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Intervention for High-normal Blood Pressure in Adults With Type 2 Diabetes (IPAD)

Primary Purpose

Diabetes Mellitus, Type 2, Adverse Event, Blood Pressure

Status
Recruiting
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Allisartan Isoproxil
Amlodipine 5mg
Standard treatment by current guideline
Sponsored by
XueQing Yu
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 2

Eligibility Criteria

45 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • irrespective of sex;
  • aged between 45 and 79 years;
  • with office-measured seated BP 120-139 mm Hg systolic and below 90 mm Hg diastolic;
  • diagnosed of type 2 diabetes mellitus (T2DM), currently on diabetic therapy;
  • informed consent provided and long-term follow-up possible

Exclusion Criteria:

  • poor control of blood glucose, HbA1c > 10.0%
  • administration of any antihypertensive medications within 1 month;
  • a history of hypoglycemic coma / seizure;
  • confirmed diagnosis of type 1 diabetes mellitus;
  • alanine-aminotransferase (ALT) or aspartate-aminotransferase (AST) over three times the upper limit of normal;
  • estimated glomerular filtration rate < 45 ml/min/1.73m2;
  • a history of congestive heart failure with left ventricular ejection fraction < 40%;
  • coronary artery disease requiring RAS blockers for secondary prevention;
  • acute on-set of stroke within 6 months prior to randomization;
  • a ratio of urinary albumin (in mg/L) to urinary creatinine (in g/L) (ACR) ≥ 300 mg/g;
  • known contraindications for the active study medications;
  • a history of psychological or mental disorder;
  • pregnancy or currently planning to have babies or lactation;
  • severe diseases such as severe heart diseases;
  • an expected residual life span less than 3 years;
  • a malignancy that clinical investigators consider as unsuitable to participate;
  • currently participating in another clinical trial.

Sites / Locations

  • Guangdong General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

intensive treatment group

standard treatment group

Arm Description

Real antihypertensive agents will be provided for this arm, to decrease systolic BP to lower than 120 mm Hg. In this group, the following study medications will be used: tablets with Allisartan Isoproxil 240 mg (first-line medication); tablets with Amlodipine 5 mg (second-line medication). Treatment will be started with Allisartan 240 mg. If necessary to reach the BP goal, Amlodipine (first 5 mg or then 10 mg daily) will be given in addition. If intolerable side effects occur, first-line medication may be replaced by second-line medication.

In this arm participants are followed up and no medications be used until BP becomes ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic. Medications are determined by investigators in lines with recommendations by current Chinese guidelines to decrease BP to lower than 140 mm Hg systolic and to lower than 90 mm Hg diastolic.

Outcomes

Primary Outcome Measures

Composite of Major Adverse Cardiovascular and Cerebrovascular Events
The major adverse cardiovascular and cerebrovascular events defined in the study include cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, hospitalization for congestive heart failure and hospitalization for unstable angina.

Secondary Outcome Measures

Stroke
Stroke (ICD-Code I60, I61, I63, I64) is a focal neurological deficit with symptoms continuing for more than 24 hours or leading to death with no apparent cause other than vascular. Stroke as an endpoint in IPAD includes definite ischemic stroke, primary intracerebral hemorrhage and subarachnoid hemorrhage with evidence from CT or MRI scan within 14 days of onset or autopsy confirmation, and stroke of unknown type etiology when CT, MRI, or autopsy are not done and information is inadequate to diagnose the etiology definitely.
Cardiovascular Death
Cardiovascular death include death caused by stroke, MI, HF, sudden death or any other death attributed to cardiovascular diseases. Sudden death (ICD-Code I46.1, R96) encompasses any death of unknown origin occurring instantly or within an estimated 24 hours after the onset of acute symptoms as well as unattended death for which no likely cause can be established by autopsy or recent medical history.
Acute Myocardial Infarction
Acute myocardial infarction (MI) (ICD-Code I21) is defined when any one of the following criteria occurs. (1) Detection of a rise and/or fall of cardiac biomarker values, with at least one value above the 99th percentile upper reference limit and with at least one of the following manifestations: symptoms of ischaemia that should have lasted for at least 30 minutes and should not have been responsive to sublingual administration of nitrates; new or presumed new significant ST-segment-T wave changes or new left bundle branch block (LBBB); development of pathological Q waves in the ECG; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. (2) Identification of an intracoronary thrombus by angiography or autopsy. (3) Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased.
Hospitalization of Unstable Angina
Unstable angina (ICD-Code I20.0) is defined as new onset or worsening angina pectoris requiring hospitalization with angiographically documented coronary atherosclerosis or transient electrocardiographic changes of the ST-segment or T-wave without evidence for myocardial necrosis. This diagnosis excludes patients with angina pectoris admitted to the hospital only for investigation.
Hospitalization of Congestive Heart Failure
Congestive heart failure (HF) (ICD-Code I50) requires the presence of three conditions, namely symptoms, such as dyspnea, clinical signs, such as ankle edema or crepitations, and the necessity to initiate treatment with open-label diuretics, vasodilators or antihypertensive drugs. HF cases may also be adjudicated as chronic stable HF but this is not considered an outcome of the present study.
All-cause Mortality
All-cause mortality refers to death from any causes.
Overt Albuminuria
Overt albuminuria is defined as a ratio of urinary albumin (in mg/L) to urinary creatinine (in g/L) in urine specimens of at least 300 mg/g.
Worsened Renal Function
Estimated glomerular filtration rate (eGFR) decreased by more than 30% as compared with baseline
End-Stage Renal Disease
End-stage renal disease (ICD-Code N18.5) is the need for long-term renal replacement therapy (dialysis).
Diabetic Retinopathy Requiring Interventional Operation or Surgery
Diabetic retinopathy requiring interventional operation or surgery is defined as the confirmed diagnosis of diabetic retinopathy, indicated for interventional operation or surgery, which is documented by ophthalmologists.
Peripheral Arterial Diseases Requiring Revascularization
Peripheral arterial diseases requiring revascularization are defined as the confirmed diagnosis of any one of the peripheral arterial diseases indicated for revascularization.
New Atrial Fibrillation or Flutter
Atrial fibrillation or flutter is confirmed and documented with electrocardiogram indicating the occurence of atrial fibrillation or flutter. New development of atrial fibrillation or flutter is defined only if a participant at baseline has no history of and his or her electrocardiogram shows no signs of atrial fibrillation or flutter.
Decline of Health-related Quality of Life
Decline of Health-related Quality of Life, which is assessed using the EQ-5D-5L QOL questionnaire.
Cancer
Cancer defined in the present study is recorded only when there is pathologically confirmed evidence.

Full Information

First Posted
August 21, 2017
Last Updated
February 21, 2023
Sponsor
XueQing Yu
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1. Study Identification

Unique Protocol Identification Number
NCT03264352
Brief Title
Intervention for High-normal Blood Pressure in Adults With Type 2 Diabetes
Acronym
IPAD
Official Title
Intervention for High-normal Blood Pressure in Adults With Type 2 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 1, 2018 (Actual)
Primary Completion Date
September 2025 (Anticipated)
Study Completion Date
September 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
XueQing Yu

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Lowering of blood pressure (BP) in high-risk hypertensive individuals reduces major adverse cardiovascular and cerebrovascular events. Diabetic patients with hypertension benefit from BP lowering treatment. The present trial, IPAD in brief, is a randomized, open-label, parallel-designed, multicenter study involving nearly 12,000 patients to be recruited and to be followed up for a median of four years. IPAD tests the hypothesis that antihypertensive medications in adults with type 2 diabetes, whose seated BP 120-139 mm Hg systolic and below 90 mm Hg diastolic, results in 20% difference in the incidence of major adverse cardiovascular and cerebrovascular events. During follow-up for participants in the intensive group, the sitting systolic pressure should be decreased to below 120 mm Hg, by titration and combination of the study medications of an angiotensin type-1 receptor blocker Allisartan (240 mg/day), a dihydropyridine calcium-channel blocker (amlodipine 5-10 mg/day), and/or other medications if necessary. For those in the standard group, the sitting systolic pressure should be monitored and controlled below 140 mm Hg.
Detailed Description
The IPAD trial is a randomized, open-label, parallel-designed, multicenter study. 11,414 patients will be recruited in three years with a median follow up of four years. IPAD tests the hypothesis that intensive antihypertensive medical therapy in adult patients with type 2 diabetes, whose seated BP ranges from 120 to 139 mm Hg systolic and < 90 mm Hg diastolic, results in 20% reduction in the incidence of major adverse cardiovascular and cerebrovascular events (the primary endpoint), a composite of stroke, cardiovascular death, nonfatal myocardial infarction (MI), hospitalization for heart failure (HF) and hospitalization for unstable angina. Secondary endpoints of this study include: stroke; cardiovascular death; MI; hospitalization for HF; hospitalization for unstable angina; all-cause mortality; overt albuminuria; worsened renal function (the estimated glomerular filtration rate decreased by > 30% from baseline); end-stage renal disease; development of diabetic retinopathy that needs interventional operation; peripheral arterial diseases; new on-set atrial fibrillation or flutter; cancer; decline of health-related quality of life. Inclusion criteria for the study include T2DM patients aged between 45 and 79 years within the aforementioned BP ranges. for participants in the intensive group, the sitting systolic BP should decrease to < 120 mm Hg, using titration and combination of study medications consisting of an angiotensin type-1 receptor blocker Allisartan (240 mg/day) and a dihydropyridine calcium-channel blocker (amlodipine 5-10 mg/day), and/or other medications if necessary.For those in the standard group, the sitting systolic pressure should be monitored and controlled below 140 mm Hg. Across the whole study, 820 primary endpoints are expected to occur. Interim analyses will be carried out on an intention-to-treat basis. At the completion of the trial, both an intention-to-treat and a per-protocol analysis will be performed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2, Adverse Event, Blood Pressure, Prehypertension, Cardiovascular Risk Factor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
11414 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
intensive treatment group
Arm Type
Active Comparator
Arm Description
Real antihypertensive agents will be provided for this arm, to decrease systolic BP to lower than 120 mm Hg. In this group, the following study medications will be used: tablets with Allisartan Isoproxil 240 mg (first-line medication); tablets with Amlodipine 5 mg (second-line medication). Treatment will be started with Allisartan 240 mg. If necessary to reach the BP goal, Amlodipine (first 5 mg or then 10 mg daily) will be given in addition. If intolerable side effects occur, first-line medication may be replaced by second-line medication.
Arm Title
standard treatment group
Arm Type
Placebo Comparator
Arm Description
In this arm participants are followed up and no medications be used until BP becomes ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic. Medications are determined by investigators in lines with recommendations by current Chinese guidelines to decrease BP to lower than 140 mm Hg systolic and to lower than 90 mm Hg diastolic.
Intervention Type
Drug
Intervention Name(s)
Allisartan Isoproxil
Other Intervention Name(s)
Xinlitan
Intervention Description
Allisartan Isoproxil 240mg daily will be used to lower BP to below 120 mm Hg systolic.
Intervention Type
Drug
Intervention Name(s)
Amlodipine 5mg
Other Intervention Name(s)
Qiaohean
Intervention Description
Amlodipine 5mg daily will be added to Allisartan Isoproxil and afterwards increased to 10mg daily, if necessary to reach the blood pressure goal (below 120 mm Hg systolic).
Intervention Type
Other
Intervention Name(s)
Standard treatment by current guideline
Intervention Description
No BP-lowering medications are used until BP becomes ≥ 140 mm Hg systolic and/or 90 mm Hg diastolic. Medications are determined by investigators in lines with recommendations by current Chinese guidelines to decrease BP to lower than 140 mm Hg systolic and to lower than 90 mm Hg diastolic.
Primary Outcome Measure Information:
Title
Composite of Major Adverse Cardiovascular and Cerebrovascular Events
Description
The major adverse cardiovascular and cerebrovascular events defined in the study include cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, hospitalization for congestive heart failure and hospitalization for unstable angina.
Time Frame
From date of randomization until the date of first documented incidence of the major adverse cardiovascular events prespecified, whichever comes first, assessed up to 60 months
Secondary Outcome Measure Information:
Title
Stroke
Description
Stroke (ICD-Code I60, I61, I63, I64) is a focal neurological deficit with symptoms continuing for more than 24 hours or leading to death with no apparent cause other than vascular. Stroke as an endpoint in IPAD includes definite ischemic stroke, primary intracerebral hemorrhage and subarachnoid hemorrhage with evidence from CT or MRI scan within 14 days of onset or autopsy confirmation, and stroke of unknown type etiology when CT, MRI, or autopsy are not done and information is inadequate to diagnose the etiology definitely.
Time Frame
From date of randomization until the date of first documented incidence of stroke, assessed up to 60 months.
Title
Cardiovascular Death
Description
Cardiovascular death include death caused by stroke, MI, HF, sudden death or any other death attributed to cardiovascular diseases. Sudden death (ICD-Code I46.1, R96) encompasses any death of unknown origin occurring instantly or within an estimated 24 hours after the onset of acute symptoms as well as unattended death for which no likely cause can be established by autopsy or recent medical history.
Time Frame
From date of randomization until the date of cardiovascular death, assessed up to 60 months.
Title
Acute Myocardial Infarction
Description
Acute myocardial infarction (MI) (ICD-Code I21) is defined when any one of the following criteria occurs. (1) Detection of a rise and/or fall of cardiac biomarker values, with at least one value above the 99th percentile upper reference limit and with at least one of the following manifestations: symptoms of ischaemia that should have lasted for at least 30 minutes and should not have been responsive to sublingual administration of nitrates; new or presumed new significant ST-segment-T wave changes or new left bundle branch block (LBBB); development of pathological Q waves in the ECG; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. (2) Identification of an intracoronary thrombus by angiography or autopsy. (3) Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased.
Time Frame
From date of randomization until the date of first documented incidence of acute MI, assessed up to 60 months.
Title
Hospitalization of Unstable Angina
Description
Unstable angina (ICD-Code I20.0) is defined as new onset or worsening angina pectoris requiring hospitalization with angiographically documented coronary atherosclerosis or transient electrocardiographic changes of the ST-segment or T-wave without evidence for myocardial necrosis. This diagnosis excludes patients with angina pectoris admitted to the hospital only for investigation.
Time Frame
From date of randomization until the date of first documented hospitalization of unstable angina, assessed up to 60 months.
Title
Hospitalization of Congestive Heart Failure
Description
Congestive heart failure (HF) (ICD-Code I50) requires the presence of three conditions, namely symptoms, such as dyspnea, clinical signs, such as ankle edema or crepitations, and the necessity to initiate treatment with open-label diuretics, vasodilators or antihypertensive drugs. HF cases may also be adjudicated as chronic stable HF but this is not considered an outcome of the present study.
Time Frame
From date of randomization until the date of first documented hospitalization of HF, assessed up to 60 months.
Title
All-cause Mortality
Description
All-cause mortality refers to death from any causes.
Time Frame
From date of randomization until the date of death from any causes, assessed up to 60 months.
Title
Overt Albuminuria
Description
Overt albuminuria is defined as a ratio of urinary albumin (in mg/L) to urinary creatinine (in g/L) in urine specimens of at least 300 mg/g.
Time Frame
From date of randomization until the date of confirmed development of overt albuminuria, assessed up to 60 months.
Title
Worsened Renal Function
Description
Estimated glomerular filtration rate (eGFR) decreased by more than 30% as compared with baseline
Time Frame
From date of randomization until the date of first documented incidence of this event, assessed up to 60 months.
Title
End-Stage Renal Disease
Description
End-stage renal disease (ICD-Code N18.5) is the need for long-term renal replacement therapy (dialysis).
Time Frame
From date of randomization until the date of documented diagnosis of end-stage renal disease, assessed up to 60 months.
Title
Diabetic Retinopathy Requiring Interventional Operation or Surgery
Description
Diabetic retinopathy requiring interventional operation or surgery is defined as the confirmed diagnosis of diabetic retinopathy, indicated for interventional operation or surgery, which is documented by ophthalmologists.
Time Frame
From date of randomization until the date of first documented interventional or surgical operation for diabetic retinopathy, assessed up to 60 months.
Title
Peripheral Arterial Diseases Requiring Revascularization
Description
Peripheral arterial diseases requiring revascularization are defined as the confirmed diagnosis of any one of the peripheral arterial diseases indicated for revascularization.
Time Frame
From date of randomization until the date of first documented revascularization for peripheral arterial diseases, assessed up to 60 months.
Title
New Atrial Fibrillation or Flutter
Description
Atrial fibrillation or flutter is confirmed and documented with electrocardiogram indicating the occurence of atrial fibrillation or flutter. New development of atrial fibrillation or flutter is defined only if a participant at baseline has no history of and his or her electrocardiogram shows no signs of atrial fibrillation or flutter.
Time Frame
From date of randomization until the date of first documented incidence of atrial fibrillation or flutter, assessed up to 60 months.
Title
Decline of Health-related Quality of Life
Description
Decline of Health-related Quality of Life, which is assessed using the EQ-5D-5L QOL questionnaire.
Time Frame
up to 60 months
Title
Cancer
Description
Cancer defined in the present study is recorded only when there is pathologically confirmed evidence.
Time Frame
From date of randomization until the date of first confirmed diagnosis of a cancer of any type, assessed up to 60 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: irrespective of sex; aged between 45 and 79 years; with office-measured seated BP 120-139 mm Hg systolic and below 90 mm Hg diastolic; diagnosed of type 2 diabetes mellitus (T2DM), currently on diabetic therapy; informed consent provided and long-term follow-up possible Exclusion Criteria: poor control of blood glucose, HbA1c > 10.0% administration of any antihypertensive medications within 1 month; a history of hypoglycemic coma / seizure; confirmed diagnosis of type 1 diabetes mellitus; alanine-aminotransferase (ALT) or aspartate-aminotransferase (AST) over three times the upper limit of normal; estimated glomerular filtration rate < 45 ml/min/1.73m2; a history of congestive heart failure with left ventricular ejection fraction < 40%; coronary artery disease requiring RAS blockers for secondary prevention; acute on-set of stroke within 6 months prior to randomization; a ratio of urinary albumin (in mg/L) to urinary creatinine (in g/L) (ACR) ≥ 300 mg/g; known contraindications for the active study medications; a history of psychological or mental disorder; pregnancy or currently planning to have babies or lactation; severe diseases such as severe heart diseases; an expected residual life span less than 3 years; a malignancy that clinical investigators consider as unsuitable to participate; currently participating in another clinical trial.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jiyan Chen, MD
Phone
86-13802911148
Email
chen-jiyan@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jiyan Chen, MD
Organizational Affiliation
Guangdong Provincial People's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Guangdong General Hospital
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
501080
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yingqing Feng, MD
Phone
86-13602863389
Email
fyq1819@163.com
First Name & Middle Initial & Last Name & Degree
Qi Zhong, MD
Phone
86-13580366163
Email
zhongqi219@126.com

12. IPD Sharing Statement

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Intervention for High-normal Blood Pressure in Adults With Type 2 Diabetes

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