Analysis And Rationale On The Design And Amendment Of Phase Ⅱ Clinical Trial Protocol Of Tetramethylpyrazine Nitrone Tablets In The Treatment Of Diabetic Kidney Disease

Background:Diabetic kidney disease(DKD)is a type of chronic kidney disease(CKD)caused by diabetes and a leading cause of end-stage renal disease(ESRD).The rising tendency of the global prevalence of diabetes means that the population at risk of DKD is increasing.DKD is a heterogeneous disease in terms of clinical manifestations,pathophysiology,and disease progression,so there are few drugs currently used for DKD treatment with limited efficacy,and DKD patients still need effective treatment drugs.Tetramethylpyrazine nitrone(TBN)tablets is an innovative class 1 chemical drug developed by the research group,which can protect against renal cell damage by removing free radicals in renal cells and improving mitochondrial function,significantly reducing urinary albumin in DKD rats,and improving renal function.In recent years,the number of drugs approved for DKD indications in China has been increasing,which means that more and more DKD trials will be carried out.However,there are currently no technical guidelines for chemical drugs used in DKD clinical research at home and abroad.Purpose:Review and analyze the design of the existing DKD clinical trial plan,and design the protocol of TBN tablet for DKD Phase Ⅱ clinical trial based on the drug characteristics of TBN tablet.Furthermore,combined with the problems encountered in clinical practice,the protocol design was revised to provide a reference for the design of clinical trial protocols of other DKD drugs or the design of technical guidelines for future clinical studies of chemotherapy for DKD.Methods:Through a literature review of major databases,this study summarizes the characteristics of DKD and the mechanism of action of relevant therapeutic drugs,and lists and analyzes the key design points of the relevant clinical trial protocol through the clinical trial registration platform.Then,based on the actual implementation of clinical trials,the design points and revision process of the TBN tablets DKD phase Ⅱ protocol were comprehensively analyzed,and the basic ideas and key points of the design of the protocol were summarized.and summarize some central and overall trials before and after the protocol revision.The enrollment progress was compared to quantify the impact of the protocol revision on the trial progress.Results:In reference to the design of 37 other DKD drug clinical trial protocols and TBN tablet protocols,the design of DKD drug clinical trial protocols first needs to clarify the clinical orientation of the drugs under study.It is suggested to improve DKD-related bioindicators as outcome indicators in phase Ⅱ trials.For example,urinary albumin-to-creatinine ratio(UACR),24-hour urine protein content,etc.Phase ⅡI confirmatory trials can delay or prevent disease progression of DKD as the endpoint,for example,the time of progression to ESRD and reduction of e GFR by 30%.According to the existing drug clinical trials and regulatory guidelines of DKD,the duration of phase Ⅱ trials is generally designed to be 3-6 months,preferably over 6 months of the treatment cycle.The median follow-up period for phase ⅡI trials is generally between 20 and 60 months.DKD clinical trials are mainly based on the urinary albumin?to?creatinine ratio(UACR)and/or estimated glomerular filtration rate,e GFR)as the primary outcome variable.The inclusion range of UACR and e GFR can be determined according to the clinical orientation of the drug under study.Patients with UACR of 30-300 mg/g and e GFR≥60 m L/min/1.73m~2can be selected for the mild DKD clinical trial.Subjects with UACR of 300-3000 mg/g and e GFR≥30 m L/min/1.73m~2can be selected for the treatment of moderate and severe DKD clinical trials.DKD trial generally excludes patients with severe liver and kidney dysfunction.In addition,it is recommended to use related scales of stroke,diabetic foot,and cardiovascular disease to define the severity of disease,to achieve accurate exclusion.Currently,DKD clinical trials are mainly placebo-controlled.ACEI/ARB is generally recommended as the basic treatment.According to the actual treatment situation of patients,it is determined whether to be prescribed as a basic drug and can continue during the trial if the conditions are met.The revision of the Phase Ⅱa and Ⅱb protocol of TBN for the treatment of DKD increased the trial enrollment progress by 191.43%and 26.87%respectively,which effectively accelerated the trial progress while taking into account the scientific nature.Conclusion:According to literature and case analysis,DKD drug clinical trial should determine the main outcome variables,administration period,main inclusion criteria,and concomitant medication according to the clinical development orientation and mechanism of drugs.Meanwhile,At the same time,the design of trail protocol must be scientific and operable.