Consideraciones bioéticas sobre los incentivos a participantes voluntarios sanos en investigaciones Fase I

Los ensayos clínicos en Fase I se realzan con la participación de voluntarios sanos de prueban la seguridad y tolerabilidad de los productos farmacéuticos en investigación. En ellos, los participantes están expuestos a riesgos de medicamentos del estudio sin la posibilidad de un beneficio médico directo y, por lo general, deben pasar días o semanas en un centro de investigación. Los incentivos, como pagos monetarios se utilizan para incentivar la inscripción y compensar a los participantes por su tiempo. Estas características de los ensayos voluntarios sanos de fase I crean un contexto de investigación que difiere notablemente de la mayoría de las otras investigaciones clínicas, pues la mayoría de ellos son personas vulnerables económicamente. Este artículo presenta el objetivo de analizar factores bioéticos que inciden en el otorgamiento de incentivos a participantes voluntarios sanos en investigaciones Fase I.

Phase I Clinical Trials are conducted with the participation of healthy volunteers to test the safety and tolerability of pharmaceutical products. In them, participants are exposed to study drug risks without the possibility of direct medical benefit and usually must spend days or weeks at a research site. Incentives such as monetary payments are used to encourage enrollment and compensate participants for their time. These characteristics of Phase I healthy volunteer trials create a research context that differs markedly from most other clinical research, as most of them are financially vulnerable individuals. This paper aims to analyze bioethical factors that influence the granting of incentives to healthy volunteer participants in Phase I research.

Research progress on factors influencing the success rate of ureteral access sheath / 国际外科学杂志

During the operation of flexible ureteroscope, the ureteral access sheath is effectively placed, which accelerates the circulation of fluid in the kidney, thus reducing the pressure in the kidney and enhancing the clarity of the operation field. The success rate of lithotripsy and the risk of postoperative infection depend on the position of the ureteral access sheath. This article reviews the factors affecting the insertion process of the ureteral access sheath and the methods to improve the success rate of the insertion of the ureteral access sheath.

Application of medical failure mode and effect analysis in blood sample management in phase I clinical trials / 中国临床药理学与治疗学

AIM: To explore the application effect of medical failure mode and effect analysis in the blood sample management of phase I clinical trials, and to provide a basis for improving the quality of blood sample management. METHODS: Convenient sampling was used to draw blood samples from healthy subjects in phase I clinical trials as the research objects. According to whether the medical failure mode and effect analysis method was implemented, they were divided into 3 080 control groups and 3 064 observation groups. The unqualified rate of blood samples, the number of unqualified items, the satisfaction of subjects and the passing rate of the researcher's examination between the two groups were compared. RESULTS: The unqualified rate of blood samples in the control group was 1.95%, and the unqualified rate of blood samples in the observation group was 0.59%. The difference between the two groups was statistically significant (P<0.05). The number of unqualified items in the blood samples of the observation group was lower than that of the control group, and the difference between the two groups was statistically significant (P<0.05). The satisfaction of subjects in the observation group and the passing rate of the investigator were higher than those in the control group, and the difference between the two groups was statistically significant (P<0.05). CONCLUSION: The implementation of medical failure mode and effect analysis not only provides qualified biological samples for the detection and analysis of drug concentration in clinical trials, but also enhances the standardization and specialization of researchers, and contributes to the improvement of the overall quality of clinical trials.

Risk management of biological agents in phase I clinical trials: Case sharing / 中国临床药理学与治疗学

To point out the importance of risk management for biological agents in phase I clinical trials, taking a healthy subject for an example who suffered from agranulocytosis after the application of Tozumab. In order to ensure the safety of the subjects and smooth progress of clinical trials, risk management should be implemented in several aspects such as: informing, screening, administration, subject training, and adverse event management and so on.

A novel model-assisted design in phase I clinical trials: Bayesian optimal interval design / 中国临床药理学与治疗学

AIM: To introduce a novel and flexible model-assisted design for Phase I clinical trials: Bayesian optimal interval (BOIN) design, including the process of implementation, practical implementation, and evaluation of its performance. METHODS: BOIN design decides dose escalation/de-escalation by comparing the observed toxicity rate at the current dose with an escalation boundary and a de-escalation boundary that are optimized to minimize the probability of making incorrect decision of dose assignment. The application of the BOIN design is illustrated using a trial example. RESULTS: BOIN combines the advantages of the algorithm-based methods and model-based methods. It enjoys desirable statistical properties -it is optimal, safe, robust and easy to implement. Simulation study shows that the BOIN substantially outperforms the existing designs with higher accuracy to identify the maximum tolerated dose (MTD). CONCLUSION: BOIN design possesses the similar statistical performance to the much more complicated model-based designs. It is simple to implement, and easy to calibrate to meet the safety requirement mandated by regulatory agents. The BOIN design has been widely used in different types of cancers. It is a novel design that holds great potential to substantially improve phase I trials in China.

Referral pattern of periodontal disease among general dental practitioners in Iraq / Padrão de referência da doença periodontal entre os clínicos odontológicos gerais no Iraque

Objectives: To evaluate the type of "periodontal treatment" performed by general dental practitioners and the referral patterns of periodontists in Iraq. Material and methods: A total of 201 general dentists were asked to complete a self-administered questionnaire consisting of nine questions regarding periodontal treatment and the referral patterns of periodontists. Results: The study showed that 91.1% of general dental practitioners (GDPs) performed "phase-I therapy", and most of them done "scaling". Regarding surgical periodontal therapy, only 12.9% of them performed surgical periodontal therapy, half of the GDPs did gingivectomy, and less than 30% performed crown lengthening. When evaluating maintenance therapy after periodontal treatment, it was found that 77.9% of the GDPs scheduled appointments for patients in the maintenance phase, 49.4% of them after one month, 24.7% after three months, and 15.6% after six months. Using TRUF analysis, most general dentists believed that the patient and periodontal factors were responsible for the recurrence of periodontal disease. Conclusions: There is still a lack of awareness of periodontal surgical procedures among the "general dental practitioners". Thus, it is essential to increase the comprehension of periodontal treatment among general dentists. (AU)

Objetivo: Avaliar o tipo de "tratamento periodontal" realizado por dentistas generalistas e os padrões de encaminhamento aos periodontistas, no Iraque. Material e métodos: Um total de 201 dentistas generalistas preencheram um questionário autoaplicável que consistiu em nove perguntas sobre o tratamento periodontal e os padrões de encaminhamento para periodontistas. Resultados: O estudo mostrou que 91,1% dos dentistas gerais (DG) realizavam "terapia fase I" e a maioria realizava "raspagem". Em relação à terapia periodontal cirúrgica, apenas 12,9% deles realizavam, sendo que metade dos DG realizavam gengivectomia e menos de 30% realizavam aumento de coroa clínica. Ao avaliar a terapia de manutenção após o tratamento periodontal, constatou-se que 77,9% dos DGs agendaram consultas para pacientes em fase de manutenção, sendo 49,4% após um mês, 24,7% após três meses e 15,6% após seis meses. Usando a análise TRUF, a maioria dos dentistas gerais acredita que o paciente e os fatores periodontais são responsáveis pela recorrência da doença periodontal. Conclusões: Ainda existe um desconhecimento dos procedimentos cirúrgicos periodontais entre os "dentistas generalistas". Assim, é essencial aumentar a compreensão do tratamento periodontal entre os cirurgiões-dentistas gerais (AU)

Metabolism of saponins from traditional Chinese medicines: a review / 药学学报

Saponins are important components in traditional Chinese medicine (TCM) with significant biological activities, which could be divided into triterpenoid saponins and steroidal saponins according to structures of the aglycone skeletons. This article reviews the in vivo metabolic pathways of some typical natural saponins such as ginsenosides, licorice saponins, saikosaponins, timosaponins and diosgenin glycosides. Saponins often show poor absorbance after oral administration. The in vivo metabolism of saponins generally contain two steps. These compounds usually undergo hydrolysis in stomach and gut. Then they are absorbed into blood and metabolized in liver. The secondary glycosides and the aglycones produced in gastrointestinal tract often show higher bioavailability and better bioactivity, while downstream metabolites in liver are mainly produced by phase I metabolism. Clarification of the in vivo metabolism of bioactive saponins is helpful for the understanding of the effective ingredients in TCM, as well as the discovery of new drugs from natural products.

An open-label, multicenter, phase I trial of a cremophor-free, polymeric micelle formulation of paclitaxel combined with carboplatin as a first-line treatment for advanced ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG-3016) / 부인종양

OBJECTIVE: This phase I study aimed to determine the maximum tolerated dose (MTD) of Genexol-PM, when combined with carboplatin, as a first-line treatment in patients with advanced ovarian cancer. METHODS: This open-label, multicenter, phase I, dose-escalation study included 18 patients (median age: 59.0 years, range: 40–75 years) diagnosed with advanced epithelial ovarian cancer. All patients had measurable residual disease after debulking surgery. Patients were assigned to groups (n=6 each group) that received different doses of Genexol-PM (220, 260, and 300 mg/m², once every 3 weeks) and 5 area under the curve (AUC) carboplatin. Safety and efficacy were analyzed for each dose group. RESULTS: In this intention-to-treat population, 3 out of 18 patients dropped out of the study: 1 due to dose-limiting toxicity (DLT), 1 due to hypersensitivity, and 1 was lost during follow-up. DLTs were not reported at 220 mg/m² or 260 mg/m², but at 300 mg/m², 1 patient experienced DLT (grade 3 general pain). The MTD of Genexol-PM was not determined, but a dose of 300 mg/m² or less could be recommended for the phase II study. Most patients (73.9%) with adverse events recovered without sequelae, and no death occurred that was related to the disease or treatment. The best overall response rate was 94.1%. CONCLUSION: Genexol-PM combined with carboplatin was well tolerated as a first-line treatment, and good responses were observed in patients with advanced ovarian cancer. Based on these results, we recommended a dose of 300 mg/m² or less for a phase II study.

Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. MATERIALS AND METHODS: This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. RESULTS: PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. CONCLUSION: The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

Influence of drug metabolizing enzyme inhibitors on liver injury susceptibility to trans-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside / 药学学报

By using the drug metabolizing enzyme inhibitors, the effects of metabolic factors on potential liver injury induced by the main component, trans-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside(trans-SG), in Polygonum multiflorum was investigated. The main metabolic enzyme isoforms involved in trans-SG metabolism were also screened. The results showed that trans-SG at the dosage 31 mg·kg-1 did not cause liver injury; and the combination of trans-SG with the phase I metabolic enzyme inhibitor, 1-benzylimidazole (10 mg·kg-1), did not change the degree of liver injury(compared with LPS + trans-SG group, P > 0.05). However, the combination of trans-SG with phase II metabolic enzyme inhibitor, ketoconazole(35 mg·kg-1), significantly increased the degree of liver injury(compared with LPS + trans-SG group, P < 0.05). The phase I metabolites of trans-SG were not detected in human liver microsomes phase I metabolism system, while the phase II trans-SG metabolites were detected in recombinant human UGT isozymes phase II metabolism system. Six isoforms of uridine diphosphate glucuronate transferase(UGT)exhibited abilities to metabolize trans-SG and the order of metabolic ability was: UGT1A1 > UGT1A9 > UGT1A7 > UGT1A10 > UGT2B7 > UGT1A8. The results showed that trans-SG was mainly metabolized by UGT in phase II metabolism. The inhibition of drug metabolizing enzymes of phase II can increase the liver injury susceptibility of trans-SG, which provides a reference to the evaluation of susceptible factors and drug incompatibility research of Polygonum multiflorum.

Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1. RESULTS: Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m2/day (n=3), 2 mg/m2/day (n=3), 3.3 mg/m2/day (n=3), 5 mg/m2/day (n=3), 7 mg/m2/day (n=3), 9 mg/m2/day (n=6), and 12 mg/m2/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m2/day. The MTD was determined as 12 mg/m2/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). CONCLUSION: This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m2/day on D1 and D8 every 3 weeks.

Screening study for genetic polymorphisms affecting pharmacokinetics of pioglitazone

Pioglitazone is known to have antidiabetic effects through decreasing peripheral, hepatic and vascular insulin resistance by the stimulation of PPAR gamma. To address the possible genetic factors affecting the pharmacokinetics (PK) of pioglitazone, 27 male Korean volunteers were enrolled from two separate bioequivalence studies. Each subject was administered 15 mg pioglitazone and reference drug PK parameters were used. We used Illumina Human610 Quad v1.0 DNA Analysis BeadChip for whole genome SNPs analysis and whole genome genotyping data was processed by linear regression analysis for PK parameters. We found 35 significant SNPs (P < 0.0001) in C(max), 1,118 significant SNPs (P < 0.0001) in T(max) and 1,259 significant SNPs (P < 0.0001) in AUC(inf) from whole genome analysis. For clinical pharmacological purpose, we selected SNPs from several phase I and II drug metabolizing enzyme and analyzed PK parameters with genotypes. Four SNPs (rs7761731 and rs3799872 from CYP39A1; rs156697 from GSTO2; rs1558139 from CYP4F2) showed significant associations with pioglitazone C(max). In the T(max) group, seven SNPs from 3 genes (rs3766198 from CYP4B1; rs2270422 from GSTZ1; rs2054675, rs10500282, rs3745274, rs8192719, and rs11673270 from CYP2B6) had significant associations. In the AUC(inf) group, seven SNPs from 4 genes (rs11572204 from CYP2J2; rs4148280 from UGT2A1, rs4646422 from CYP1A1; rs3745274, rs8192719, rs11673270, and rs707265 from CYP2B6) showed significant associations with pioglitazone absorption. These results showed that genetic makeup could affect the PK parameters and these informations could be provide information for personalized pioglitazone therapy.

Immunogenicity and Safety of Trivalent Split Influenza Vaccine in Healthy Korean Adults with Low Pre-Existing Antibody Levels: An Open Phase I Trial

PURPOSE: A phase I clinical trial was conducted to evaluate the immunogenicity and safety of newly developed egg-cultivated trivalent inactivated split influenza vaccine (TIV) in Korea. MATERIALS AND METHODS: The TIV was administered to 43 healthy male adults. Subjects with high pre-existing titers were excluded in a screening step. Immune response was measured by a hemagglutination inhibition (HI) assay. RESULTS: The seroprotection rates against A/California/7/2009 (H1N1), A/Perth/16/2009 (H3N2) and B/Brisbane/60/2009 were 74.42% [95% confidence interval (CI): 61.38–87.46], 72.09% (95% CI: 58.69–85.50), and 86.05% (95% CI: 75.69–96.40), respectively. Calculated seroconversion rates were 74.42% (95% CI: 61.38–87.46), 74.42% (95% CI: 61.38–87.46), and 79.07% (95% CI: 66.91–91.23), respectively. There were 25 episodes of solicited local adverse events in 21 subjects (47.73%), 21 episodes of solicited general adverse events in 16 subjects (36.36%) and 5 episodes of unsolicited adverse events in 5 subjects (11.36%). All adverse events were grade 1 or 2 and disappeared within three days. CONCLUSION: The immunogenicity and safety of TIV established in this phase I trial are sufficient to plan a larger scale clinical trial.

Application of PDCA method in improving quality system of phase I labs / 中国药学杂志

OBJECTIVE: To describe the continuous improvement process of the quality system of phase I labs by using (plan-do-check-action) PDCA method. METHODS: Considering the particular characteristics of phase I labs, PDCA cycle was applied to the quality management system as well as the research programs. RESULTS: As a quality management tool, PDCA method holds the same goal as ISO 17025 system, that is, to improve the management system of phase I labs. CONCLUSION: PDCA method is very useful in helping phase I labs achieve the quality goals, which, as a result, can ensure the accuracy and reliability of the research results.

Perioperative nursing of phase I breast reconstruction surgery during modified radical mastectomy / 现代临床护理

Objective Investigate the nursing process of phase I breast reconstruction surgery during modified radical mastectomy. Method Given psychological care, diet and preparation before operation; and flap care, wound care, exercise and complications care after operation on 82 patients of phase I breast reconstruction surgery during modified radical mastectomy . Results All 82 patients finished the operations successfully. The average of postoperative appearance evaluation scores are good. One case of bleeding, infection and prosthetic capsular contracture, and two cases of limb swelling were all cured. Conclusion Nursing processes of psychological care, diet and preparation before operation will help the ongoing of the operation, and nursing processes of flap, wound, exercise and complications care will guarantee the success of the operation of phase I breast reconstruction surgery during modified radical mastectomy.

Ethical Issues in the Recruitment of Subjects during Phase I Clinical Trial / 中国医学伦理学

Subject recruitment is an important part of clinical researches. It should follow the ethical principles of fairness and representativeness. The recruitment process should pay attention to protecting the privacy of sub-jects. Various recruitment materials must be approved by the ethics committee before use. Whether could recruit el-igible subjects during Phase I clinical trials will have a significant impact on the results, which should attract the relevant persons′attention including the ethics committee, researchers, clinical research associate and the sponsor.

Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively. RESULTS: Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression. CONCLUSION: This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.

Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination. MATERIALS AND METHODS: Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months. CONCLUSION: In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

Assessment of statistical power for covariate effects in data from phase I clinical trials

One of the important purposes in population pharmacokinetic studies is to investigate the relationships between parameters and covariates to describe parameter variability. The purpose of this study is to evaluate the model's ability to correctly detect the parameter-covariate relationship that can be observed in phase I clinical trials. Data were simulated from a two-compartment model with zero-order absorption and first-order elimination, which was built from valsartan's concentration data collected from a previously conducted study. With creatinine clearance (CLCR) being used as a covariate to be tested, 3 different significance levels of 0.001

Strategy discussion of strengthening ECG monitoring in phase I clinical trials of investigational new drugs / 中国药学杂志

OBJECTIVE: To discuss the strategy of strengthening ECG monitoring in phase I study and to provide references for the necessity of thorough QT/QTc study and for the subsequent development strategies. METHODS: Relevant progresses in cardiac safety studies and guidelines of QT/QTc study were referred to in discussing the study strategy. RESULTS: The applicable scope, protocol design and quality control of the strengthening ECG monitoring study have been preliminarily explored. CONCLUSIONS: Based on the phase I clinical trials, cardiac safety of the new drugs is preliminarily evaluated and screened, without increasing drug exposure, and this study during phase I clinical trial will provide basis and reference for the further QT/QTc trial.