ChiCTR2000032392 版本V1.4 版本创建时间2021/07/02 02:09:47 中国临床试验注册中心

审核状态：

Project audit state：

通过审核

Successful

注册号：

Registration number：

 ChiCTR2000032392 

最近更新日期：

Date of Last Refreshed on：

 2020-04-27 08:56:48 

注册时间：

Date of Registration：

 2020-04-27 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

聚苯乙烯磺酸镧散

Public title：

Lanthanum Polystyrene Sulphonate Powder

注册题目简写：

English Acronym：

研究课题的正式科学名称：

评价聚苯乙烯磺酸镧散在慢性肾脏病高磷血症患者中单中心、多剂量、多次给药的耐受性、药效学和药代动力学 Ⅰb/Ⅱa 期临床试验

Scientific title：

Evaluation of Lanthanum Polystyrene Sulphonate Powder in patients with chronic kidney disease (CKD) and hyperphosphatemia,single centers，multi-dose,tolerance, pharmacodynamic and pharmacokinetic Ib/II a phase of clinical trials

研究课题代号(代码)：

Study subject ID：

在二级注册机构或其它机构的注册号：

The registration number of the Partner Registry or other register：

申请注册联系人：

张丽美 

研究负责人：

温晓艳 

Applicant：

Limei Zhang 

Study leader：

Xiaoyan Wen 

申请注册联系人电话：

Applicant telephone：

 +86 13842088563

研究负责人电话：

Study leader's
telephone：

+86 18704019565

申请注册联系人传真 ：

Applicant Fax：

研究负责人传真：

Study leader's fax：

申请注册联系人电子邮件：

Applicant E-mail：

 zhanglimei@nkbp.com

研究负责人电子邮件：

Study leader's E-mail：

 wenxiaoyan@nkbp.com

申请单位网址(自愿提供)：

Applicant website(voluntary supply)：

研究负责人网址(自愿提供)：

Study leader's website(voluntary supply)：

申请注册联系人通讯地址：

辽宁省沈阳市浑南新区南屏东路18-1号

研究负责人通讯地址：

辽宁省沈阳市浑南新区南屏东路18-1号

Applicant address：

18-1 Nanping Road East, Hunnan New District, Shenyang, China

Study leader's address：

18-1 Nanping Road East, Hunnan New District, Shenyang, China

申请注册联系人邮政编码：

Applicant postcode：

研究负责人邮政编码：

Study leader's postcode：

申请人所在单位：

辽宁远大诺康生物制药有限公司

Applicant's institution：

Liaoning Grand Nuokang Biopharmaceuticcal Co.,LTD

研究负责人所在单位：

辽宁远大诺康生物制药有限公司

Affiliation of the Leader：

Liaoning Grand Nuokang Biopharmaceuticcal Co.,LTD

是否获伦理委员会批准：

是

Approved by ethic committee：

Yes

伦理委员会批件文号：

Approved No. of ethic committee：

 20Y047-001

伦理委员会批件附件：

Approved file of Ethical Committee：

 查看附件View

批准本研究的伦理委员会名称：

吉林大学第一医院伦理委员会

Name of the ethic committee：

Ethic Committee of The First Hospital of Jilin University

伦理委员会批准日期：

Date of approved by ethic committee：

 2020-04-09 00:00:00

伦理委员会联系人：

赵丽媛

Contact Name of the ethic committee：

Liyuan Zhao

伦理委员会联系地址：

吉林省长春市新民大街71号

Contact Address of the ethic committee：

71 Xinmin Street, Changchun, Jilin, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

伦理委员会联系人邮箱：

Contact email of the ethic committee：

研究实施负责（组长）单位：

吉林大学第一医院

Primary sponsor：

The First Hospital of Jilin University

研究实施负责（组长）单位地址：

吉林省长春市新民大街71号

Primary sponsor's address：

71 Xinmin Street, Changchun, Jilin, China

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

中国

省(直辖市)：

辽宁

市(区县)：

沈阳

Country：

China

Province：

Liaoning

City：

Shenyang

单位(医院)：

远大生命科学（辽宁）有限公司

具体地址：

辽宁省沈阳市浑南新区南屏东路18-1号

Institution
hospital：

Grand Life Science (Liaoning) Co.,LTD

Address：

18-1 Nanping Road East, Hunnan New District, Shenyang, China

经费或物资来源：

国家卫生计生委医药卫生科技发展研究中心

Source(s) of funding：

Development Center for Medical Science & Technology National health and family planning commission of the People's Republic of China

研究疾病：

高磷血症  

Target disease：

Hyperphosphatemia

研究疾病代码：

Target disease code：

研究类型：

干预性研究

Study type：

Interventional study

研究所处阶段：

 I期+II期 

Study phase：

1-2

研究设计：

随机平行对照 

Study design：

Parallel 

研究目的：

评价聚苯乙烯磺酸镧散在慢性肾脏病高磷血症患者中多剂量、多次给药的耐受性； 评价聚苯乙烯磺酸镧散在慢性肾脏病高磷血症患者中的药效学； 评价聚苯乙烯磺酸镧散在慢性肾脏病高磷血症患者中多剂量、多次给药的药代动力学。  

Objectives of Study：

To evaluate the tolerance of lanthanum polystyrene sulfonate powder in patients with chronic kidney disease and hyperphosphatemia with multi-dose and multi-dose . To evaluate the pharmacodynamics of lanthanum polystyrene sulfonate in patients with chronic kidney disease and hyperphosphatemia. To evaluate the pharmacokinetics of lanthanum polystyrene sulfonate powder in patients with chronic kidney disease and hyperphosphatemia with multiple doses and multiple doses.

药物成份或治疗方案详述：

药物成分聚苯乙烯磺酸镧，本研究共设置4个递增剂量组，每个剂量组12例受试者，8例服用试验药，2例服用安慰剂，2例服用阳性对照药碳酸镧；各剂量组组服用试验药及安慰剂受试者每次给药剂量分别为1.5 g、3 g、4.5 g、6g，服用阳性对照药碳酸镧受试者每次给药剂量为0.5mg；各组受试者在D1早上进餐条件下给药1次，D2-D10进餐条件下连续给药，3次/天，午餐时间为早餐后4 h，晚餐时间为早餐后10 h，服药时间为开始进餐30min后，在D11早上进餐条件下给药1次（后续组别给药时间根据第一组药效而调整）。每个剂量组首次给药后D2、D5、D8、D11、D15进行耐受性评价。在试验过程中将在方案计划的时间点对受试者进行尿样和血样采集，用于药效和药代动力学分析。由于聚苯乙烯磺酸镧散尚未在慢性肾脏病高磷血症患者中应用，无患者PK参数作参考，本研究将采用哨兵入组方式，同一剂量组首先入组2例受试者给予试验药物聚苯乙烯磺酸镧散，观察96 h后入组剩余受试者，剩余受试者按照3：1：1（6例服用试验药物，2例服用阳性对照药物，2例服用安慰剂）的比例随机服用试验药物、阳性对照组（阳性对照组仅参与随机，不参与设盲）或者安慰剂；不同剂量组的受试者依次入组，前一组结束后，将根据耐受性结果以及药代动力学特征决定是否开展更高剂量组的多次给药研究。 

Description for medicine or protocol of treatment in detail：

Lanthanum Polystyrene Sulphonate In this study, 4 increasing dose groups were set up, 12 subjects in each dose group, 8 subjects taking the Lanthanum Polystyrene Sulphonate Powder, 2 subjects taking the placebo, 2 subjects taking the positive control drug lanthanum carbonate; Each dose of Lanthanum Polystyrene Sulphonate Powder and placebo was 1.5 g, 3 g, 4.5 g and 6g, respectively. Each dose of positive control lanthanum carbonate was 0.5mg.The subjects in each group were given once under the dining condition of D1 morning, and continuously under the dining condition of D2-D10, 3 times / day, the lunch time was 4 hours after breakfast, and the dinner time was 10 hours after breakfast, The administration time was 30 minutes after the beginning of the meal, and was given once in the morning of D11 (the administration time of the following groups was adjusted according to the efficacy of the first group). The tolerance of D2, D5, D8, D11 and D15 was evaluated after the first administration in each dose group. During the trial, urine and blood samples will be collected from the subjects at the planned time point for pharmacodynamic and pharmacokinetic analysis.Because polystyrene sulfonic acid lanthanum powder has not been applied in the patients with chronic kidney disease (CKD) hyperphosphatemia, no patients pharmacokinetic parameters for reference, this study will adopt 2 sentry into the group, the same dose group into the first group of 2 cases of polystyrene sulfonic acid lanthanum subjects to test drugs, observation group into the remaining subjects after 96 h, the remaining participants according the ratio of 3:1:1 (6 cases of experimental drugs, 2 cases of positive control drugs , 2 cases with placebo) random test drugs, positive control group (positive control group only participate in random, not participate in blind) or a placebo. Subjects of different dose groups were enrolled in turn. After the end of the previous group, multiple dosing studies of the higher dose group were determined based on tolerance results and pharmacokinetic characteristics. 

纳入标准：

1)试验前签署知情同意书、并对试验内容、过程及可能出现的不良反应充分了解；
2)能够按照试验方案要求完成研究，能够接受饮食管理，在试验期间统一低蛋白饮食；
3)受试者（包括伴侣）愿意自筛选至最后一次研究药物给药后6个月内自愿采取有效避孕措施，具体避孕措施见附录4；
4)年龄为18～65岁男性和女性受试者（包括18岁和65岁）；
5)男性受试者体重不低于50公斤、女性受试者体重不低于45公斤。BMI＝体重（kg）/身高2（m2），体重指数在18~30 kg/m2范围内（包括临界值）；
6)慢性肾脏病高磷血症患者，且两次空腹1.78mmol/L≤血磷≤2.26mmol/L。

Inclusion criteria

1) Sign the informed consent before the trial, and fully understand the test content, process and possible adverse reactions;
2) be able to complete the study according to the requirements of the trial protocol, be able to accept diet management, and unify the low-protein diet during the experimental period;
3) subjects (including partners) are willing to voluntarily take effective contraceptive measures within 6 months from the screening to the last study drug administration, the specific contraceptive measures are shown in appendix 4;
4) male and female subjects aged from 18 to 65 years (including 18 years and 65 years);
5) the weight of male subjects shall not be less than 50 kg, and that of female subjects shall not be less than 45 kg.BMI = weight (kg)/height 2( m2), BMI in the range of 18 to 30 kg/m2 (including the critical value);
6) patients with chronic kidney disease with hyperphosphatemia, the fasting blood phosphorus value for two times blood phosphorus 1.78mmol/L to 2.26mmol/L.

排除标准：

1)有临床意义的药物过敏史或特应性变态反应性疾病史（哮喘、荨麻疹、湿疹性皮炎）或已知对试验用药或类似试验用药的药物过敏；
2)筛选前6个月内有严重外伤或接受过重大手术，或计划在试验期间接受手术者；
3)在筛选前3个月内献血或大量失血（> 450 mL）；
4)存在活动性结核（TB）临床、影像学或实验室检查证据者；
5)试验前3个月每日吸烟量多于5支者；
6)有吸毒和/或酗酒史（每周饮用14个单位的酒精：1单位=啤酒285 mL，或烈酒25 mL，或葡萄酒100 mL）；
7)慢性肾脏病原发病为糖尿病肾病、痛风相关性肾病、自身免疫性疾病及结缔组织病（如系统性红斑狼疮、ANCA相关性血管炎、抗GBM病、过敏性紫癜、原发性干燥综合征、硬皮病等）者；既往已行肾移植手术者；
8)合并需要激素类药物（包括糖皮质激素、性激素）治疗或试验过程中可能需要激素治疗疾病者；
9)有吞咽困难或任何影响药物吸收的胃肠道疾病史；
10)患有任何增加出血性风险的疾病，如痔疮、急性胃炎或胃及十二指肠溃疡等；
11)控制不佳的高血压，静息时测量收缩压≥160 mmHg和（或）舒张压≥100 mmHg，最多复查两次确认；
12)筛选前12个月内急性冠状动脉综合征（如心肌梗死、不稳定心绞痛住院），或经皮冠状动脉介入，或冠状动脉旁路移植术治疗史；或筛选前12个月内有动/静脉血栓事件，如脑血管意外（包括卒中或短暂性脑缺血发作史）、深静脉血栓及肺栓塞等；
13)不受控制的严重心律失常，如复发性和高度症状性室性心动过速，心房颤动伴快速心室反应或室上性心动过速，且入组前的12个月未经药物或其他治疗方式控制；
14)不稳定的严重的消化系统、呼吸系统、精神神经系统、内分泌系统、血液系统、恶性肿瘤等疾病，由研究医生判断不适合参加试验者；
15)筛选前1月内急性或严重感染病史者；
16)顽固性便秘及严重腹泻者；
17)在筛选前14天内服用降磷药物，如碳酸镧、碳酸钙、醋酸钙、氢氧化铝、司维拉姆；对镧离子释放可能有影响的药物，如质子泵抑制剂；影响药物排泄的药物，如大黄类、山梨醇及含阳离子的泻药等；以及对合并用药有影响的药物，如盐酸环丙沙星、甲状腺素、锂剂等；
18)筛选前1周内服用肾衰宁、海昆肾喜胶囊、尿毒清、开同（复方α酮酸）等降毒素药物者；
19)在服用研究用药前3个月内参加过任何药物或医疗器械的临床试验者；
20)血红蛋白≤80g/L；白蛋白≤25g/L；
21)高钙血症，血钙≥2.52 mmol/L；低钙血症，血钙≤1.80mmol/L （血钙白蛋白校正：校正血钙值mmol/L=钙测定值mmol/L+0.02×（40g/L-血白蛋白测定值g/L））；
22)严重甲状旁腺功能亢进，甲状旁腺激素（PTH）> 1200 pg/mL；
23)除慢性肾脏病原发病或并发症相关实验室检测值外，经研究者判断异常且有临床意义者；
24)女性受试者在筛查期或基线期血妊娠结果阳性者；
25)乙型肝炎病毒表面抗原（HBsAg）阳性且HBV DNA大于检测值上限者，丙型肝炎病毒（HCV）抗体阳性且HCV RNA大于检测值上限者；艾滋病抗原/抗体阳性者；梅毒螺旋体抗体阳性且快速血浆反应素（RPR）试验阳性者；
26)有美国纽约心脏病学会（NYHA）定义III-IV心力衰竭病史，或左室射血分数小于50%；
27)研究者认为具有其他不适宜参加本试验因素的受试者。

Exclusion criteria：

1) clinically significant history of drug allergy or atopic allergic disease (asthma, urticaria, eczematous dermatitis) or known allergy to experimental drugs or similar experimental drugs;
2) Severe trauma or major operation within 6 months before screening, or planned operation during the trial;
3) Blood donation or massive blood loss (> 450 ml) within 3 months before screening;
4) There are clinical, imaging or laboratory evidence of active tuberculosis (TB);
5) More than 5 cigarettes per day were smoked 3 months before the experiment;
6) Have a history of drug and / or alcohol abuse (14 units of alcohol per week 1 unit = 285 ml of beer, or 25 ml of spirits, or 100 ml of wine);
7) patients with chronic kidney disease (CKD) are diabetic nephropathy, gout related nephropathy, autoimmune diseases and connective tissue diseases (such as systemic lupus erythematosus, ANCA related vasculitis, anti GBM disease, allergic purpura, primary Sjogren's syndrome, scleroderma, etc.); patients who have had kidney transplantation before;
8) Patients who need hormone drugs (including glucocorticoids and sex hormones) or may need hormone therapy during the trial;
9) Have a history of dysphagia or any gastrointestinal disease affecting drug absorption;
10) Suffer from any disease that increases the risk of bleeding, such as hemorrhoids, acute gastritis or gastric and duodenal ulcer;
11) The systolic blood pressure >=160 mmHg and (or) diastolic blood pressure >=100 mmHg were measured at rest for poor control of hypertension, review at most twice to confirm;
12) Acute coronary syndrome within 12 months before screening (such as myocardial infarction, unstable angina pectoris in hospital), percutaneous coronary intervention, or Treatment history of coronary artery bypass grafting ,or arteriovenous thrombosis events within 12 months before screening, such as cerebrovascular accident (including stroke or transient ischemic attack history), deep vein thrombosis and pulmonary embolism, etc;
13) Uncontrolled severe arrhythmias, such as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response or supraventricular tachycardia, were not controlled by drugs or other treatments 12 months before admission;
14) Unstable and serious diseases such as digestive system, respiratory system, mental nervous system, endocrine system, blood system, malignant tumor, etc. shall be judged by the research doctor as unsuitable for the participants;
15) Patients with acute or severe infection within 1 month before screening;
16) Stubborn constipation and severe diarrhea;
17) Take dephosphorization drugs within 14 days before screening, such as lanthanum carbonate, calcium carbonate, calcium acetate, aluminum hydroxide, and swaram; drugs that may affect the release of lanthanum ions, such as proton pump inhibitors; drugs that affect drug excretion, such as rhubarb, sorbitol, and cathartic drugs containing cations; and drugs that affect the combination of drugs, such as ciprofloxacin hydrochloride, thyroxine Lithium, etc.
18) Those who took Shenshuaining, haikunshenxi capsule, Niaoduqing, Kaitong (compound α - ketoacid) and other toxin-lowering drugs within one week before screening;
19) Those who have participated in clinical trials of any drug or medical device within 3 months before taking the Investigational Product;
20) Hemoglobin <=80g/L; albumin <=25g/L;
21) Hypercalcemia, blood calcium >=2.52 mmol/L; hypocalcemia, blood calcium <=1.80 mmol/L (blood calcium albumin correction: corrected blood calcium value mmol/L = calcium measurement value mmol/L + 0.02x(40 g/L-blood albumin measurement value g/L));
22) Severe hyperparathyroidism, PTH >1200 pg/mL;
23) Except for laboratory test values related to the pathogenesis or complications of chronic kidney disease, researcher judges that it is abnormal and has clinical significance;
24) Female subjects with positive blood pregnancy results in screening or baseline period;
25) Those with HBsAg positive and HBV DNA greater than the upper limit of detection value, those with HCV antibody positive and HCV RNA greater than the upper limit of detection value, those with HIV antigen / antibody positive, those with Treponema pallidum antibody positive and RPR test positive;
26) Have a history of III-IV heart failure defined by NYHA, or left ventricular ejection fraction less than 50%;
27) The researchers believe that there are other subjects who are not suitable for participating in this trial

研究实施时间：

Study execute time：

从 From 2020-04-09 00:00:00至 To 1990-01-01 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2020-05-18 00:00:00 至 To 1990-01-01 00:00:00

干预措施：

Interventions：

组别：

第一组

样本量：

 12

Group：

Group 1

Sample size：

干预措施：

给药剂量：服用试验药和安慰剂受试者给药剂量为每次1.5g，服用对照药受试者给药剂量为每次0.5g；受试者在D1早上给药1次，D2-D12每天给药3次，在D13早上给药1次

干预措施代码：

Intervention：

Dose: 1.5g each time for subjects taking the experimental drug and placebo, and 0.5g each time for subjects taking the control drug；D1 was administered once; D2-D12 was administered three times a day; D13 was administered once;

Intervention code：

组别：

第二组

样本量：

 12

Group：

Group 2

Sample size：

干预措施：

给药剂量：服用试验药和安慰剂受试者给药剂量为每次3.0g，服用对照药受试者给药剂量为每次0.5g；受试者在D1早上给药1次，D2-D12每天给药3次，在D13早上给药1次

干预措施代码：

Intervention：

Dose: 3.0g each time for subjects taking the experimental drug and placebo, and 0.5g each time for subjects taking the control drug；D1 was administered once; D2-D12 was administered three times a day; D13 was administered once;

Intervention code：

组别：

第三组

样本量：

 12

Group：

Group 3

Sample size：

干预措施：

给药剂量：服用试验药和安慰剂受试者给药剂量为每次4.5g，服用对照药受试者给药剂量为每次0.5g；受试者在D1早上给药1次，D2-D12每天给药3次，在D13早上给药1次

干预措施代码：

Intervention：

Dose: 4.5g each time for subjects taking the experimental drug and placebo, and 0.5g each time for subjects taking the control drug；D1 was administered once; D2-D12 was administered three times a day; D13 was administered once;

Intervention code：

组别：

第四组

样本量：

 12

Group：

Group 4

Sample size：

干预措施：

给药剂量：服用试验药和安慰剂受试者给药剂量为每次6.0g，服用对照药受试者给药剂量为每次0.5g；受试者在D1早上给药1次，D2-D12每天给药3次，在D13早上给药1次

干预措施代码：

Intervention：

Dose: 6.0g each time for subjects taking the experimental drug and placebo, and 0.5g each time for subjects taking the control drug；D1 was administered once; D2-D12 was administered three times a day; D13 was administered once;

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 吉林 

市(区县)：

 长春 

Country：

China

Province：

Jilin

City：

Changchun

单位(医院)：

 吉林大学第一医院 

单位级别：

 三甲 

Institution
hospital：

The First Hospital of Jilin University

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

血磷含量

指标类型：

主要指标

Outcome：

phosphate concentrations

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

血镧

指标类型：

主要指标

Outcome：

Plasma lanthanum concentrations

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

24h尿磷含量

指标类型：

次要指标

Outcome：

24h Urinary phosphate concentrations

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

血PTH含量

指标类型：

次要指标

Outcome：

Plasma PTH concentrations

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

血钙含量

指标类型：

次要指标

Outcome：

Plasma calcium concentrations

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

血液

组织：

Sample Name：

blood

Tissue：

人体标本去向

 使用后销毁  

说明

Fate of sample：

Destruction after use  

Note：

标本中文名：

尿液

组织：

Sample Name：

urea

Tissue：

人体标本去向

 使用后销毁  

说明

Fate of sample：

Destruction after use  

Note：

征募研究对象情况：

Recruiting status：

尚未开始

Not yet recruiting

年龄范围：

Participant age：
最小 Min age 18 岁 years
最大 Max age 65 岁 years

性别：

男女均可

Gender：

Both

随机方法（请说明由何人用什么方法产生随机序列）：

受试者的随机号由与本研究无关的独立统计师产生。独立统计师采用SAS 9.4或以上的PLAN过程，用区组随机法生成随机号。本研究采用哨兵入组方式，各剂量组首先入组的2例受试者（接受试验药物聚苯乙烯磺酸镧散）不进行区组随机。对各剂量组剩余后入组的受试者进行区组随机：按照3：1：1（6例服用试验药物，2例服用阳性对照药物，2例服用安慰剂）的分配比例将受试者随机分入聚苯乙烯磺酸镧散组、阳性对照组和安慰剂对照组，男女均可。

Randomization Procedure (please state who generates the random number sequence and by what method)：

The independent statistician used the PLAN process of SAS 9.2 to generate 50 random numbers.

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

不公开/Private

盲法：

未说明

Blinding：

Not stated

是否共享原始数据：

IPD sharing

是Yes

共享原始数据的方式（说明：请填入公开原始数据日期和方式，如采用网络平台，需填该网络平台名称和网址）：

2029.01，纸质

The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：

2029.01，paper

数据采集和管理（说明：数据采集和管理由两部分组成，一为病例记录表(Case Record Form, CRF)，二为电子采集和管理系统(Electronic Data Capture, EDC)，如ResMan即为一种基于互联网的EDC：

Clinflash系统 v4.0.1.01

Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：

Clinflash system, v4.0.1.01

数据与安全监察委员会：

Data and Safety Monitoring Committee：

无/No

注册人：

Name of Registration：

  2020-04-27 08:50:46