Ignite Creation Date:
2024-05-06 @ 2:47 AM
Last Modification Date:
2024-10-26 @ 11:23 AM
Study NCT ID:
NCT02129231
Status:
COMPLETED
Last Update Posted:
2014-05-06
First Post:
2014-04-30
Brief Title:
Statins for Oxidative Stress and Mitochondrial Function in Diabetic Polyneuropathy
Sponsor:
University of Guadalajara
Organization:
University of Guadalajara
Study Overview
Official Title:
EzetimibeSimvastatin and Rosuvastatin for Oxidative Stress and Mitochondrial Function in Diabetic Polyneuropathy a Randomized Double Blinded Placebo Controlled Clinical Trial
Status:
COMPLETED
Status Verified Date:
2014-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Aims To evaluate the effect of ezetimibesimvastatin and rosuvastatin on oxidative stress and mitochondrial function in patients with DPN
Methods We performed a randomized double-blinded placebo-controlled phase II clinical trial in adult patients with type 2 Diabetes Mellitus T2DM who had Diabetic Polyneuropathy DPN evaluated by composite scores and nerve conduction studies NCS HBA1C 12 108 mmolmol previous exclusion of other neuropathies Ninety-eight persons with T2DM were allocated 111 to either placebo ezetimibesimvastatin 1020 mg or rosuvastatin 20 mg for 16 weeks and healthy controls not randomized were included for comparisons Primary outcomes were lipid peroxidation LPO nitric oxide NO and total antioxidant capacity TAC secondary were clinical NCS and metabolic parameters Results were expressed as mean standard deviation SD or standard error of the mean SEM frequencies and percentages Non-parametric analysis was used
Methods We performed a randomized double-blinded placebo-controlled phase II clinical trial in adult patients with type 2 Diabetes Mellitus T2DM who had Diabetic Polyneuropathy DPN evaluated by composite scores and nerve conduction studies NCS HBA1C 12 108 mmolmol previous exclusion of other neuropathies Ninety-eight persons with T2DM were allocated 111 to either placebo ezetimibesimvastatin 1020 mg or rosuvastatin 20 mg for 16 weeks and healthy controls not randomized were included for comparisons Primary outcomes were lipid peroxidation LPO nitric oxide NO and total antioxidant capacity TAC secondary were clinical NCS and metabolic parameters Results were expressed as mean standard deviation SD or standard error of the mean SEM frequencies and percentages Non-parametric analysis was used
Detailed Description:
Introduction Nerve dysfunction system in patients with diabetes is known as diabetic neuropathy and is considered as the most prevalent microvascular complication -up to 60- in type 2 Diabetes Mellitus T2DM subjects Diabetic polyneuropathy DPN comprise 70 of all cases Its diagnosis is established by means of validated scores based on clinical features and abnormal nerve conduction studies NCS Pathophysiologic findings include loss of multifocal and focal nerve fibers secondary to axonal degeneration an segmental demyelinization basically due to oxidative stress induced by chronic hyperglycemia which leads to neural apoptosis Other mechanisms involved in peripheral nerve injure is nitrosative stress induced by nitric oxide NO
Ezetimibe diminishes cholesterol esters content in chylomicrons by reducing liver cholesterol intake which in consequence increases LDL uptake and plasma depuration as monotherapy it reduces LDL-C by 17 When combined with simvastatin cholesterol reduction is potentially increased furthermore pleiotropic effects of statins include an increase on nuclear factor kappa B activity and amelioration of superoxide ions after 12 week treatment Another hydroxy-methyl-glutaryl coenzyme A inhibitor rosuvastatin has an antioxidant effect by acting as free radical carrier diminishing mitochondrial and cellular lipid peroxidation LPO production
We conducted this study to evaluate the effect of ezetimibesimvastatin and rosuvastatin on oxidative stress in patients with DPN
Methods Study design A randomized double blinded placebo controlled phase II clinical trial was performed in the Clinic and Experimental Therapeutics Institute University of Guadalajara Mexico Subjects were assigned to three group treatments in blocks with a parallel sequence 111 through a randomized computer-based list generated by a different researcher unaware of drugs given Patients were divided to control group that received placebo ezetimibesimvastatin and rosuvastatin as a daily single dose for 16 weeks The selection period was performed from February 2012 to January 2013 We selected 5 non-randomized healthy subjects HS from a blood bank to compare the oxidative stress status
Study population Inclusion criteria were 18 years old T2DM according to American Diabetes Association and DPN by Dyck et al3 criteria HbA1c 12 and informed consent signed They were excluded if renal or hepatic failure pregnant or breastfeeding other neuropathies alcohol-induced radiculopathy autoimmune cancer-related and eliminated if lack treatment adherence 80 of drug intake severe adverse drug reaction andor serious health illness Patients were selected by invitation in forums outpatients recruited from primary care clinics and database collected previously by our Institute from February 2010 to 2012 Patients were instructed to take their drugs only by night at the same time every day as follows placebo 100 mg ezetimibesimvastatin 1020 mg and rosuvastatin 20 mg All drugs were similar in physical characteristics and presented in dark vials carefully filled by another group researcher who placed a respective tag with the patient code Also patients were provided with a diary where they would write down the date and time of drug administration and drug adverse reactions felt Such information was collected and registered every 4 weeks Primary outcomes were oxidative stress markers LPO NO and TAC before and after 16 week intervention Secondary outcomes were clinical NCS and metabolic fasting glucose HbA1c total cholesterol high and low density lipoproteins HDL LDL and triglycerides parameters Safety profile was assessed with drug adverse reactions renal urea creatinin and hepatic alamin- and aspartate-aminotransferase gama-glutamyltransferase bilirubins and phosphokinase laboratory variables
Oxidative stress and mitochondrial function markers LPO was measured according to kit specifications Oxford Biomedical Research Inc FR12 200 μL of serum where processed with a chromogen substance that reacts with malondialdehyde MDA and 4-hydroxy-alkenals HNA the absorbance measured at 586 nm and results expressed in nmolmL
Previous deproteinization of the samples we performed a colorimetric for determining the concentration of NO with 85 µL of serum Nitric Oxide Assay Kit User protocol 482650 with results expressed as pmolmL
Total antioxidant capacity TAC was realized with 200 µL of serum to obtain values of millimole mM equivalent of uric acid Total Antioxidant Power Kit No 02090130 Oxford Biomedical Research
Clinical and nerve conduction variables Neuropathic symptoms NSS and disability scores NIS described by Dyck et al were obtained by physical examination and anamnesis We also measured the latency duration amplitude and motor nerve conduction velocity from fibula tibial median and ulnae nerves and sensitivity parameters from sural median and ulnae nerves as required by the American Association of Electrodiagnostic Medicine
Ethical considerations The study was approved by the Research and Ethics Committee of the Health Science University Center University of Guadalajara Mexico Identification codes were assigned to each participant to guarantee patient confidentiality and an informed consent form was signed before entering the protocol according to national and international laws and also as stipulated by the Helsinki Statements httpwwwwmanetes30 publications 10 policiesb317cpdf accessed January 2011
Statistical analysis The sample size was obtained by a clinical study design formula taking in account a difference change of 005 nmolmL in LPO 95 confidence interval 80 potency and two-tailed p005 which resulted in 21 for each group Quantitative variables were expressed as mean standard deviation Kolmogorov-Smirnov and Shapiro-Wilk tests were performed to determine the non-parametric distribution of variables Friedman and Wilcoxon tests were realized for before and after measurements and Kruskal-Wallis with Mann-Whitneys U as post-hoc analysis for between group comparisons Qualitative variables were expressed as frequencies and percentages Chi square test was used to evaluate differences in dichotomy variables before and after treatment between group comparisons were determined by Fishers exact test and χ2 as needed Significance level was established with p value 005
Ezetimibe diminishes cholesterol esters content in chylomicrons by reducing liver cholesterol intake which in consequence increases LDL uptake and plasma depuration as monotherapy it reduces LDL-C by 17 When combined with simvastatin cholesterol reduction is potentially increased furthermore pleiotropic effects of statins include an increase on nuclear factor kappa B activity and amelioration of superoxide ions after 12 week treatment Another hydroxy-methyl-glutaryl coenzyme A inhibitor rosuvastatin has an antioxidant effect by acting as free radical carrier diminishing mitochondrial and cellular lipid peroxidation LPO production
We conducted this study to evaluate the effect of ezetimibesimvastatin and rosuvastatin on oxidative stress in patients with DPN
Methods Study design A randomized double blinded placebo controlled phase II clinical trial was performed in the Clinic and Experimental Therapeutics Institute University of Guadalajara Mexico Subjects were assigned to three group treatments in blocks with a parallel sequence 111 through a randomized computer-based list generated by a different researcher unaware of drugs given Patients were divided to control group that received placebo ezetimibesimvastatin and rosuvastatin as a daily single dose for 16 weeks The selection period was performed from February 2012 to January 2013 We selected 5 non-randomized healthy subjects HS from a blood bank to compare the oxidative stress status
Study population Inclusion criteria were 18 years old T2DM according to American Diabetes Association and DPN by Dyck et al3 criteria HbA1c 12 and informed consent signed They were excluded if renal or hepatic failure pregnant or breastfeeding other neuropathies alcohol-induced radiculopathy autoimmune cancer-related and eliminated if lack treatment adherence 80 of drug intake severe adverse drug reaction andor serious health illness Patients were selected by invitation in forums outpatients recruited from primary care clinics and database collected previously by our Institute from February 2010 to 2012 Patients were instructed to take their drugs only by night at the same time every day as follows placebo 100 mg ezetimibesimvastatin 1020 mg and rosuvastatin 20 mg All drugs were similar in physical characteristics and presented in dark vials carefully filled by another group researcher who placed a respective tag with the patient code Also patients were provided with a diary where they would write down the date and time of drug administration and drug adverse reactions felt Such information was collected and registered every 4 weeks Primary outcomes were oxidative stress markers LPO NO and TAC before and after 16 week intervention Secondary outcomes were clinical NCS and metabolic fasting glucose HbA1c total cholesterol high and low density lipoproteins HDL LDL and triglycerides parameters Safety profile was assessed with drug adverse reactions renal urea creatinin and hepatic alamin- and aspartate-aminotransferase gama-glutamyltransferase bilirubins and phosphokinase laboratory variables
Oxidative stress and mitochondrial function markers LPO was measured according to kit specifications Oxford Biomedical Research Inc FR12 200 μL of serum where processed with a chromogen substance that reacts with malondialdehyde MDA and 4-hydroxy-alkenals HNA the absorbance measured at 586 nm and results expressed in nmolmL
Previous deproteinization of the samples we performed a colorimetric for determining the concentration of NO with 85 µL of serum Nitric Oxide Assay Kit User protocol 482650 with results expressed as pmolmL
Total antioxidant capacity TAC was realized with 200 µL of serum to obtain values of millimole mM equivalent of uric acid Total Antioxidant Power Kit No 02090130 Oxford Biomedical Research
Clinical and nerve conduction variables Neuropathic symptoms NSS and disability scores NIS described by Dyck et al were obtained by physical examination and anamnesis We also measured the latency duration amplitude and motor nerve conduction velocity from fibula tibial median and ulnae nerves and sensitivity parameters from sural median and ulnae nerves as required by the American Association of Electrodiagnostic Medicine
Ethical considerations The study was approved by the Research and Ethics Committee of the Health Science University Center University of Guadalajara Mexico Identification codes were assigned to each participant to guarantee patient confidentiality and an informed consent form was signed before entering the protocol according to national and international laws and also as stipulated by the Helsinki Statements httpwwwwmanetes30 publications 10 policiesb317cpdf accessed January 2011
Statistical analysis The sample size was obtained by a clinical study design formula taking in account a difference change of 005 nmolmL in LPO 95 confidence interval 80 potency and two-tailed p005 which resulted in 21 for each group Quantitative variables were expressed as mean standard deviation Kolmogorov-Smirnov and Shapiro-Wilk tests were performed to determine the non-parametric distribution of variables Friedman and Wilcoxon tests were realized for before and after measurements and Kruskal-Wallis with Mann-Whitneys U as post-hoc analysis for between group comparisons Qualitative variables were expressed as frequencies and percentages Chi square test was used to evaluate differences in dichotomy variables before and after treatment between group comparisons were determined by Fishers exact test and χ2 as needed Significance level was established with p value 005
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None