注射剂Ⅰ期临床试验相较于口服制剂Ⅰ期临床试验有更高要求,从试验设计到实施的各环节都需在保障受试者安全的基础上做到严谨科学.耐受性试验给药剂量设计充分考虑药物理化性质和溶剂选择,制定合适的给药方案;药物运输管理环节应格外关注药物储存条件,保障药物质量;药物配制和给药是保证临床试验质量的重中之重,研究者需要从各方面细节保证...     

新药Ⅰ期临床试验健康受试者筛选案例分析——实验室指标纳入标准探讨

目的:探讨Ⅰ期临床试验受试者纳入标准。方法:对117例健康成年人进行Ⅰ期临床试验受试者筛选,对检查结果进行了分析。结果:各项指标完全正常的健康人比例为10.71%,因实验室检查结果异常排除54例(47.32%),包括:血液学检查29例(53.70%)、腹部B超19例(35.19%)、心电图(ECG)4例(7.41%)、胸透2例(3.70%)。实际纳入的受试者58例(49.57%)。结论:理想的健康受试者比例较低,可考虑选择相对健康候选者作为I期临床试验的受试者;Ⅰ期临床试验需建立适当的实验室筛选指标参考范围;为避免Ⅰ期临床试验偏倚,可考虑设计安慰剂对照组。     

新药Ⅰ期临床试验中健康受试者的管理

Ⅰ期临床试验之目的是研究人体对药物的耐受程度,并通过药物代谢动力学研究,了解药物在人体内的吸收、分布、代谢和消除的规律,为制定给药方案提供依据.Ⅰ期临床试验必须全过程高度重视受试者的安全.因此,加强试验中健康受试者的管理是非常必要的.主要包括受试者的招募、培训、筛选、食宿、用药等环节的管理.     

Ⅰ类新药布格呋喃的临床耐受性和安全性研究

目的:确定健康受试者对单次和多次口服布格呋喃胶囊的耐受性和安全性。方法:本研究分为单次给药和多次给药两组,单次给药耐受性试验纳入36名健康志愿者,男女各半,分为6个剂量组:15,30,45,60,75和90 mg组,其中包括安慰剂6名。多次给药的耐受性试验纳入10名健康志愿者,男女各半,服用布格呋喃胶囊25 mg,tid,观察9 d。两组的观察指标包括:生命体征、血常规、血生化、电解质、心电图,记录不良事件,7 d后电话随访。结果:所有46名志愿者完成研究。布格呋喃对体温、脉搏和呼吸影响较多,主要是降低脉搏、呼吸次数和体温变化(升高或降低),但是安慰剂组也出现了体温的波动。心电图和实验室检查未见有临床意义的异常。单次给药组36例受试者中安慰剂组6受试者没有不良反应出现,服用药物的受试者有9例出现不良反应,以困倦最多见。连续给药组10例受试者中有8例有不同程度的不良反应,以口干最多见。不良反应均为轻、中度,给予观察或对症处理后均缓解。不良反应的出现与剂量无依赖关系。结论:通过对健康受试者单次和连续给药进行的耐受性试验,结果表明布格呋喃耐受性良好。     

注射用比伐卢定对健康志愿者纤维蛋白原和凝血酶时间的影响

目的:研究比伐卢定注射液对健康志愿者纤维蛋白原和凝血酶时间的影响。方法:48名健康志愿者随机分为4个试验组,分别为静脉注射比伐卢定0.5,0.75和1.05 mg.kg-1组以及以0.75 mg.kg-1静脉推注后,立即续以1.75 mg.kg-1.h-1的速度匀速静脉滴注4 h组。每组12人,其中9名给予比伐卢定注射剂,3名接受安慰剂。静脉注射组在给药前和给药后20 min,45 min,1 h,2 h,24 h和72 h,静脉推注加静脉滴注组在静脉推注前和静脉滴注开始后2,4,6,8,24和72 h,取血测定纤维蛋白原(fibrinogen,Fib)浓度和凝血酶时间(thrombin time,TT)。结果:比伐卢定剂量依赖性地延长TT,停药后2 h,TT值逐渐恢复正常。比伐卢定剂量依赖性地降低Fib浓度,尤其是静脉推注加静脉滴注组降低明显,但这可能是由于检测方法的影响,产生的假性降低现象。结论:在比伐卢定II期临床试验中,应密切监测受试者的凝血指标,注意观察受试者是否发生出血不良事件。在有直接凝血酶抑制剂存在时,应避免使用冯.克劳斯法检测Fib浓度。     

钙拮抗剂Fendiline的药动学和耐受性

作者研究了健康人口服单剂和多剂钙拮抗剂芬地林(fendiline)的血药浓度和耐受情况。 54名健康志愿者参加双盲、随机、安慰剂对照试验。在单剂给药试验中,受试者分别服用盐酸芬地林200、400、600、800、1000、1200mg或安慰剂,在服药后的48小时内定期测定血药浓度。结果各组受试者的主观、客观反应均无显著差异,药动学数据表明,剂量超过800mg时药物的吸收不完全。在多剂给药试验中,受试者开始服用盐酸芬地林或安慰剂400 mgbid,6天后因普遍出现震颤、头晕等副作用而剂量减至300mgbid,第11天继续减至200mgbid,共服药28天。测定     

国产基因重组人尿激酶型原（Pro—urokinase／u—PA）Ⅰ期临床安全性、耐受性研究

目的：对国内研究的注射用基因重组人尿激酶型纤溶酶原激活剂（pro-urokinase,u-PA）进行Ⅰ期临床试验，以评价其用于中国健康成人受试者的安全性和耐受性。方法：试验日期；健康受试者23例（男11例，女12例），随机分为5，20，35mg和50mg四个剂量组。静脉给药：其中1／4剂量在1min内静脉推注，其余3／4剂量在60min内静脉滴注完毕，给药前和给药后2，24h取外周血测定血液生化指标、凝血和纤溶指标，并随时观察受试者的全身状态和可能的药物不良反应。结果：全部受试者用药前后的血压、心率／律、呼吸等重要生命体征未见异常变化；血、尿常规、肝肾功能，电解质、空腹血糖等亦未见明显变化。与溶栓有关的血液学指标（活化的部分凝血活酶时间，凝血酶原时间，凝血酶原活动度，纤维蛋白原，α2－抗纤溶酶和纤维蛋白降解产物），在部分受试者有改变，但变化均在正常范围内、且与剂量无明显相关，无明确临床意义。全部受试者注射药物的局部皮肤，无刺激性炎症和皮下激血、出血等变化。结论：中国健康成人受试者对于上述剂量的基因重组人尿型纤溶酶原激活剂的安全性及耐受性良好。     

华法林钠片在健康受试者生物等效性试验中的安全性分析

目的 探讨健康受试者参加华法林钠片生物等效性试验的安全性。方法 收集2017—2020在首都医科大学宣武医院开展的4项随机、开放、四周期、交叉对照设计的华法林钠片生物等效性（BE）试验中188例受试者,比较空腹与餐后给药所发生不良事件（TEAEs）的差异及TEAEs与性别和年龄的相关性。结果 4个试验中共报告了116例次TEAEs,与试验药物相关的TEAEs 29例次,均属于轻度,主要为凝血功能指标异常（14例次）和肝功能指标异常（10例次）。餐后给药试验中肝功能指标异常的发生例次多于空腹给药试验（8∶2）,与试验药物具有相关性的TEAEs发生率出现随年龄增加而增高的趋势。结论 健康受试者参加BE试验单次口服华法林钠片的安全性良好,与试验药物相关的不良事件多与华法林的药理机制有关,年龄是不良事件发生类型和发生率的潜在影响因素。     

中药临床研究应用加载设计常见问题及注意事项梁伟雄简

加载设计指的是在使用安慰剂的对照试验中，设计方案为所有受试者在接受标准疗法的基础上，试验组加用试验药物，对照组加用模拟试验药的安慰剂。中药临床研究近年来加载设计应用较多，应该明确使用该设计的目的、常见的问题和注意事项。     

Comparison of Test Statistics for the Sequential Parallel Design

The sequential parallel design has been proposed to improve the efficiency of clinical trials in psychiatry. The design randomizes patients into three treatment groups. Each group has two phases. The three groups are (1) placebo in the first phase followed by placebo in the second phase, (2) placebo in the first phase followed by drug in the second phase, and (3) drug in the first phase followed by drug in the second phase. We consider the case of binary response data. The analysis of data in the second phase of the trial is restricted to placebo patients who failed to respond in the first phase of the trial. A crucial element in the choice of test statistics is the underlying assumptions of treatment effect in the two phases of the trial. We develop various likelihood-based statistics when the treatment effect is different in the two phases and for the special case in which the treatment effect is equal in the two phases. These statistics are compared in simulation studies to determine their underlying null and nonnull behavior. The score test under the assumption of equal treatment effects is seen to have advantages in terms of Type I error and robustness to assumptions.     

Group sequential design and analysis of clinical equivalence assessment for generic nonsystematic drug products

Clinical trials with therapeutical endpoints are designed with three arms to demonstrate both the efficacy and the equivalence of the test generic treatment and the reference treatment. A generic drug product is determined to be equivalent to the reference drug product if the ratio or difference between the mean responses is bounded within the pre-specified equivalence limits. Often the trials are oversized for the placebo arm. For improvement, we propose a group sequential design with hierarchical testing for the purpose of terminating the placebo arm before testing equivalence between the test and the reference treatments. The hierarchical feature of the proposal will reduce the sample size of the placebo arm and provide treatments to patients in a more efficient manner in a clinical trial setting. After dropping the placebo arm, the option of allocating the planned but unused sample size from the placebo group to the test and reference groups will increase the sample size and power of the equivalence test without inflating the type I error rate by delaying spending it.     

Double-blind,placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia

Summary

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with I gacetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratocy tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.     

A simple and flexible graphical approach for adaptive group-sequential clinical trials

In this article, we introduce a graphical approach to testing multiple hypotheses in group-sequential clinical trials allowing for midterm design modifications. It is intended for structured study objectives in adaptive clinical trials and extends the graphical group-sequential designs from Maurer and Bretz (Statistics in Biopharmaceutical Research 2013; 5: 311–320) to adaptive trial designs. The resulting test strategies can be visualized graphically and performed iteratively. We illustrate the methodology with two examples from our clinical trial practice. First, we consider a three-armed gold-standard trial with the option to reallocate patients to either the test drug or the active control group, while stopping the recruitment of patients to placebo, after having demonstrated superiority of the test drug over placebo at an interim analysis. Second, we consider a confirmatory two-stage adaptive design with treatment selection at interim.     

正常吸毒者口服脱毒舒胶囊Ⅰ期临床耐受性试验

目的：评价正常吸毒者口服脱毒舒胶囊的安全性和耐受性。方法：43名正常吸毒受试者进行单次及多次给药的耐受性试验。其中,单次给药者31人,经筛选合格后随机分配到7个剂量组（1、2、3、4、5、6和7粒组）。多次给药者12人,男女各半,分为3粒组和4粒组,连续给药6d,前3d1d2次,1次3（或4）粒;后3d1d2次,1次2粒。观察记录给药前后不同时间的体格检查、生命体征、心电图、血常规、尿常规、血液生化等指标。结果：给药后体格检查、体征未见有临床意义的改变。实验室检查中单次组共有4组（3、4、5、6粒给药组）的BUN值和两组（3、7粒给药组）的Cr值试验前后变化有统计学意义（P〈0．05）,多次给药两组的BUN值和Cr值试验前后变化都有统计学意义（P〈0．05）;少数病例的CK值变化有临床意义,但该组均数前后变化分析无统计学差异。试验中不良事件均为轻中度且为一过性,未见严重不良事件发生。结论：脱毒舒胶囊单次给药1～7粒,受试者均可耐受;多次给药（前3d早晚各4粒,后3d早晚各2粒）受试者可以耐受。推荐Ⅱ期临床研究用药剂量为多次给药,疗程6d,前3d早晚各4（或3）粒,后3d早晚各2（或1）粒,但需注意受试者睡眠、饮食、心肌酶和大小便等的变化。     

信息管理系统在I期临床试验质量控制中的作用

目的探讨药物临床试验信息管理系统在Ⅰ期临床试验质量控制中的作用。方法在2017年8月-2018年8月的4个Ⅰ期临床试验项目中应用药物临床试验信息管理系统,根据"药物临床试验数据现场核查要点"分析机构质控员与申办方监查员在原始数据核查及质量控制中发现的问题,与传统纸质记录管理模式的4个Ⅰ期临床试验项目分析比较。结果使用药物临床试验信息管理系统后的Ⅰ期临床试验项目中发生的受试者的筛选/入组数据链完整性、临床试验检查/化验等数据的溯源、试验用药品管理过程与记录、受试者的管理等方面存在问题均明显低于系统使用前(χ^2=11.922,P<0.001)。结论药物临床试验信息管理系统在I期临床试验项目中的应用对受试者信息完整性,药品管理规范性,临床试验的真实性、完整性、可信性及可溯源性都有较大提升,能提升Ⅰ期临床试验的质量。     

米氮平联合奥替溴铵及复合乳酸菌胶囊治疗难治性腹泻型肠易激综合征的疗效观察

目的：观察米氮平联合奥替溴铵及复合乳酸菌胶囊治疗难治性腹泻型肠易激综合征（RIBS-D）的临床疗效。方法：82例RIBS-D患者随机分为试验组（43例）与对照组（39例）,两组均给奥替溴铵及复合乳酸菌胶囊,试验组加服米氮平,对照组加服安慰剂,疗程4周。结果：试验组与对照组的总有效率分别为95.35％、12.82％（P＜0.01）;试验组焦虑及抑郁评分较对照组显著降低,生活质量评分较对照组显著升高,差异均有统计学意义（P＜0.01）。结论：米氮平联合奥替溴铵及复合乳酸菌胶囊治疗RIBS-D患者,能明显改善症状、焦虑抑郁状态及生活质量,十分安全。     

Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with 1 g acetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratory tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.     

Application of Clinical Trial Simulation to Compare Proof-of-Concept Study Designs for Drugs with a Slow Onset of Effect; An Example in Alzheimer's Disease

Objective Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200–400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials.Materials and Methods A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A ‘positive trial’ reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025).Results A 4 × 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability.Conclusion CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US$4M in direct costs and a firm decision 8–12 months earlier than a 12-week parallel group trial.     

Pseudostat Cortecs Ltd

Cortecs is developing Pseudostat, an oral vaccine derived from Pseudomonas aeruginosa, for the potential treatment and prophylaxis of lung infection with P aeruginosa and Haemophilus influenza, common in respiratory disorders such as cystic fibrosis, bronchitis and bronchiectasis. It is expected that a phase III trial will commence this year, and that a European registration submission will be made by the end of the year [262793]. In January 1998, Cortecs confirmed that phase III trials for Pseudostat for bronchitis are being prepared [276928]. Two Pseudostat phase II clinical trials commenced in July 1996 against chronic bronchitis [214837]. Results of the first trial were announced in August 1997. A total of 91 patients received Pseudostat or placebo. Five months following the completion of immunization, the number of acute infective episodes in the placebo group was about 10-fold higher than the treated group [258965]. The second study involved a total of 80 patients with chronic bronchitis, as defined by Medical Research Council criteria, but no history of consistent P aeruginosa in their sputum. The patients were followed for up to seven months after the first tablet, and efficacy outcome measures were as for the first study. Initial analysis was encouraging: after the treatment course the Pseudostat group took up no hospital days, compared to 48 days for the placebo group. Pseudostat also reduced episodes of acute infection by 90% [262793]. In July 1996, a phase II clinical trial commenced in Australia with Pseudostat in patients with cystic fibrosis (CF). The trial involved approximately 40 patients. In August 1996, the company initiated phase II trials in patients with CF in the UK [223065]. Cortecs was scheduled to begin European phase II trials for CF in the third quarter of 1997. For the US, trials for CF are planned in 1998 [259009]. An open phase I/II study has been completed in nine patients, with bronchiectasis, who after oral vaccination, twice daily for three days, starting on days 0, 28 and 56, exhibited a specific immune response. Additionally, there was a several-fold reduction in the white blood cell content of the sputum (white blood cells in sputum reflect the severity of infection). However, the white blood cell content of the patients' sputum rose again following 28 days of discontinued treatment [207633]. Phase I trials with an oral formulation were completed in healthy volunteers at the Australian Institute of Mucosal Immunology (AIMI). No adverse or toxic effects associated with Pseudostat were observed [170099].