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- NCT01081834 - A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin as Monotherapy in the Treatment of Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Diet and Exercise
- NCT00968812 - A Randomized, Double-Blind, 3-Arm Parallel-Group, 2-Year (104-Week), Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-28431754 Compared With Glimepiride in the Treatment of Subjects With Type 2 Diabetes Mellitus Not Optimally Controlled on Metformin Monotherapy
- NCT01381900 - A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 18-Week Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Alone or in Combination With a Sulphonylurea
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Data Request StatusStatus: Withdrawn/Closed
Project Title: An individual participant data meta-analysis to evaluate a new category of hypoglycemic drugs (SGLT-2Is) on type 2 diabetes mellitus patient subgroups
Scientific Abstract: Background: sodium-dependent glucose transporter 2 inhibition (SGLT-2Is) is a series of new hypoglycemic drugs for Type 2 diabetes mellitus(T2DM), the evaluation of its efficacy and safety in Asian populations is not yet comprehensive. Objective: The objective of this study is to compare and summarize the efficacy and safety of SGLT-2Is in subgroups of T2DM patients by individual participant data (IPD) meta-analysis. Study Design: Two-Stage IPD meta-analysis of randomized controlled trials (RCTs) with at least one arm of SGLT-2Is treatment. Participants: Adult T2DM patients. Main Outcome Measure: Glycated hemoglobin(HbA1c). Secondary outcome measures will be other blood glucose related indicators,blood lipid related indicators,and diabetic complications events. Statistical Analysis: We will conduct a 2-Stage IPD meta-analysis of RCTs. First stage, we will calculate the mean of HbA1c and standard deviation of each arm for each individual trial. In the second stage, we will conduct a traditional network meta-analysis to obtain the results of pairwise comparisons and the rank of this outcome in this subgroup.
Brief Project Background and Statement of Project Significance:
Diabetes is a group of metabolic diseases characterized by hyperglycemia.T2DM,where the body does not produce enough insulin by the pancreas to turn glucose into energy, is the most common type of diabetes. Being diagnosed as diabetes often means long-term use of hypoglycemic drugs. In recent years, a series of new hypoglycemic drugs have appeared: sodium-dependent glucose transporter 2 inhibition (SGLT-2Is), inhibitors that block the action of SGLT-2, a transport protein that responsible for the absorption of glucose in the intestinal epithelial cells, the reabsorption in the renal tubules, and the uptake and release of glucose in all cells.
According to the latest data released by the International Diabetes Federation (IDF) in 2019, there are currently 463 million diabetics among adults between 20 and 79 years old in the world. This number is expected to reach 578.4 million by 2030. Diabetes is now a major problem threatening human health, and T2DM is the most common type of diabetes. In view of the development of hypoglycemic agents and the growth in the number of people with T2DM, detailed information of these new drugs is needed to provide more reliable basis for clinicians when making decisions, and provide reference for guideline makers and regulatory decision-making departments.
Today, lots of RCTs comparing the efficacy and safety of these new hypoglycemic drugs have been published, which can be integrated to obtain high-quality evidence. There is a large population of T2DM patients in Asia, but most RCTs of hypoglycemic drugs were carried out in western populations. Whether the conclusions of these RCTs can be verified in Asian population is an essential question. Considering that the efficacy and safety of drugs may be affected by many factors, drugs may have different effects on patients with different baseline conditions. The integration of evidence among Asian population is of great significance to duplicate and verify the effectiveness of RCTs in real-world studies, in order to further find which kind of new drug is more suitable for Asian T2DM patients.
Specific Aims of the Project: The objective of this study is to compare and summarize the efficacy and safety of SGLT-2Is in subgroups of T2DM patients by IPD meta-analysis. For instance, we assumed that the hypoglycemic effects of this new type of hypoglycemic agents may be different among patients with different ages, races, baseline body weights, and baseline level of HbA1c, while the risk of causing complications also may differ among patients with different baseline disease conditions or different family histories, etc.
What is the purpose of the analysis being proposed? Please select all that apply.:
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
We want to compare SGLT-2Is with other hypoglycemic drugs or placebo, so we included RCTs with at least one arm of SGLT-2Is treatment.
In order to achieve the above-mentioned objective, we need to obtain the IPD of RCTs which meet our inclusion criteria. We established a core research team and searched this online website by using ?SGLT-2Is? and the names of all drugs and products of this type as keywords. After searching and reviewing the basic information, we selected trials in which the study population focused on Asian population, and 3 RCTs of SGLT-2Is versus placebo or active comparators for T2DM were included, which may contained the information of the baseline indicators, interventions and outcomes that we concern.
These 3 studies included in this data application are also included in a data application with the same name we submitted on the Vivli website. We applied for the YODA project in accordance with Vivli requirements. In addition to these three studies, we also applied for 4 other SGLT-2 clinical trials on the Vivli website, which are: NCT00881530, NCT01368081, NCT00789035, NCT00749190. We hope to use this total of 7 studies to complete our research.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: The primary outcome of interest will be HbA1c. Secondary outcomes include other blood glucose related indicators (Fasting plasma glucose, 2-hours postprandial plasma glucose, fasting C peptide, Homeostasis model assessment-?, Homeostasis model assessment-IR), blood lipid related indicators (Low density lipoprotein cholesterol, High density lipoprotein cholesterol, Total cholesterol, Triglycerides), other indicators (Estimated glomerular filtration rate,Body weight, Body mass index, Waist circumference, waist-to-hip ratio, Systolic blood pressure, Diastolic blood pressure, Heart rate), and the incidents of all-cause motality, adverse gastrointestinal events, respiratory diseases, endocrine decompensation,cardiovascular diseases,liver and renal dysfunction ,infectious diseases and diabetic complications. The selection of specific outcome indicators will be adjusted or calculated according to the details of the data we obtained. All continuous indicators will be recorded as their specific values, and all dichotomous indicators will be recorded as 0 or 1 according to whether the event occurs or not.
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
We want to compare SGLT-2Is with other hypoglycemic drugs or placebo, so we included RCTs with at least one arm of SGLT-2Is treatment.
Theoretically, all the current listed drugs and searchable products of this types of new hypoglycemic agents were covered. After searching and reviewing the basic information, we selected trials in which the study population focused on the Chinese population or the Asian population. 3 randomized controlled trials of SGLT-2Is versus placebo or active comparators for T2DM were included. That is to say, we regard any one of SGLT-2Is drugs as our main independent variable.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
We also hope to collect the baseline characteristics of patients in every RCT, which are critical for our IPD meta-analysis, including gender, age, race, duration of type 2 diabetes, whether they have baseline disease conditions, whether they have a family history of type 2 diabetes, and other related baseline indicators (HbA1c, Fasting plasma glucose, 2-hours postprandial plasma glucose, body weight, Body mass index, Waist circumference, etc.). Subgroups will be defined based on these baseline indicators.
The selection of specific subgroup indicators will be adjusted or calculated according to the details of the data we obtained.
Statistical Analysis Plan:
The data we requested for each RCT will include all outcomes we mentioned above, as well as baseline characteristics of patients. If we are able to obtain these data, our detailed statistical analysis steps will be as follows.
1.We will check the obtained data for missing values, outliers, and logic errors. We will appropriately treat logical error values and outliers as missing values, and we will not fill in missing values. Our statistical analysis will only base on the subjects with data.
2.We will clean up the data, including unified units of measurements, unified grouping standards, recode variables, etc. To ensure accurate pooling of data, items will be consistently labelled and coded. In this way, we will obtain a set of RCTs database with consistent structure.
3.We will assess the risk of bias of these RCTs that have been included with obtained data. The risk of bias assessment tool will be the Cochrane Collaboration's tool for assessing risk of bias in randomized trials. The level of risk of bias will be divided into three categories: low, medium and high. The risk of bias will affect the quality of the evidence we obtain and will be shown in articles.
After completing the above three steps, the data will be ready for IPD meta-analysis if the risk of bias is acceptable. Here we will take "compare SGLT-2Is with other control on the effect of reducing HbA1c in Asian population" as an example to illustrate our statistical analysis method of two-stage IPD meta-analysis.
First stage, we will extract all Asian patients who received SGLT-2Is or placebo or other hypoglycemic drugs from each included RCTs, and then calculate the mean of HbA1c and standard deviation of each arm in each RCT. In this way, we will get the level of changes in HbA1c caused by each intervention in each RCT.
In the second stage, we will conduct a traditional network meta-analysis to integrate the data we obtained in first stage. We will build a complete network of evidence, including SGLT-2Is and all interventions included in RCTs. According to the data obtained in the first stage, SGLT-2Is and other interventions can be directly or indirectly compared to obtain the results of pairwise comparisons. Thus, we will obtain comprehensive information on the efficacy of reducing HbA1c and the rank of the efficacy of all interventions, figuring out how this type of new drugs performed in reducing HbA1c among Asians.
This two-stage IPD meta-analysis can also be conducted in patients of different age, different baseline disease conditions, different family histories, etc. Then we may figure out how this type of new drugs performed among different populations.
The analysis will base on an intention-to-treat (ITT) analysis strategy, which means that subjects will remain in the original group for results analysis, regardless of whether they have completed the trial, or whether they have actually received the treatment in this group.
Test of heterogeneity will be carried out using I2 statistic, and we defined I2 values below 30% as low heterogeneity, 30?50% as moderate heterogeneity, 50?75% as substantial heterogeneity and >75% as considerable heterogeneity. Random effects meta-analyses will be performed due to the expected heterogeneity between studies. Publication bias will be estimated in funnel plots. All analyses will be performed in Stata V.15 (STATA Corp, Texas, USA).
Narrative Summary: Type 2 diabetes mellitus ,where the body does not produce enough insulin by the pancreas to turn glucose into energy, is the most common type of diabetes. In recent years, a series of new hypoglycemic drugs have appeared: sodium-dependent glucose transporter 2 inhibition (SGLT-2Is). The objective of this study is to compare and summarize the efficacy and safety of SGLT-2Is in subgroups of T2DM patients by an individual participant data (IPD) meta-analysis,expect to comprehensively evaluate the efficacy and safety of this type of new drugs in different subgroups.
The proposed dates for completion of the key milestones of the project would be:
? Initiation: By June 2021
? Data cleaning and harmonization: By August 2021
? Completion of analyses: By December 2021
? First manuscript draft: By February 2022
? Submission of manuscript: By May 2022
Dissemination Plan: These above conclusions will be written as a series of IPD meta-analysis articles and will be published in "peer-reviewed journals",such as DIABETES, Diabetologia, and Diabetes, Obesity and Metabolism. The publication plan is expected to be completed during the second quarter to the third quarter of 2022.