A Long Term, Open Label, Randomised Study in Patients With Type 2 Diabetes, Comparing the Combination of Rosiglitazone and Either Metformin or Sulfonylurea With Metformin Plus Sulfonylurea on Cardiovascular Endpoints and Glycaemia
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 4,447
- 试验地点
- 1
- 主要终点
- Number of Participants With Cardiovascular Death/Cardiovascular Hospitalisation Events
研究概览
简要总结
This study is a phase 3b, multicentre, randomised, open label, parallel group study. A 4-week run-in period will be followed by a median of 6 years of treatment with study medication in addition to continuation of background glucose lowering therapy. Patients inadequately controlled on background metformin will be randomised to receive, in addition to metformin, either rosiglitazone or a sulfonylurea(glibenclamide, gliclazide or glimepiride) in a ratio of 1:1. Patients inadequately controlled on background SU will be randomised to receive, in addition to SU, either rosiglitazone or metformin in a ratio of 1:1. Equal numbers of patients receiving background metformin and SU at entry will be entered into the study.
详细描述
A RECORD follow-up study is being performed to monitor the incidence of cancer and bone fractures in RECORD patients for a period of 4 years after the end of the main RECORD study (2008 - 2012).
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
- None
入排标准
- 年龄范围
- 40 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with type II diabetes mellitus as defined by 1999 World Health Organisation criteria.
- •Glycated haemoglobin (HbA1c) >7.0 % to = 9.0 % at visit
- •Use of an oral glucose lowering agent for a minimum of 6 months prior to screening and unchanged for 2 months prior to screening.
- •Body mass index >25.0 kg/m2.
排除标准
- •Patients receiving any other glucose lowering therapy which is not metformin or a sulfonylurea.
- •Patients with systolic blood pressure >180 mmHg or diastolic blood pressure >105 mmHg.
- •Patients who have required the use of insulin for glycaemic control at any time in the past.
- •Hospitalisation for any major cardiovascular event in the last 3 months.
研究组 & 干预措施
rosiglitazone in addition to background metformin
Participants inadequately controlled on background metformin (MET) were randomised to receive rosiglitazone (RSG), in addition to MET. RSG was initiated as a 4 mg once daily dose and was increased to a maximum dose of 8 mg per day as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Rosiglitazone (Drug)
rosiglitazone in addition to background metformin
Participants inadequately controlled on background metformin (MET) were randomised to receive rosiglitazone (RSG), in addition to MET. RSG was initiated as a 4 mg once daily dose and was increased to a maximum dose of 8 mg per day as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Metformin (Drug)
rosiglitazone in addition to background sulfonylurea
Participants inadequately controlled on background SU were randomised to receive, in addition to SU, RSG. RSG was initiated as a 4 mg once daily dose and was increased to a maximum dose of 8 mg per day as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Rosiglitazone (Drug)
rosiglitazone in addition to background sulfonylurea
Participants inadequately controlled on background SU were randomised to receive, in addition to SU, RSG. RSG was initiated as a 4 mg once daily dose and was increased to a maximum dose of 8 mg per day as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Sulfonylurea (Drug)
Sulfonylurea in addition to background metformin
Participants inadequately controlled on background MET were randomised to receive, in addition to MET, a sulfonylurea (SU) (glibenclamide, gliclazide, or glimepiride). The SU was gradually increased to the maximum permitted dose (glibenclamide 15 mg per day or miconizied equivalent of 10.5 mg per day; gliclazide 240 mg per day; glimepiride 4 mg per day) as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Sulfonylurea (Drug)
Sulfonylurea in addition to background metformin
Participants inadequately controlled on background MET were randomised to receive, in addition to MET, a sulfonylurea (SU) (glibenclamide, gliclazide, or glimepiride). The SU was gradually increased to the maximum permitted dose (glibenclamide 15 mg per day or miconizied equivalent of 10.5 mg per day; gliclazide 240 mg per day; glimepiride 4 mg per day) as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Metformin (Drug)
Metformin in addition to background sulfonylurea
Participants inadequately controlled on background SU were randomised to receive, in addition to SU, MET. MET was gradually increased to the maximum permitted dose of 2550 mg per day as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Sulfonylurea (Drug)
Metformin in addition to background sulfonylurea
Participants inadequately controlled on background SU were randomised to receive, in addition to SU, MET. MET was gradually increased to the maximum permitted dose of 2550 mg per day as required to achieve a target HbA1c of less than or equal to 7.0 percent.
干预措施: Metformin (Drug)
结局指标
主要结局
Number of Participants With Cardiovascular Death/Cardiovascular Hospitalisation Events
时间窗: Baseline through End of Study (up to 7.5 years)
The number of participants with cardiovascular death events (death due to cardiovascular causes or deaths with insufficient information to rule out a cardiovascular cause) and cardiovascular hospitalisation events (hospitalisation for a cardiovascular event, excluding planned admissions not associated with a worsening of the disease/condition of the participant) was recorded.
Independent Re-adjudication Outcome: Number of Participants Who Died Due to Any Cause
时间窗: Baseline through End of Study (up to 7.5 years)
All deaths identified during the original record study and discovered after the re-adjudication efforts began were included.
Independent Re-adjudication (IR) Outcome: Number of Participants With a First Occurrence of a Major Adverse Cardiovascular Event (MACE) Defined as CV (or Unknown) Death, Non-fatal MI, and Non-fatal Stroke Based on Original RECORD Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
IR was based on original RECORD endpoint definitions. CV death= no unequivocal non-CV cause (sudden death, death from acute vascular events, heart failure, acute MI, other CV causes, and deaths adjudicated as unknown cause). MI event=hospitalization + elevation of specific cardiac biomarkers above the upper limit of normal + cardiac ischemia symptoms/new pathological electrocardiogram findings. Stroke event=hospitalization + rapidly developed clinical signs of focal/global disturbance of cerebral function for more than 24 hours, with no apparent cause other than a vascular origin.
Independent Re-adjudication Outcome: Number of Participants With a First Occurrence of a Major Adverse Cardiovascular Event (MACE) Defined as CV (or Unknown) Death, Non-fatal MI, and Non-fatal Stroke Based on Contemporary Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
Independent re-adjudication was based on the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions. CV death included death resulting from an acute MI; sudden cardiac death and death due to heart failure, stroke, and to other CV causes. Deaths of unknown cause were counted as CV deaths. MI was defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Stroke was defined as an acute episode of neurological dysfunction caused by focal or global brain, spinal cord, or retinal vascular injury.
Independent Re-adjudication Outcome: Number of Participants With a CV (or Unknown) Death, Based on Original RECORD Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
The number of participants with a CV death (or unknown) as determined by independent re-adjudication using the original RECORD endpoint definitions was recorded. CV death was defined as any death for which an unequivocal non-CV cause could not be established. CV death included death following heart failure, death following acute myocardial infarction (MI), sudden death, death due to acute vascular events, and other CV causes. Deaths due to unknown causes were classified as "unknown deaths," but were counted as CV deaths for the analysis of this endpoint.
Independent Re-adjudication Outcome: Number of Participants With a CV (or Unknown) Death, Based on Contemporary Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
The number of participants with a CV (or unknown) death as determined by independent re-adjudication using the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions was recorded. CV death included death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure, death due to stroke, and death due to other CV causes. Deaths of unknown cause were counted as CV deaths.
Independent Re-adjudication Outcome: Number of Participants With an Event of Myocardial Infarction (Fatal and Non-fatal), Based on Original RECORD Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
The number of participants with an MI (fatal or non-fatal) event as determined by independent re-adjudication using the original RECORD endpoint definitions was recorded. An event of MI was defined as hospitalization plus elevation of cardiac biomarkers troponin (TN) I and/or TNT above the upper limit of normal (ULN) or creatinine kinase (CK) MB (M=muscle type; B=brain type) isoenzyme \>= 2x the ULN or CK \> 2x the ULN plus typical symptoms of cardiac ischemia or new pathological electrocardiogram findings, or cause of death adjudicated as MI.
Independent Re-adjudication Outcome: Number of Participants With an Event of Myocardial Infarction (Fatal and Non-fatal), Based on Contemporary Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
The number of participants with an MI (fatal or non-fatal) event as determined by independent re-adjudication using the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions was recorded. An event of MI was defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia.
Independent Re-adjudication Outcome: Number of Participants (Par.) With an Event of Stroke (Fatal and Non-fatal), Based on Original RECORD Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
Par. with a stroke (fatal or non-fatal) event as determined by independent re-adjudication using the original RECORD endpoint definitions was recorded. A stroke event=hospitalization plus rapidly developed clinical signs of focal (or global) disturbance of cerebral function lasting more than 24 hours (unless interrupted by thrombolysis, surgery, or death), with no apparent cause other than a vascular origin, including par. presenting clinical signs/symptoms suggestive of subarachnoid haemorrhage/intracerebral haemorrhage/cerebral ischemic necrosis or cause of death adjudicated as stroke.
Independent Re-adjudication Outcome: Number of Participants With an Event of Stroke (Fatal and Non-fatal), Based on Contemporary Endpoint Definitions
时间窗: Baseline through End of Study (up to 7.5 years)
The number of participants with a stroke (fatal or non-fatal) event as determined by independent re-adjudication using the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions was recorded. An event of stroke was defined as an acute episode of neurological dysfunction caused by focal or global brain, spinal cord, or retinal vascular injury.
次要结局
- Number of Participants With CV/Microvascular Events(Baseline through End of Study (up to 7.5 years))
- Number of Participants With Glycaemic Failure Events(Baseline through to end of randomised dual therapy)
- Model Adjusted Change From Baseline in Body Weight at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Model Adjusted Change From Baseline in Alanine Aminotransferase at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Model Adjusted Change From Baseline in Waist Circumference at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Number of Participants With the Indicated Type of Malignant Neoplasms/Cancer Events Reported as an SAE or Death by Location (Including Location of Special Interest): Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With Cardiovascular Events and All-cause Deaths(Baseline through End of Study (up to 7.5 years))
- Total Number of Cardiovascular Hospitalisations and Cardiovascular Deaths(Baseline through End of Study (up to 7.5 years))
- Number of Participants With First Cardiovascular Hospitalisations/Cardiovascular Deaths by Stratum(Baseline through End of Study (up to 7.5 years))
- Number of Participants With Addition of Third Oral Agent/Switch to Insulin(Baseline through End of Study (up to 7.5 years))
- The Number of Participants Starting Insulin at Any Time During the Study(Baseline through End of Study (up to 7.5 years))
- Model Adjusted Change From Baseline in HbA1c at Month 60(Baseline and Month 60 of randomised dual therapy treatment period)
- Model Adjusted Change From Baseline in Fasting Plasma Glucose at Month 60(Baseline to Month 60 of the randomised dual therapy treatment period)
- Model Adjusted Mean Change From Baseline in Insulin and Pro-insulin at Month 60(Baseline to Month 60 of the randomised dual therapy treatment period)
- Number of HbA1c and Fasting Plasma Glucose (FPG) Responders at Month 60(Baseline to Month 60 of the randomised dual therapy treatment period)
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) Homeostasis Model Assessment (HOMA) Beta Cell Function and Insulin Sensitivity at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Total Cholesterol (TC), Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, Triglycerides, and Free Fatty Acids (FFAs) at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Total Cholesterol (TC):High-density Lipoprotein (HDL) Cholesterol and Low-density Lipoprotein (LDL) Cholesterol:HDL Cholesterol Ratios at Month 60(Baseline to Month 60 of the randomised dual therapy treatment period)
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Apolipoprotein B (Apo-B) at Month 60(Baseline to Month 60 of the randomised dual therapy treatment period)
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Fibrinogen at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Plasminogen Activator Inhibitor-1 (PAI-1) Antigen at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Number of Participants With the Indicated Type of Neoplasm/Cancer Event Reported as a Serious Adverse Event (SAE) or Death: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Urinary Albumin Creatinine Ratio at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Model Adjusted Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Model Adjusted Ratio to Baseline (Expressed as a Percentage) for C-Reactive Protein at Month 60(Baseline to Month 60 of the randomised dual therapy treatment phase)
- Number of Participants With the Indicated Type of Neoplasm/Cancer Event Reported as a Serious Adverse Event (SAE) or Death: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Participants With the Indicated Type of Malignant Neoplasms/Cancer Events Reported as an SAE or Death by Location (Including Location of Special Interest): Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Participants Who Died Due to the Indicated Cancer-related Event: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants Who Died Due to the Indicated Cancer-related Event: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Participants With a Bone Fracture Event - Overall and by Gender: Main Study and Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With a Bone Fracture Event - Overall and by Gender: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Participants With the Indicated Bone Fracture by Fracture Site: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With a Bone Fracture Event Reported as the Indicated Serious Adverse Event (by Higher Level Group Term) or Death: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With a Bone Fracture Event Reported as the Indicated Serious Adverse Event (by Higher Level Group Term) or Death: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Participants With an Event of Death Due to a Bone Fracture-related Event: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With the Indicated Bone Fracture by Fracture Site: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Participants With Potentially High Morbidity Fractures: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With Potentially High Morbidity Fracture Events and Non-high Morbidity Fracture Events, in Participants With Prior Hand/Upper Arm/Foot Fractures (H/UA/FF): Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With Bone Fracture Events of the Indicated Cause: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Participants With Bone Fracture Events of the Indicated Cause: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Bone Fracture Events With the Indicated Outcome: Main Study + Observational Follow-up Combined(From the beginning of the main study through the end of the observational follow-up (up to 11.4 years))
- Number of Bone Fracture Events With the Indicated Outcome: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))
- Number of Participants With the Indicated Serious Adverse Event: Observational Follow-up(From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years))