Clinical Evaluation Of The Safety And Efficacy Of Hv For The Treatment Of Patients With SCA3/MJD

Chapter 1:Study of the Safety and Tolerability of Hv for the Treatment of Patients with SCA3/MJD in Single-doseObjective:To evaluate the safety and tolerability of Hv for the treatment of adult SCA3/MJD patients in single-dose, then to provide reference for multi-dose administration.Methods:It was a single center clinical study based on the principle of randomicity, openness, single dose escalation.12 eligible adult SCA3/MJD patients were screened and divided into 3 groups randomly with each group containing 4 subjects. The subjects were randomly assigned to the following three groups,400 mg,600 mg,800 mg, with each one received only one dose by single oral administration from low dose to high dose in turn. Only the first dose group observation was completed and the drug was confirmed safely resistant, can the experiment turn to the next dose test. We took close observation on the vital signs and ECG of the subjects during the test. The blood, urine, liver and kidney function, blood electrolytes, blood biochemical indicators of the subjects were monitored before and after administration and assess of the adverse drug reactions.Results:The twelve subjects among the three groups, consisted of six men and six women, whose age ranges from 34 to 45 years old (40.42±3.82), with course of disease between 2 and 11 years (6.67±3.39), CAG repeat times of MJD-1 gene between 71 and 80 (74.08±5.09), SARA score between 2 and 11 (17.00±7.62) and ICARS score from 7 to 31 (6.21±2.99), The twelve subjects all complete the test according to the plan, and the detection indexes in each experiment all have no extremely changes after administer medication. There are two subjects each in the 600 mg and 800 mg dosage group have a transient diarrhea symptoms. Considered it’s a light drug adverse reaction, and it’s correlated with medication.Conclusion:Hv is safe in the treatment of SCA3/MJD patients with single oral 400 mg-800 mg.Chapter 2:Research of the safety and efficacy of different doses of Hv for the treatment of SCA3/MJD Patients in multi-doseObjective:To evaluate the the safety and efficacy of different doses of Hv for the treatment of adult SCA3/MJD patients in multi-dose.Methods:It was single-center clinical study based on randomized, double-blind, placebo (PLA)-controlled, dose-controlled principle. Participations consisted of 36 SCA3/MJD patients aged from 18 to 50 years, were randomly divided into three groups of 800mg/day dose group, 1200 mg/day dose group, and the placebo control group, each with 12 subjects. They were treated continuously with Hv oral administration twice a day for 12 weeks. We took close observation on the vital signs and eletro cardio gram (ECG) of each subject, and determined the blood routine, urine routine, hepatic/renal function, serum electrolytes and biochemical etc to evaluate the drug adverse reaction. We also observed the change of the SARA and ICARS scores 12 weeks before and after the Hv administration.Results:there were 36 patients in the research, including 20 males and 16 females, aged 19 to 45 years (36.66±6.08),1 to 16 years course of disease(4.47±2.43). The MJD-I gene with CAG fragment repeat 67-85 times (75.75±3.60), SARA scores 3-18 (10.21±3.69), ICARS sores 7-49 (28.94±9.95). There two of 36 subjects withdraw because of untolerant drug adverse reaction as dizziness and emesis 2 weeks after administer medication (they all in the large dosage group). And it’s count to shedding cases. The rest of 36 subjects all complete the test according to the plan. The expulsion rate is 5.56%. There are 7 in 12 subjects have light adverse reaction in low dosage goupe, and considered there might be 6 cases are correlated with medication by analysis; and there are 11 in 12 subjects have light adverse reaction in large dosage goupe, and considered there might be 10 cases are correlated with medication by analysis. The adverse reaction of dizziness, vomiting and unsteady gait, and the other 34 completed the research, expulsion rate 5.56%. In the completed the research, the main adverse drug reaction include dizziness, lethargy, blurred vision, abdominal distension, anorexia and transient hepatic dysfunction (in 1 case). The demographic dates of the subjects were detected by variance analysis, include age, sex, course of disease, time of CAG repeat, SARA scores and ICARS scores, with no statistics differences in all the three groups. In the low dose group, SARA score changes of the total score before and after the medication had significant differences, as well as the ICARS score changes of the total score (P=0.000, P=0.000). In the high dose group, SARA score changes of the total score before and after the medication had significant differences, as well as the ICARS score changes in the total score (P=0.001, P=0.001). In the placebo control group, SARA score changes of the total score before and after the medication had significant differences, as well as the ICARS score changes in the total score (P=0.007, P=0.001).The SARA score changes of the total score among the three groups were significantly different, as well as the ICARS score changes in the total score (P=0.021, P=0.018)Conclusions:The SCA3/MJD patients treated with Hv tablets of 800 mg/day-1200 mg/day for 12 weeks were well tolerated. The share the same adverse reactions with epilepsy patients and the normal people, such as dizziness, drowsiness, blurred vision, abdominal distension, loss of appetite and so on. The incidence and frequency of the adverse events in 800 mg/day dose group was significantly lower than the 600 mg/day dose group, and there existed a dose relevance between them. The clinical symptoms can be improved after Hv (800 mg/day, or 1200 mg/day) oral administration for 12 weeks in SCA3/MJD patients. Chapter 3:Pharmacokinetic study on SCA3/MJD patients orally administrated with single-dose and multi-dose of Hv.Objective:To study pharmacokinetics mode of SCA3/MJD patiens who take Hv by oral application single or multiple dosing, and explore the relationship among the dosage, blood drug concentration and drug affect (curative and adverse effect). Then provided evidence to formulate dosing of Clinical trials II period and monitor blood drug concentration.Methods:(1) Administrated with single-dose:It was a single center clinical study based on the principle of randomicity, openness, single dose escalation. Participations were 12 SCA3/MJD adult patients, randomly divided into three groups of 400mg dose group,600mg dose group, and 800mg dose group, each with 4 subjects. They were administrated with single-dose of Hv. We use HPLC-UV to detect the concentration of Hv in patients’plasma, and DAS 2.1.1 to calculate the pharmacokinetic parameters. Finally, we make statistical analysis of these data. (2) Administrated with multi-dose:It was a single center clinical study based on the principle of randomicity, double-blind, placebo control, dose-controlled principle. Research subjects were 36 SCA3/MJD patients aged 18 to 50 years old, they were randomly divided into three groups, small dose 800 mg group, large dose 1200 mg group, and the placebo control group, each with 12 subjects. They were taken Hv orally twice a day for 12 weeks. We use HPLC-UV to detect the concentration of Hv in patients’ plasma, and DAS 2.1.1 to calculate the pharmacokinetic parameters. Finally, we make the linear correlation analysis between AUC, Cmax and efficacy index by statistical analysis software.Results:After single-dose of Hv oral administration (400mg,600mg, 800mg):Tmax were 2.75±0.50,3.25±1.26 and 3.25±0.50h; Cmax were 49.04±2.24,59.85±5.98 and 67.71±4.65 mg-L-1; AUC0-24 were 1117.86±174.68,1560.13±484.22 and 1580.64±197.47 mg·h·L-1; t1/2were 23.94±7.46,25.84±13.43 and 18.52±0.48 h. AUC0-72 and Cmax were separately linear correlated with the dose of Hv; The 90% confidence intervals for the slope of AUC0-72 and Cmax were not fall into the range of judgment, revealing that Hv took a non-linear pharmacokinetic process in patients’body; After multi-dose of Hv oral administration (400mg, 600mg, Bid):the first day:Tmax were 10.42±3.7 and 7.58±4.14 h; Cmax were 58.21±4.78 and 74.19±10.55 mg·L·-1; AUC0-24 were 982.97±101.36 and 1320.42±203.9 mg·h·L-1; the seventh day:Tmax were 5.83±4.15 and 7.13±5.16 h; Cmax were 93.06±17.53 and 129.09±19.6 mg·L·-1; AUC0-12 were 879.78±176.07 and 1213.88±177.44 mg·h·L-1; the average trough concentrations of the three months were 39.71±15.62 and 52.52±17.56 mg·L-1; Accumulate factor (Cmax of the first day/Cmax of the seventh day) were 1.60 and 1.74; plasma concentrations of Hv were closely related to adverse reaction; the average trough concentrations of the three months were significantly related to IGF-1 (P<0.01).Conclusion:Single-dose of Hv oral administration (400-800 mg) takes a non-linear pharmacokinetic process in SCA3/MJD patients’body; After orally administrated with multi-dose of Hv, plasma concentrations of Hv in SCA3/MJD patients’body were closely related to adverse reaction; The recommended clinical treatment of Hv for the SCA3/MJD patients is 800 mg/day (400 mg, Bid), meanwhile monitor the plasma concentrations of Hv and personalized medicine.Chapter 4:Study on the Serum Marker of the SCA3/MJD Patients Treated of HvObjective:To study the concentration change of IGF-land IGFBP-3 in SCA/MJD patients’serum after different doses of Hv.Methods:Research subjects were 36 SCA3/MJD patients aged 18 to 50years old, they were randomly divided into three groups, small dose 800mg/day group, large dose 1200 mg/day group, and the placebo control group, each with 12 subjects. They were treated with continuous Hv oral administration for 12 weeks, accepted the SARA, ICARS score before and after 12 weeks of Hv administration. We used enzyme-linked immunosorbent assay (ELISA) to test the concentration changes of IGFs-1 and IGFBP-3 in patients’serum, and analyzed the dependability of the concentration of IGF-land IGFBP-3 in serum of all the subjects with baseline data, and the diversity of the concentration of IGF-land IGFBP-3 in serum before and after medication in different dosage groups.Results:The concentration of IGF-1 in patients’serum is positively correlated with body mass index. In the 800 mg/day group, concentrations of IGFs-1 and IGFBP-3 before and after Hv administration had significant difference (P=0.023, P=0.000); in the 1200 mg/day group, concentrations of IGFBP-3 before and after Hv administration had significant difference (P=0.000); in the placebo control group, concentrations of IGFBP-3 before and after Hv administration had significant difference (P=0.000). Analysis of variance on datas showed that concentration changes of IGFs-1 and IGFBP-3 among these three groups had no significant difference (P>0.05).Conclusions:The concentration of IGF-1 in patients’serum can reflect the nutritional status of SCA3/MJD patients. The levels of IGFs-1 and IGFBP-3 in patients’serum can not be taken as an index of outcome assessment for 12 weeks’Hv administration. Chapter 5:Study of the Magnetic Resonance Spectroscopy of SAC3/MJD PatientsObjective:We peformed 1Hmagnetic resonance spectroscopy (1H-MRS) on multiple cerebellar regions to evaluated the metabolite patter and the disease Severity in spinacerebellal ataxia 3/ Machado-Joseph disease(SCA3/MJD) patients. and observed the alteration of the metabolic pattern (by’H-MRS) on multiple cerebellar regions of the (SCA3/MJD) patients treated with different doses of Hv.Methods:Participations were 36 SCA3/MJD patients aged 18 to 50 years old and 27 sex, age-matched healthy volunteers; all the patients were randomly divided into three groups small dose 400 mg group, large dose 600 mg group, and the placebo control group, each with 12 subjects. They were treated with continuous Hv oral administration for 12 weeks. We implemented PRESS on all the subjects before Hv administration and the 36 patients after 12 weeks’Hv administration, making cerebellar vermis, cerebellar peduncles, cerebellar cortex, and dentate nucleus as the region of interests (ROI), and finally got access to NAA/Cr, Cho/Cr, NAA/Cho ratios. We also scored the 36 patients by SARA, ICARS before and 12 weeks after Hv administration, analyzing the differences of NAA/Cho+Cr, Cho/Cr, NAA/Cho ratios between SCA3/MJD patients and the control group, and exploring whether the relevance existed between these ratios and course of disease, CAG repeat times, SARA, ICARS scores respectively, as well as the relevance of ratios and SARA, ICARS scores in different dosage group. Conclusions:The NAA/Cho ratio in dentate nucleus, NAA/Cr ratio in both cerebellar cortex and cerebellar vermis and NAA/Cho ratio in cerebellar peduncles between patients and controls had significant difference (P<0.05). The ratios in controls are higher than the SCA3/MJD patients. The Cho/Cr, NAA/Cho ratio in cerebellar cortex and NAA/Cr ratio in dentate nucleus were positively correlated with course of disease, CAG repeat times and SARA, ICARS scores respectively; Cho/Cr, NAA/Cho ratio in cerebellar vermis and NAA/Cr ratio in cerebellar peduncles were positively correlated with SARA score; NAA/Cho ratio in cerebellar cortex was positively correlated with ICARS score; Cho/Cr ratio in cerebellar vermis and NAA/Cr ratio in cerebellar peduncles is highly positively correlated with SARA score (r>0.933, P<0.01). Atα=0.05 level, changes in magnetic resonance speetroscopy of ROIs in cerebella before and after Hv administration had no significant difference (P>0.05).Conclusions:1H-MRS can show the neural metabolic changes in cerebella of SCA3/MJD patients, so as to evaluate the severity of the disease. The 1-MRS changes in SCA3/MJD patients’cerebella can not be taken as an index of outcome assessment for 12 weeks’Hv administration.