Ignite Creation Date:
2024-05-06 @ 8:00 AM
Last Modification Date:
2024-10-26 @ 11:55 AM
Study NCT ID:
NCT02648685
Status:
COMPLETED
Last Update Posted:
2020-02-11
First Post:
2015-12-25
Brief Title:
The Study to Investigate the Contribution of Basal and Postprandial Glucose to Overall Hyperglycemia in T2DM
Sponsor:
West China Hospital
Organization:
West China Hospital
Study Overview
Official Title:
The Study to Investigate the Contribution of Basal and Post-prandial Blood Glucose to Overall Glycaemia in Subjects With Normal Glycaemic Metabolism and Type 2 Diabetes
Status:
COMPLETED
Status Verified Date:
2020-02
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:
There was no any China mainland data showing the contribution of BBG and PBG to HbA1c in T2DM patients treated with OADs using the CGM method Therefore this study is aimed to investigate the contribution of BBG and PBG to HbA1c in Chinese T2DM patients treated with OADs using CGMS Its expected to generate evidence to support the concept of individualized therapy when patients are uncontrolled by OADs
Detailed Description:
Background The current evidence shows that hyperglycemia is one of the important cause of atherosclerosisIn the DCCT study1 comparing with the conventional therapy group HbA1c9 the risk of retinopathy kidney disease and neuropathy was significantly reduced in the intensive therapy group HbA1c7 The EDIC study2 shows that there is a reduction42 p002 in the incidence of cardiovascular event in the intensive therapy group and the risk of nonfatal myocardial infarction stroke cardiovascular death reduced by 57 p002 Based on those evidence we could tell that a continued cardiovascular benefit after early intensive glucose control was evident among T1DM patients Similarly the UKPDS study34 demonstrated that in the newly diagnosed T2DM patients the incidence of the microvascular complication was 25 lower and the cardiovascular complication include fatal and nonfatal MI was 16 lower in the intensive glucose control group which is coincident with the conclusion from EDIC study The blood glucose of the diabetes patients are consist of 3 partsnormal basal blood glucose basal hyperglycemia and postprandial hyperglycemia which is a further increase based on the basal hyperglycemia5 HbA1c is the standard indicator for glucose metabolism which is determined by Basal blood glucose BBG and post prandial glucose PPG levels HbA1c is a risk factor for diabetes vascular lesions has become the consensus and UKPDS study shows that increasing HbA1c and fasting blood glucose levels maight be associated with the regression of beta cell function basal hyperglycemia is a major cause of diabetic cardiovascular complications6 Most previous studies focused on HbA1c and FPG level to determine the control of blood glucose78 But now the relationship between PPG increasing and diabetes complications are gradually valued Evidence shows PPG and HbA1c is main predictor of cardiovascular events and all-cause mortality in T2DM9-11 The contribution of basal and post-prandial blood glucose to overall glycaemia is one of point to investigate glucose metabolism impaired Wenhui Li 12et al found that the relationship between fasting post-absorption blood glucose and HbA1c level is more closely than with PPG Especially the blood glucose at 800 AM is closely related with HbA1c r084 The A1c-Derived Average Glucose study ADAG 13also got the similar conclusion However some other study shows the relationship between PPG and HbA1c is much more closer 14 The main reason that lead to this argument is the lack of an accepted accurate method to assess the contribution of basal and post-prandial blood glucose to overall glycaemia and the contribution is associated with the choice of therapeutic strategy
Currently few studies have been done to investigate the newly diagnosed or treatment-naive type 2 diabetes Only Peter R et al found that the contribution of fasting hyperglycemia derived from a standardized meal test to excess hyperglycemia increase as glycaemia control deteriorates becoming dominant with an HbA1c in excess of 70 While in the T2DM patients treated by OAD different researchers have concluded differences such as Monnier et al516 found that in the T2DM patients treated by OAD if HbA1c 7 the relative contribution of PPG was around 697 but this proportion decreased gradually accompany with the increasing HbA1c When HbA1c102 the contribution of PPG was only 305 Kikuchi et al17 concluded the similar result with Monnier in the T2DM patients of Japan Riddle et al18 found that when HbA1c8 PPG contributes more to HbA1c with the deterioration of blood glucose the relative contribution of FPG increased to 70
However blood glucose fluctuation is affected by many factors such as disease duration sex diet food cooking methods and race19 Our previous study found compared with NGT the intra-day blood glucose fluctuation was similar in IGR patients but it had already occurred In the newly diagnosed type 2 diabetic patients the inter-day and intra-day blood glucose fluctuation was significantly increased besides the effect of different ratio of carbohydrate in the diet was different20-24 For Asian yellow there are less research and the conclusions are not consistent Japanese scholars Kikuchi 17obtained the similar conclusion with Monnier but the study done by Taiwanese researchers 25 show that in the good blood glucose control patients the relative contribution of PPG was up to 70 but with the blood glucose control deterioration FPG and PPG to its effect is similar about 50 each
Until now the research on the contribution of the BBG and PPG to HbA1c is less and the results are different May be different from the research methods and the study population At present all the research use 61mmolL WHO criteriaor 56mmolLADA criteria as normal FBG level WHO criteria to calculate the fasting or postprandial hyperglycemia not according to the blood glucose fluctuation curve of NGT population so that the BBG and PPG contribution of HbA1c might be underestimated or overestimated In addition Peter and Monnier used MTT method which would cause difference result from the T2DM patients in the real world Peter Monnier Riddle and Kikuchi monitored the blood glucose by collecting pre or postprandial blood sample frequently or SMBG The contribution of the postprandial glucose to HbA1c is underestimated As the continuous glucose monitoring system CGMS is becoming more and more widely used it is considered as a better method to evaluate the contribution of BBG and PPG to HbA1c because of the minimizing bias which is resulted of research methodology25 There was no any China mainland data showing the contribution of BBG and PBG to HbA1c in T2DM patients treated with OADs using the CGM method Therefore this study is aimed to investigate the contribution of BBG and PBG to HbA1c in Chinese T2DM patients treated with OADs using CGMS Its expected to generate evidence to support the concept of individualized therapy when patients are uncontrolled by OADs
Objectives Primary objective is to investigate the relative contribution of BBG and PBG to overall glycaemia in T2DM with OAD The secondary is to investigate the absolute contribution of BBG and PBG to overall glycaemia in T2DM with OAD treatment investigate the correlation between overall glycaemia exposure and HbA1c and regression equation of HbA1c to BBG and PBG
Sample size According to MONNIER research the contribution of PBG to whole day hyperglycemia use 61mmolL as base line is HbA1c73 697418n58 HbA1c73-845134418n58 HbA1c85-924418358n58 HbA1c93-1024060478n58 HbA1c102305358n58 If there are 5 groups the mean CSS is 85494 SD is 3355α005After enter the SAS 801 software every group has 22 sizes and totally 110 cases with 5 groups So more than 132 cases will be enrolled rate of dropout and withdraw is 20 the cases will need 11011002132
One-Way ANOVA
Treatments 5 CSS of Means 85494 Standard Deviation 3355 Alpha 005
N per Power Group
0800 17 0850 19 0900 22 SAS 801 software
Because this is exploratory research so we justified the sample
T2DM subjects the primary endpoint is the relative contribution of FBG The contribution will be calculated by individual subject A sample size of 60 for each group produces a two-sided 95 confidence interval for relative contribution of FBG with a precision of approximately 65 when the estimated standard deviation is 25 refer to previous study so the total subjects of five group is 300
Normal glycaemic subjects a sample size of 100 normal glycaemic subjects produces a two-sided 95 confidence interval for AUC with a precision of approximately 008dmmolL-1when the estimated standard deviation is 04dmmolL-1refer to previous study
Number of subjects per treatment arm N normal glycaemic group100 N T2DM with OADs300
Cases with one of the following reasons should be removed
Misdiagnos
No medication or no regular medication
Irregular diet
No test recording
Using any drug which might interfere the glucose metabolism and mislead the result
Study design This is a single center two groups cross sectional study
One group consists of normal glycaemic subjects N100
One group consists of T2DM subjects treated with OADs N 300 which will be divided into 5 sub-groups by HbA1c level and each sub-group will include 60 subjects HbA1c65 65-70 70-80 80-90 90 CGMS will be used to collect blood glucose data The normal glycaemic subjects will not receive any treatment during this study The T2DM subjects will maintain their previous OADs treatment and no other new treatment will be added during this study
Relative and absolute contribution will be calculated by two ways
Refer the methods of Monnier and Riddle to calculate the contribution with WHO normal FBG cut point of 61 mmolL
AUC 24h total high glycaemiathe area above the curve of FBG 61 mmolL
AUCPPGthe area above pre-prandial glucose in a 4-h period after each mealX3 meals
AUC BBG AUC 24h total high glycaemia - AUCPPG
Using the data of the group with normal glycaemic subjects as the basis to calculate the contribution no need to select a normal FBG cut-off point therefore avoid the overestimated or underestimated contribution of FBG due to the conflict of different FBG cut-off point in western guideline and China guideline with 56 mmolL and 61 mmolL respectively
AUC24h NGT totalthe area above the curve of glucose 0 mmolL
AUC 24h T2DM total the area above the curve of glucose 0 mmolL
Total high glycaemia AUC 24h total high glycaemia AUC 24hT2DM total -AUC 24h NGT total
AUC PPGthe area above post-prandial glucose in a 4-h period after each mealX3 meals in T2DM patients
AUC BBG AUC 24h total high glycaemia- AUCPPG
Relative glucose contribution calculation
Relative contribution of BBG AUC BBG AUC 24h total high glycaemia X100
Relative contribution of PPG AUC PPG AUC 24h total high glycaemiaX100
Absolute glucose contribution calculation
Refer Monnier et al Absolute PBG contribution HbA1cAUCPBGAUCtotal
Refer Peter at al Absolute PBG contribution mean HbA1c-T2DM - mean HbA1c-NGTAUCPBG AUCtotal Absolute BBG contribution mean HbA1c-T2DM - mean HbA1c-NGTAUCtotal-AUCPBG AUCtotal
The contribution with ADA normal FBG cut point of 56mmolL is the same as above
Adverse events record and report
Definition any adverse medical events which happened during the study regardless of the relationship with Investigational product
Adverse events information obtain observed by the physician reported by subjects In addition the physician should ask the adverse events information in every visit
RecordingTime severity duration treatment and outcome of the adverse event
Standard for determining the severity of adverse events
llight does not affect the normal function of subjects
moderate to a certain extent affect the normal function of subjects
severe significantly affect the normal function of subjects Timeline
912015----1112015 previous preparationapply for ethical approval
11182015---7312017 Screen subjects in community complete the subjects who were eligible for the trial and to wear 72h continuous glucose monitor systerm
812017---1112016 Supplement experiment omission organize data and data lock
1112017---1302018 Statistical analysis draw conclusions the paper writing Complete the report of the project finishing
Currently few studies have been done to investigate the newly diagnosed or treatment-naive type 2 diabetes Only Peter R et al found that the contribution of fasting hyperglycemia derived from a standardized meal test to excess hyperglycemia increase as glycaemia control deteriorates becoming dominant with an HbA1c in excess of 70 While in the T2DM patients treated by OAD different researchers have concluded differences such as Monnier et al516 found that in the T2DM patients treated by OAD if HbA1c 7 the relative contribution of PPG was around 697 but this proportion decreased gradually accompany with the increasing HbA1c When HbA1c102 the contribution of PPG was only 305 Kikuchi et al17 concluded the similar result with Monnier in the T2DM patients of Japan Riddle et al18 found that when HbA1c8 PPG contributes more to HbA1c with the deterioration of blood glucose the relative contribution of FPG increased to 70
However blood glucose fluctuation is affected by many factors such as disease duration sex diet food cooking methods and race19 Our previous study found compared with NGT the intra-day blood glucose fluctuation was similar in IGR patients but it had already occurred In the newly diagnosed type 2 diabetic patients the inter-day and intra-day blood glucose fluctuation was significantly increased besides the effect of different ratio of carbohydrate in the diet was different20-24 For Asian yellow there are less research and the conclusions are not consistent Japanese scholars Kikuchi 17obtained the similar conclusion with Monnier but the study done by Taiwanese researchers 25 show that in the good blood glucose control patients the relative contribution of PPG was up to 70 but with the blood glucose control deterioration FPG and PPG to its effect is similar about 50 each
Until now the research on the contribution of the BBG and PPG to HbA1c is less and the results are different May be different from the research methods and the study population At present all the research use 61mmolL WHO criteriaor 56mmolLADA criteria as normal FBG level WHO criteria to calculate the fasting or postprandial hyperglycemia not according to the blood glucose fluctuation curve of NGT population so that the BBG and PPG contribution of HbA1c might be underestimated or overestimated In addition Peter and Monnier used MTT method which would cause difference result from the T2DM patients in the real world Peter Monnier Riddle and Kikuchi monitored the blood glucose by collecting pre or postprandial blood sample frequently or SMBG The contribution of the postprandial glucose to HbA1c is underestimated As the continuous glucose monitoring system CGMS is becoming more and more widely used it is considered as a better method to evaluate the contribution of BBG and PPG to HbA1c because of the minimizing bias which is resulted of research methodology25 There was no any China mainland data showing the contribution of BBG and PBG to HbA1c in T2DM patients treated with OADs using the CGM method Therefore this study is aimed to investigate the contribution of BBG and PBG to HbA1c in Chinese T2DM patients treated with OADs using CGMS Its expected to generate evidence to support the concept of individualized therapy when patients are uncontrolled by OADs
Objectives Primary objective is to investigate the relative contribution of BBG and PBG to overall glycaemia in T2DM with OAD The secondary is to investigate the absolute contribution of BBG and PBG to overall glycaemia in T2DM with OAD treatment investigate the correlation between overall glycaemia exposure and HbA1c and regression equation of HbA1c to BBG and PBG
Sample size According to MONNIER research the contribution of PBG to whole day hyperglycemia use 61mmolL as base line is HbA1c73 697418n58 HbA1c73-845134418n58 HbA1c85-924418358n58 HbA1c93-1024060478n58 HbA1c102305358n58 If there are 5 groups the mean CSS is 85494 SD is 3355α005After enter the SAS 801 software every group has 22 sizes and totally 110 cases with 5 groups So more than 132 cases will be enrolled rate of dropout and withdraw is 20 the cases will need 11011002132
One-Way ANOVA
Treatments 5 CSS of Means 85494 Standard Deviation 3355 Alpha 005
N per Power Group
0800 17 0850 19 0900 22 SAS 801 software
Because this is exploratory research so we justified the sample
T2DM subjects the primary endpoint is the relative contribution of FBG The contribution will be calculated by individual subject A sample size of 60 for each group produces a two-sided 95 confidence interval for relative contribution of FBG with a precision of approximately 65 when the estimated standard deviation is 25 refer to previous study so the total subjects of five group is 300
Normal glycaemic subjects a sample size of 100 normal glycaemic subjects produces a two-sided 95 confidence interval for AUC with a precision of approximately 008dmmolL-1when the estimated standard deviation is 04dmmolL-1refer to previous study
Number of subjects per treatment arm N normal glycaemic group100 N T2DM with OADs300
Cases with one of the following reasons should be removed
Misdiagnos
No medication or no regular medication
Irregular diet
No test recording
Using any drug which might interfere the glucose metabolism and mislead the result
Study design This is a single center two groups cross sectional study
One group consists of normal glycaemic subjects N100
One group consists of T2DM subjects treated with OADs N 300 which will be divided into 5 sub-groups by HbA1c level and each sub-group will include 60 subjects HbA1c65 65-70 70-80 80-90 90 CGMS will be used to collect blood glucose data The normal glycaemic subjects will not receive any treatment during this study The T2DM subjects will maintain their previous OADs treatment and no other new treatment will be added during this study
Relative and absolute contribution will be calculated by two ways
Refer the methods of Monnier and Riddle to calculate the contribution with WHO normal FBG cut point of 61 mmolL
AUC 24h total high glycaemiathe area above the curve of FBG 61 mmolL
AUCPPGthe area above pre-prandial glucose in a 4-h period after each mealX3 meals
AUC BBG AUC 24h total high glycaemia - AUCPPG
Using the data of the group with normal glycaemic subjects as the basis to calculate the contribution no need to select a normal FBG cut-off point therefore avoid the overestimated or underestimated contribution of FBG due to the conflict of different FBG cut-off point in western guideline and China guideline with 56 mmolL and 61 mmolL respectively
AUC24h NGT totalthe area above the curve of glucose 0 mmolL
AUC 24h T2DM total the area above the curve of glucose 0 mmolL
Total high glycaemia AUC 24h total high glycaemia AUC 24hT2DM total -AUC 24h NGT total
AUC PPGthe area above post-prandial glucose in a 4-h period after each mealX3 meals in T2DM patients
AUC BBG AUC 24h total high glycaemia- AUCPPG
Relative glucose contribution calculation
Relative contribution of BBG AUC BBG AUC 24h total high glycaemia X100
Relative contribution of PPG AUC PPG AUC 24h total high glycaemiaX100
Absolute glucose contribution calculation
Refer Monnier et al Absolute PBG contribution HbA1cAUCPBGAUCtotal
Refer Peter at al Absolute PBG contribution mean HbA1c-T2DM - mean HbA1c-NGTAUCPBG AUCtotal Absolute BBG contribution mean HbA1c-T2DM - mean HbA1c-NGTAUCtotal-AUCPBG AUCtotal
The contribution with ADA normal FBG cut point of 56mmolL is the same as above
Adverse events record and report
Definition any adverse medical events which happened during the study regardless of the relationship with Investigational product
Adverse events information obtain observed by the physician reported by subjects In addition the physician should ask the adverse events information in every visit
RecordingTime severity duration treatment and outcome of the adverse event
Standard for determining the severity of adverse events
llight does not affect the normal function of subjects
moderate to a certain extent affect the normal function of subjects
severe significantly affect the normal function of subjects Timeline
912015----1112015 previous preparationapply for ethical approval
11182015---7312017 Screen subjects in community complete the subjects who were eligible for the trial and to wear 72h continuous glucose monitor systerm
812017---1112016 Supplement experiment omission organize data and data lock
1112017---1302018 Statistical analysis draw conclusions the paper writing Complete the report of the project finishing
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