Specification of phase Ⅰ of new drugs' clinical tolerance trials

Phase Ⅰ of clinical trials is the first stage of clinical pharmacology and body safety evaluation,including body tolerance test and pharmacokinetics test.The aim is providing evidence for dosage regimen and be the cornerstone of the preliminary assessment of efficacy and safety of phase Ⅱ of clinical trials.This text discussed the technique and requirement of phase Ⅰ of new drugs' clinical tolerance trials.

Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial

Human umbilical cord mesenchymal stem cells(hUC-MSCs)support revascularization,inhibition of inflammation,regulation of apoptosis,and promotion of the release of beneficial factors.Thus,they are regarded as a promising candidate for the treatment of intractable spinal cord injury(SCI).Clinical studies on patients with early chronic SCI(from 2 months to 1 year post-injury),which is clinically common,are rare;therefore,we will conduct a prospective,multicenter,randomized,placebo-controlled,single-blinded clinical trial at the Third Affiliated Hospital of Sun Yat-sen University,West China Hospital of Sichuan University,and Shanghai East Hospital,Tongji University School of Medicine,China.The trial plans to recruit 66 early chronic SCI patients.Eligible patients will undergo randomization at a 2:1 ratio to two arms:the observation group and the control group.Subjects in the observation group will receive four intrathecal transplantations of stem cells,with a dosage of 1×106/kg,at one calendar month intervals.Subjects in the control group will receive intrathecal administrations of 10 mL sterile normal saline in place of the stem cell transplantations.Clinical safety will be assessed by the analysis of adverse events and laboratory tests.The American Spinal Injury Association(ASIA)total score will be the primary efficacy endpoint,and the secondary efficacy outcomes will be the following:ASIA impairment scale,International Association of Neural Restoration-Spinal Cord Injury Functional Rating Scale,muscle tension,electromyogram,cortical motor and cortical sensory evoked potentials,residual urine volume,magnetic resonance imaging–diffusion tensor imaging,T cell subtypes in serum,neurotrophic factors and inflammatory factors in both serum and cerebrospinal fluid.All evaluations will be performed at 1,3,6,and 12 months following the final intrathecal administration.During the entire study procedure,all adverse events will be reported as soon as they are noted.This trial is designed to evaluate the clinical safety and efficacy of subarachnoid transplantation of hUC-MSCs to treat early chronic SCI.Moreover,it will establish whether cytotherapy can ameliorate local hostile microenvironments,promote tracking fiber regeneration,and strengthen spinal conduction ability,thus improving overall motor,sensory,and micturition/defecation function in patients with early chronic SCI.This study was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University,China(approval No.[2018]-02)on March 30,2018,and was registered with ClinicalTrials.gov(registration No.NCT03521323)on April 12,2018.The revised trial protocol(protocol version 4.0)was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University,China(approval No.[2019]-10)on February 25,2019,and released on ClinicalTrials.gov on April 29,2019.

Quality Management Model for Phase I Clinical Drug Trials:A Structural Equation Model

This study aimed to construct a quality management model for phase I clinical drug trials.A cross-sectional survey was conducted and data were collected from 604 respondents at 69 institutions in China engaged in phase I clinical drug trials.Exploratory and confirmatory factor analyses were used to develop the survey tool.Structural equation modeling was used to construct a quality management model for phase I clinical drug trials.The results showed that the final survey tool had good reliability and validity(Cronbach’sα=0.938,root mean square error of approximation=0.074,comparative fit index=0.962,and Tucker—Lewis index=0.955).The model included five dimensions:government regulation,industry management,medical institution management,research team management,and contract research organization(CRO)management.In total,22 measurement items were obtained.The structural equation model indicated government regulation,industry management,medical institution management,and CRO management significantly affected the quality of phase I clinical drug trials(β=0.195,β=0.331,β=0.279,andβ=−0.267,respectively;P<0.05).Research team management had no effect on the quality of trials(β=0.041,P=0.610).In conclusion,the model is valuable for identifying factors influencing phase I clinical drug trials and guiding quality management practices.

PHASE II CLINICAL TRIAL OF LASTET CAPSULE IN COMBINATION CHEMOTHERAPY OF MALIGNANT TUMORSIN CHINA

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Clinical Trial Phases

Developers of drugs, biologicals, and medical devices must ensure product safety, demonstrate medical benefit in people, and mass produce the product. Preclinical development starts before clinical trials and the main goals are to determine safety and effectiveness of the intervention. If preclinical studies show that the therapy is safe and effective, clinical trials are started. Clinical trial phases are steps in the research to determine if an intervention would be beneficial or detrimental to humans and include Phases 0, I, II, III, IV, and V clinical studies. Understanding the basis of clinical trial phases will help researchers plan and implement clinical study protocols and, by doing so, improve the number of therapies coming to market for patients.

药物Ⅰ期临床试验中受试者非药物相关三酰甘油、尿酸异常的相关因素

目的分析药物Ⅰ期临床试验中受试者非药物相关三酰甘油(TG)、尿酸(UA)异常的影响因素。方法选取2021-02至2022-02在首都医科大学附属北京世纪坛医院开展的药物Ⅰ期临床试验中的96例受试者作为研究对象,于筛选入组当日(D1)、D3、D5、D15、D43、D99六个时点对受试者的血清TG、UA水平进行监测,分析以上指标异常情况及相关因素。结果有42例(43.75%)出现血清TG水平异常,有66例(68.75%)出现血清UA水平异常,受试者在各监测时点血清TG、UA水平的差异均有统计学意义(P<0.05),受试者D3-D99的血清TG水平均高于D1水平,D5、D43、D99的血清UA水平均高于D1水平,差异均有统计学意义(P<0.05)。受试者血清TG水平异常与D1时点的血清TG水平和体质量指标(BMI)水平具有相关性(P<0.05),受试者血清UA水平异常与D1时点的血清UA水平具有相关性(P<0.05)。受试者D1时点TG、BMI水平预测TG异常的受试者工作特征曲线下面积(AUCROC)分别为0.857和0.684(P<0.05),受试者D1时点UA水平预测UA异常的AUCROC为0.845(P<0.05)。结论药物Ⅰ期临床试验中受试者发生非药物相关TG、UA异常的比例较高,其发生风险与基线TG、UA水平、受试者的肥胖程度等因素有关。

Study protocol of the Asian XELIRI ProjecT(AXEPT):a multinational,randomized,non-inferiority,phase Ⅲ trial of second-line chemotherapy for metastatic colorectal cancer, comparing the eicacy and safety of XELIRI with or without bevacizumab versus FOLFIRI w

Background: Capecitabine and irinotecan combination therapy(XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer(m CRC). Recently, in the Association of Medical Oncology of the German Cancer Society(AIO) 0604 trial, tri?weekly XELIRI plus bevacizumab, with reduced doses of irinotecan(200 mg/m^2 on day 1) and capecitabine(1600 mg/m^2 on days 1–14), repeated every 3 weeks, has shown favorable tolerability and eicacy which were comparable to those of capecitabine and oxaliplatin(XELOX) plus bevacizumab. The doses of capecit?abine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab(BIX) as second?line chemotherapy was well tolerated and had promising eicacy in Japanese patients.Methods: The Asian XELIRI Projec T(AXEPT) is an East Asian collaborative, open?labelled, randomized, phase Ⅲ clinical trial which was designed to demonstrate the non?inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI(5?fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second?line chemo?therapy for patients with m CRC. Patients with 20 years of age or older, histologically conirmed m CRC, Eastern Coop?erative Oncology Group performance status 0–2, adequate organ function, and disease progression or intolerance of the irst?line regimen will be eligible. Patients will be randomized(1:1) to receive standard FOLFIRI with or with?out bevacizumab(5 mg/kg on day 1), repeated every 2 weeks(FOLIRI arm) or XELIRI with or without bevacizumab(7.5 mg/kg on day 1), repeated every 3 weeks(XELIRI arm). A total of 464 events were estimated as necessary to show non?inferiority with a power of 80% at a one?sided α of 0.025, requiring a target sample size of 600 patients. The 95% conidence interval(CI) upper limit of the hazard ratio was pre?speciied as less than 1.3.Conclusion: The Asian XELIRI Projec T is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second?line treatment option of mCRC.

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with High-Grade Glioma. Final Report (Protocol BT-06), and Review of Recent Trials

Standard treatment for high-grade glioma involves surgical resection followed by radiation therapy and temozolomide. Unfortunately, there are no standard treatment recommendations after recurrence and new therapies are needed for patients whose tumor recurs after first-line treatment. This single-arm, two-stage, interventional Phase II study evaluated the efficacy and safety of a combination of antineoplastons A10 and AS2-1. Nineteen patients were enrolled in the study (safety population), but fifteen patients with a median age of 9.4 years who met eligibility criteria were evaluated. The majority of subjects (12/15) were Caucasian and 8/15 (53%) were female. More than half (53%) of patients were diagnosed with glioblastoma and 33% with anaplastic astrocytoma. All patients had failed standard therapy including surgery, radiation, and chemotherapy. Antineoplastons were administered intravenously every four hours (median dose of A10 6.9 g/kg/d and AS2-1 0.30 g/kg/d) until objective response was documented and thereafter for a further 8 months. Clinical evaluations were performed every 8 weeks. All patients enrolled in the study were included in the safety analysis but only patients fulfilling the inclusion criteria were included in the efficacy evaluation. The duration of treatment with antineoplastons ranged from 2 weeks to 120 weeks. A complete response was documented in 2/15 (13%), partial response in 2/15 (13%), stable disease in 3/15 (20%). Progression-free survival at six months was 47% and overall survival (OS) at one year was 33.3%. One patient (6.7%) survived 10 years from treatment start. A small group of patients suffered reversible Grade 3 and 4 toxicities including hypernatremia 2/19 (11%) and decrease of neutrophils 1/19 (5%). There were no chronic toxicities. There was improvement of quality of life in patients who had objective response. It is concluded that antineoplastons show efficacy with an acceptable profile in this cohort of patients with recurrent high-grade glioma.

Multicenter phase Ⅱ trial of modified FOLFIRINOX in gemcitabine-refractory pancreatic cancer

AIM To evaluate the efficacy and safety of modified FOLFIRINOX as a second-line treatment for gemcitabine(GEM)-refractory unresectable pancreatic cancer(PC).METHODS This study was a prospective, multicenter, one-arm, open-label, phase Ⅱ trial. Patients with unresectable PC, who showed disease progression during GEMbased chemotherapy were enrolled. All patients were administered FOLFIRINOX with reduced irinotecan and oxaliplatin(RIO; irinotecan 120 mg/m^2 and oxaliplatin 60 mg/m^2), which was set according to the phase Ⅰ study of FOLFIRINOX. The objective response rate(ORR), disease control rate(DCR), progressionfree survival(PFS), overall survival(OS), adverse events were evaluated. Additionally, changes in quality of life(QoL) were assessed using a questionnaire on QoL.RESULTS Between August 2015 and May 2016, a total of 48 patients were enrolled. The median follow-up time was 259 d with a median of 8.5 cycles. The ORR and DCR were 18.8% and 62.5%, respectively, including one patient who showed complete remission. The median PFS was 5.8 mo [95% confidence interval(CI): 3.7-7.9] and median OS was 9.0 mo(95%CI: 6.4-11.6). Neutropenia(64.6%) was the most common grade 3-4 adverse event, followed by febrile neutropenia(16.7%). Although 14.6% of patients experienced grade 3 fatigue, most non-hematologic AEs were under grade 2. In the QoL analysis, the global health status score before treatment was not different from the score at the last visit after treatment(45.43 ± 22.88 vs 48.66 ± 24.14, P = 0.548).CONCLUSION FOLFIRINOX with RIO showed acceptable toxicity and promising efficacy for GEM-refractory unresectable PC. However, this treatment requires careful observation of treatment-related hematologic toxicities.

Toward phase 4 trials in heart failure: A social and corporate responsibility of the medical profession

Congestive heart failure(CHF) is a chronic condition, requiring polypharmacy, allied health supports and regular monitoring. All these factors are needed to ensure compliance and to deliver the positive outcomes demonstrated from randomized controlled trials. Unfortunately many centers around the world are unable to match trial level support. The outcomes for many communities are thus unclear. Research design factors in post-marketing surveillance to address this issue. Phase 4 studies is the name given to trials designed to obtain such community level data and thus address issues of external validity. CHF phase 4 studies are relatively underutilized. We feel the onus for this research lies with the health profession. In this commentary we provide arguments as to why phase 4 studies should be viewed as a social and corporate responsibility of health professional that care for clients with CHF.

TITE(e)-U-Keyboard两阶段Ⅰ/Ⅱ期试验设计研究

目的针对肿瘤靶向制剂和细胞免疫疗法治疗效应延迟的问题,基于Ⅰ/Ⅱ期试验设计框架,构建创新试验设计方法TITE(e)-U-Keyboard。方法采用二项近似似然法纳入尚未观测到的有效性结局信息,构建近似分布,辅助决策,并将TITE(e)-U-Keyboard同Ⅰ/Ⅱ期试验设计方法U-BOIN、BOIN12从多个角度进行模拟比较研究。结果模拟结果显示在考虑有效性结局延迟的情况下三种方法的OBD选择准确率及最优剂量分配受试者数相当,但TITE(e)-U-Keyboard所需试验时长最短;敏感性分析表明有效性观察窗会对TITE(e)-U-Keyboard试验时长产生影响,且随着有效性观察窗的增加而增加。结论TITE(e)-U-Keyboard在保持良好试验设计性能的同时显著缩短了试验时长,可以解决Ⅰ/Ⅱ期临床试验中治疗效应延迟的问题,加速临床试验进程。

A multicenter phase II trial of domestic product of zoledronic acid in the treatment of malignant hypercalcemia

Objective:To evaluate the effect and safety of clinical use of zoledronic acid in the treatment of malignant hypercalcemia.Methods:A multi-center,open phase II clinical trial was conducted in 15 cases with malignant hypercalcemia who received zoledronic acid intravenously for 15 min.The level of blood calcium and side effects were recorded regularly within 28 days after injection.Results:One case was dropped out due to bad compliance.The complete response rate(the corrected serum calcium was reduced to normal level)was 100.00%(14/14).The medium time of complete response rate was 5.07 days.The medium maintain time was 22.30 days.Slight,or moderate fever was observed.Conclusion:Zoledronic acid can effectively reduce the malignant hypercalcemia.The use of zoledronic acid appears to be safety and convenient.

多学科协作在药物Ⅰ期/BE临床试验中受试者风险管理的应用研究进展

研究临床试验中各职责方通过多学科协作的方式进行合作,提高受试者管理中风险识别的水平,通过人为干预、受试者风险管理、科学化的决策来制定相关管理措施、互联网络信息化管理等措施,在每一次药物Ⅰ期/BE临床试验中最大限度地保障受试者的安全、减少不良事件发生、确保临床试验的顺利实施,提高各方在临床试验过程中受试者管理的风险责任意识,提升医院的药物临床试验的质量管理能力和发展。

Progress in phase III clinical trials of molecular targeted therapy and immunotherapy for glioblastoma

Glioblastoma(GBM)is the most common primary central nervous system tumor,whose prognosis remains poor under the sequential standard of care,such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields.Accordingly,the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management.A diverse range of targeted drugs have been tested in patients with GBM in phase III clinical trials.However,these drugs are ineffective for all patients,as evidenced by the fact that only a minority of patients in these trials showed prolonged survival.Furthermore,there are several published phase III clinical trials that involve immune checkpoint inhibitors,peptide vaccines,dendritic cell vaccines,and virotherapy.Accordingly,this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.

在鼻喷雾剂新药Ⅰ期临床研究中开展精准化临床管理的探讨

目的探讨如何开展鼻喷雾剂新药Ⅰ期临床研究的精准化临床管理。方法对培训管理、病房管理、动态心电图采集管理、受试者鼻腔管理、血样采集管理、心理教育管理六个方面的工作进行总结。结果形成了一套较为完善的针对鼻喷雾剂新药Ⅰ期临床试验的精准化临床管理模式。结论该研究成果为我国鼻喷雾剂新药Ⅰ期临床研究的精准化管理提供参考,全面提升临床试验质量。

聚乙二醇重组人粒细胞集落刺激因子注射液Ⅰ期临床药代动力学和药效学研究

目的评价聚乙二醇重组人粒细胞集落刺激因子(PEG-rhG-CSF)注射液在化疗引起的中性粒细胞减少症中的药代动力学(PK)和药效学(PD)。方法入组24例肿瘤患者接受2个周期且剂量相同化疗方案,第1周期为对照周期,第2周期于化疗药物给药结束后48 h皮下注射不同剂量的PEG-rhG-CSF 1次,共设置60、100和150μg.kg-13个剂量组,每组受试患者8例,ELISA法检测受试者血清中PEG-rhG-CSF浓度,并计算PK参数,同时监测受试者CD34+、血常规、血生化指标变化。结果 PEG-rhG-CSF 3个剂量组主要药代参数如下:T12分别为(37.5±7)、(40.8±12)、(80.7±48)h;CL_F分别是(17±9)、(9±4)、(7±2)ml.h-1.g-1;AUC0-t分别是(5,593.6±5,435)、(14,651.3±12,183)、(23,002.5±6,655)mg.h.L-1。第2周期3个剂量组的中性粒细胞绝对值(ANC)最低点均值分别为1.9×109、2.3×109、4.2×109cells.L-1,均比第1周期有所提高。结论 PEG-rhG-CSF在体内呈现非线性药代动力学特征,其在体内维持药效时间长,1次注射即可达到较好疗效。

注射用聚乙二醇化重组人粒细胞集落刺激因子Ⅰ期临床药效学

目的初步观察我国自主研发的聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)预防化疗导致中性粒细胞减少症的效果。方法未经放化疗的非小细胞肺癌、乳腺癌患者接受2个周期相同剂量的紫杉醇/卡铂方案化疗,第1周期为对照周期,第2周期在化疗药物给药结束后48h给予PEG-rhG-CSF1次,初始剂量为30μg/kg,递增剂量依次为60、100和200μg/kg,每一剂量组4例受试患者,监测中性粒细胞变化。结果第1周期有7例患者因Ⅳ度中性粒细胞计数(ANC)减少应用了重组人粒细胞集落刺激因子(rhG-CSF),第2周期仅在第1剂量组出现Ⅳ度ANC减少1例。第1周期未使用rhG-CSF的9例患者ANC均值最低点为1·37×109/L。第2周期4个剂量组的ANC均值最低点依次为0·77×109/L、4·54×109/L、3·00×109/L和5·56×109/L。结论PEG-rhG-CSF可减少化疗期间Ⅳ度ANC减少的发生率,升高ANC最低值,60、100或200μg/kg每个化疗周期给药1次能较好地预防中性粒细胞减少症。

无细胞耻垢分枝杆菌疫苗的Ⅰ期临床研究

目的:通过Ⅰ期临床研究探讨无细胞耻垢分枝杆菌疫苗(M.S疫苗)的人群安全性和耐受性,并初步观察该疫苗对结核病高危人群皮试反应强度的影响。方法:给55例健康志愿者注射不同剂量的疫苗(8.7,17.5和35.0μg),每例注射6次,每2周注射1次。通过对受试者的随访、心率和血压测试、血液常规、尿液常规、肝功能、胸部X-片以及肝、胆、脾、胰的B超检查以及PPD皮肤试验,评估M.S疫苗的不良反应,并比较疫苗注射前后PPD反应强度的变化。结果:在55例、330例次M.S疫苗注射过程中,发生14例、17例次的轻度不良反应,包括局部疼痛、淋巴结肿大、发热、局部硬结、心慌、皮疹和乏力,轻度不良反应总发生率为25.5%(14/55),未发生中度及重度不良反应;PPD皮试强阳性者经不同剂量M.S疫苗的注射,PPD皮试反应强度均显著降低(P<0.05)。结论:M.S疫苗具有较高安全性,并可显著降低结核病高危人群PPD皮试反应的强度。

华蟾素治疗肝癌、肺癌、胰腺癌的Ⅰ期临床研究:初步报道

背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌、非小细胞肺癌和胰腺癌接受华蟾素治疗,采用静脉滴注,连续14 d,21 d为一疗程。如果没有出现剂量限制性毒性,治疗将持续2个疗程。剂量递增的方案为:10、20、40、60、90和120 m l/(m2.d)。结果:入组15例患者(每个剂量组为3例)中,11例为肝癌,2例胰腺癌和2例肺癌。第五剂量组结束时没有发现剂量限制性毒性(DLT)。其中14例患者可评价疗效,6例(42.9%)为SD,8例(57.1%)为PD。在第一剂量组中,1例肝癌患者肿瘤缩小20%并维持11个月。结论:本研究最高剂量达到常规剂量的8倍,尚未出现剂量限制性毒性。部分患者获得了肿瘤缩小或稳定的疗效。

药物Ⅰ期临床试验受试者管理方法的探讨

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