Efficacy and Safety of Mudan Granule (Combined With Methylcobalamin) on Type 2 Diabetic Peripheral Neuropathy: A Randomized,Double-blind,Placebo-controlled, Parallel-arm,Multi-center Trial
试验速览
- 阶段
- 早期 1 期
- 发起方
- 入组人数
- 402
- 试验地点
- 1
- 主要终点
- Changes in total score on the Michigan Diabetic Neuropathy Score (MDNS) of Scale
研究概览
简要总结
Background: Diabetic peripheral neuropathy (DPN) is a common and disabling chronic microvascular complications in patients with type 2 diabetic Mellitus (T2DM) that is characterized by nerve damage, affecting at least half of patients diagnosed with diabetes. It has been reported that DPN significantly contributes to the increased morbidity with diabetic foot ulcers by 60% and amputation by 85% that seriously threaten the quality of life. Mudan granule, a traditional Chinese medicinal preparation, is widely used in clinical practice for DPN in China. Evidence from clinical and preclinical studies have shown that Mudan granule could relieve symptoms and reduce the incidence of DPN exacerbations. However, the previous studies are of variable quality and poorly standardized,which limits the clinical application of Mudan granule. This study evaluates the efficacy and safety of Mudan granule combined with methylcobalamin in the treatment of type 2 diabetic peripheral neuropathy, providing the highest level of evidence of Mudan granule.
Methods and design: A randomized, double-blind, placebo-controlled,parallel-arm, and multi-centric clinical trial design was used based on a co-regimen of methylcobalamin. Subjects who met the inclusion criteria were randomly divided into two groups. The patients in the study group were treated with Mudan granule combined with methylcobalamin, and the patients in the control group were treated with placebo combined with methylcobalamin. The total intervention period is 24 weeks. The sample size was 402 cases.
Major evaluation indicators: Michigan Diabetic Neuropathy Score (MDNS) changes, the changes of MDNS were compared between the two groups before and after medication, adopting the evaluation method of difference values. Secondary Evaluation Indicators:(1) nerve conduction velocity changes, the changes in nerve conduction velocity of each nerve were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values. (2)corneal nerve fiber density changes, the changes in corneal nerve fiber density of each mm2 were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values. (3)corneal nerve branch density changes, the changes in corneal nerve branch density of each mm2 were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values. (4)corneal nerve fiber length changes, the changes in corneal nerve fiber length of each mm2 were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values. (5)Toronto Clinical Scoring System (TCSS) changes, the changes of toronto clinical score were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values. (6)Traditional Chinese Medicine(TCM) syndromes efficacy score changes, the changes in TCM syndromes efficacy score were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values. (7) Clinical symptoms score changes, the changes of each of clinical symptoms score were compared between the two groups before and after medication, adopting the evaluation method of difference values.
Discussion: We postulate that patients with type 2 diabetic peripheral neuropathy will benefit from therapy with Mudan granule.
详细描述
- Research objective: To evaluate the efficacy and safety of Mudan granule combined with methylcobalamin in the treatment of type 2 diabetic peripheral neuropathy, providing the highest level of evidence of Mudan granule.
- Experimental Measures and contrast: A randomized, double-blind, placebo-controlled,parallel- arm,and multi-centric clinical trial design was used on the basis of a co-regimen of methylcobalamin.The patients in the study group were treated with Mudan granule (7g 3 times/day for 24 weeks)and patients were treated with placebo (7g 3 times/day for 24 weeks) in the control group.The sample size was determined to 402 cases through statistics calculation.
Sample size calculation basis: According to the previous study of Mudan granule combined with methylcobalamin in the treatment of DPN with 12 weeks intervention, the results of the MDNS indicated that the study group (Mudan granule + methylcobalamin) scale score was 5.48±1.19, and the control group (placebo + methylcobalamin) scale score was 8.21 ±1.24, and the mean difference between the two groups was 2.73;Assuming that Mudan granule combined with methylcobalamin in the treatment of DPN can reduce the MDNS by 0.58 after 12 weeks of intervention, it is considered better than the control group.Taking α=0.05, β=0.10, the study group and the control group with 24 weeks intervention were allocated at a ratio of 1:1. The sample size calculated by the Power Analysis and Sample Size (PASS) 11 software was not less than 167 cases in each group. Considering no more than 20% withdrawal rate, the total number of cases is 402, 201cases in each group. 3. Research design 3.1 This trial was designed as a randomized, double-blind, placebo-controlled,parallel-arm, and multi-centric clinical trial. Subjects who met the inclusion criteria were randomly divided into two groups. The patients in the study group were treated with Mudan granule combined with methylcobalamin , and the patients in the control group were treated with placebo combined with methylcobalamin. The sample size was 402 cases.
3.2 The total intervention period is 24 weeks. 3.3 Curative effect evaluation criteria 3.3.1 Major evaluation indicators Changes in total score on the Michigan Diabetic Neuropathy Score (MDNS) of Scale,MDNS was recorded on the Michigan Diabetic Neuropathy Score of Scale. The changes of MDNS were compared between the two groups before and after medication, adopting the evaluation method of difference values. The total score was 46, ranging from 0 (least severe) to 46 (most severe).
3.3.2 Secondary Evaluation Indicators
- Changes in nerve conduction velocity,the changes in nerve conduction velocity of each nerve were compared between the two groups before and after taking medicine,adopting the evaluation method of difference values.
- Changes in corneal nerve fiber density of each mm2,the changes in corneal nerve fiber density of each mm2 were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values.
- Changes in corneal nerve branch density of each mm2,the changes in corneal nerve branch density of each mm2 were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values.
- Changes in corneal nerve fiber length of each mm2,the changes in corneal nerve fiber length of each mm2 were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values.
- Changes in total score on the Toronto Clinical Scoring System (TCSS) of Scale,toronto clinical score was recorded on the Toronto Clinical Scoring System(TCSS) of Scale. The changes of toronto clinical score were compared between the two groups before and after taking medicine, adopting the evaluation method of difference values. The total score was 19, ranging from 0 (least severe) to 19 (most severe).
- Evaluation criteria of Traditional Chinese Medicine(TCM) syndromes efficacy score
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 30 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Meet the diagnostic criteria of type 2 diabetic peripheral neuropathy.
- •Meet the diagnostic criteria of TCM syndrome differentiation of qi deficiency and collaterals obstruction.
- •The patient's age is between 30-70 years.
- •At least 2 nerve conduction velocities have decreased on electromyography.
- •Sign informed consent.
排除标准
- •Recent use of antioxidants such as vitamin E or vitamin C, acute infection, liver and kidney dysfunction, acute complications of diabetes, severe cardiovascular and cerebrovascular diseases,neuropathy caused by long-term alcohol consumption and other factors.
- •Besides methylcobalamin,the drugs such as alpha lipoic acid, epalrestat, VitB12, Chinese patent medicine and decoction have been used to treat diabetic peripheral neuropathy within 4 weeks before enrollment.
- •Systolic blood pressure > 160 millimeters of mercury (mmHg) or diastolic blood pressure > 100mmHg.
- •Having the diabetic ketoacidosis, ketoacidosis and severe infection within one month.
- •Combined with cardiovascular, liver, kidney and hematopoietic system and other serious primary disease, serum transaminase beyond the normal value more than 2 times, serum creatinine greater than the upper limit of normal, psychiatric patients.
- •Pregnancy, prepared to pregnant or lactating women.
- •Having a history of multiple drug allergies or being allergic to the ingredients of Mudan granule.
- •Participate in other clinical studies within one month.
- •Drinking alcohol excessive and/or taking psychoactive substances, drug abusers and dependents over the past five years.
- •Having a history of active ophthalmopathy,ocular surgery,glaucoma,acute and chronic corneal diseases,extended-wearing contact lens and so on.
研究组 & 干预措施
Mudan granule
Based on the standard medical care, experimental group were treated with Mudan Granule 7g , 3 times/d.
Intervention: Drug: Mudan granule
干预措施: Mudan granule (Drug)
Placebo
Based on the standard medical care, placebo-controlled group were treated with Placebo 7g , 3 times/d Intervention: Drug: Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Changes in total score on the Michigan Diabetic Neuropathy Score (MDNS) of Scale
时间窗: 0,12,24 weeks
MDNS was recorded on the Michigan Diabetic Neuropathy Score of Scale. The changes of MDNS were compared between the two groups before and after medication, adopting the evaluation method of difference values. The total score was 46, ranging from 0 (least severe) to 46 (most severe).
次要结局
- Changes in nerve conduction velocity((0,24 weeks))
- Changes in corneal nerve fiber length of each mm2((0,24 weeks))
- Changes in total score on the Toronto Clinical Scoring System (TCSS) of Scale((0,12,24 weeks))
- Changes in corneal nerve branch density of each mm2((0,24 weeks))
- Changes in total score on the Clinical Symptoms Score of Scale((0,12 ,24 weeks))
- Changes in corneal nerve fiber density of each mm2((0,24 weeks))
- Changes in total score on the Traditional Chinese Medicine(TCM) Syndromes Efficacy Score of Scale((0,4,8,12,16,20,24 weeks))
研究者
Fengmei Lian
chief physician, Professor, endocrinology department of Guang'anmen Hospital of China Academy of Chinese Medical Sciences
Guang'anmen Hospital of China Academy of Chinese Medical Sciences