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

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ClinicalTrials.gov Identifier: NCT03264352
Recruitment Status : Not yet recruiting
First Posted : August 29, 2017
Last Update Posted : January 12, 2018
Sponsor:
Information provided by (Responsible Party):
Jiyan Chen, Guangdong General Hospital

Brief Summary:
Lowering of blood pressure (BP) in high-risk hypertensive individuals reduces major adverse cardiovascular (CV) events. Diabetic patients with hypertension benefit from BP lowering treatment. The present trial,IPAD in brief, is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study involving 12,000 patients to be recruited over three years and to be followed up for a median of three years and a half. IPAD tests the hypothesis that antihypertensive medications in adults with type 2 diabetes, whose seated BP 130-149 mm Hg systolic and below 90 mm Hg diastolic, results in 35% difference in the incidence of stroke. During follow-up the sitting systolic pressure should be decreased both by at least 10 mm Hg and lower than 130 mm Hg, by titration and combination of the double-blind study medications of an angiotensin type-1 receptor blocker Allisartan (240 mg/day), a dihydropyridine calcium-channel blocker (amlodipine 5-10 mg/day), and a hydrochlorothiazide (12.5-25 mg/day). In the placebo group, identical tablets will be used similarly.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Stroke Blood Pressure Prehypertension Cardiovascular Risk Factor Drug: Allisartan Isoproxil Drug: Amlodipine 5mg Drug: Hydrochlorothiazide 25 mg Drug: Allisartan Isoproxil placebo Drug: Amlodipine placebo Drug: Hydrochlorothiazide placebo Phase 4

Detailed Description:
The IPAD trial is a randomized, double-blind, placebo-controlled, multicenter study. 12,000 patients will be recruited over three years with a median follow up of 3.5 years. IPAD tests the hypothesis that antihypertensive medical therapy in adult patients with type 2 diabetes, whose seated BP ranges from 130 to 149 mm Hg systolic and ≤ 90 mm Hg diastolic, results in 35% reduction in the incidence of stroke, which is the primary endpoint. Secondary endpoints of this study include: a composite of cardiovascular death, nonfatal stroke, nonfatal MI, hospitalization for heart failure and hospitalization for unstable angina; each single event listed above; all-cause mortality; renal dysfunction; diabetic retinopathy that needs interventional operation; peripheral arterial diseases; new on-set atrial fibrillation or flutter; cancer; change of health-related quality of life; cost-effectiveness of medications. Inclusion criteria for the study include T2DM patients aged between 35 and 75 years within the aforementioned BP ranges. The sitting systolic BP should decrease by at least 10 mm Hg systolic and to ≤130 mm Hg, using titration and combination of the double-blind study medications consisting of an angiotensin type-1 receptor blocker Allisartan (240 mg/day), a dihydropyridine calcium-channel blocker (amlodipine 5-10 mg/day), and a hydrochlorothiazide (12.5-25 mg/day). In the control group, placebo tablets will be used. Across the whole study, 282 primary endpoints are expected to occur. Interim analyses will be carried out on an intention-to-treat basis at the accumulation of every 100 primary endpoints. At the completion of the trial, both an intention-to-treat and a per-protocol analysis will be performed.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Intervention for High-normal or Borderline-elevated Blood Pressure in Adults With Type 2 Diabetes
Estimated Study Start Date : February 2018
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: active-treatment group
Real antihypertensive agents will be provided for this arm, to decrease systolic BP both by at least 10 mm Hg and lower than 130 mm Hg. In the active-treatment 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); scored tablets with hydrochlorothiazide 25 mg (third-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) and afterwards hydrochlorothiazide (first 12.5 mg or then 25 mg daily) will be given in addition. If intolerable side effects occur, first-line medication may be replaced by second-line or similarly, second-line medication may be replaced by third-line medication.
Drug: Allisartan Isoproxil
Allisartan Isoproxil 240mg daily will be used.
Other Name: Xinlitan

Drug: Amlodipine 5mg
Amlodipine 5mg daily will be added to Allisartan Isoproxil and afterwards increased to 10mg daily, if necessary to reach the blood pressure goal,
Other Name: Qiaohean

Drug: Hydrochlorothiazide 25 mg
Hydrochlorothiazide 25 mg (first 12.5 mg or then 25 mg daily) will be given subsequently if the blood pressure goal is still not reached.

Placebo Comparator: placebo group
This arm receives identical agents to the active study drugs (Allisartan Isoproxil placebo, Amlodipine placebo and hydrochlorothiazide placebo) also to decrease systolic BP both by at least 10 mm Hg and lower than 130 mm Hg, with a similar schedule of administration to the parallel arm.
Drug: Allisartan Isoproxil placebo
Allisartan Isoproxil placebo is identical to Allisartan Isoproxil 240mg.

Drug: Amlodipine placebo
Amlodipine 5mg placebo is identical to Amlodipine 5mg.

Drug: Hydrochlorothiazide placebo
Hydrochlorothiazide 25mg placebo is identical to Hydrochlorothiazide 25mg.




Primary Outcome Measures :
  1. Stroke [ Time Frame: From date of randomization until the date of first documented incidence of stroke, assessed up to 60 months. ]
    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.


Secondary Outcome Measures :
  1. Composite of Major Adverse Cardiovascular Events [ 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 ]
    The major adverse cardiovascular events defined in the study include cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, hospitalization for congestive heart failure and hospitalization for unstable angina.

  2. Cardiovascular Death [ Time Frame: From date of randomization until the date of cardiovascular death, assessed up to 60 months. ]
    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.

  3. Acute Myocardial Infarction [ Time Frame: From date of randomization until the date of first documented incidence of acute MI, assessed up to 60 months. ]
    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.

  4. Hospitalization of Unstable Angina [ Time Frame: From date of randomization until the date of first documented hospitalization of unstable angina, assessed up to 60 months. ]
    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.

  5. Hospitalization of Congestive Heart Failure [ Time Frame: From date of randomization until the date of first documented hospitalization of HF, assessed up to 60 months. ]
    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.

  6. All-cause Mortality [ Time Frame: From date of randomization until the date of death from any causes, assessed up to 60 months. ]
    All-cause mortality refers to death from any causes.

  7. Overt Albuminuria [ Time Frame: From date of randomization until the date of confirmed development of overt albuminuria, assessed up to 60 months. ]
    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.

  8. End-Stage Renal Disease [ Time Frame: From date of randomization until the date of documented diagnosis of end-stage renal disease, assessed up to 60 months. ]
    End-stage renal disease (ICD-Code N18.5) is the need for long-term renal replacement therapy (dialysis).

  9. Diabetic Retinopathy Requiring Interventional Operation or Surgery [ Time Frame: From date of randomization until the date of first documented interventional or surgical operation for diabetic retinopathy, assessed up to 60 months. ]
    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.

  10. Peripheral Arterial Diseases Requiring Revascularization [ Time Frame: From date of randomization until the date of first documented revascularization for peripheral arterial diseases, assessed up to 60 months. ]
    Peripheral arterial diseases requiring revascularization are defined as the confirmed diagnosis of any one of the peripheral arterial diseases indicated for revascularization.

  11. New 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. ]
    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.

  12. Cancer [ Time Frame: From date of randomization until the date of first confirmed diagnosis of a cancer of any type, assessed up to 60 months. ]
    Cancer defined in the present study is recorded only when there is pathologically confirmed evidence.

  13. Health-related Quality of Life [ Time Frame: up to 60 months ]
    Health-related Quality of Life will be assessed using the EQ-5D-5L QOL questionnaire.

  14. Cost-effectiveness of Drug Therapy [ Time Frame: up to 60 months ]
    Cost-effectiveness of drug therapy will be assessed by calculating the incremental cost-effectiveness ratio.



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Ages Eligible for Study:   35 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • irrespective of sex;
  • aged between 35 and 75 years;
  • with office-measured seated BP 130-149 mm Hg systolic and below 90 mm Hg diastolic;
  • without previous use of antihypertensive drugs;
  • diagnosed of type 2 diabetes mellitus (T2DM), with stable diabetic therapy (dose of any one antidiabetic drug has not changed by more than two-fold and new agents have not been added within the previous 3 months)
  • a glycosylated hemoglobin (HbA1c) between 6.5% and 8.0%;
  • informed consent provided and long-term follow-up possible

Exclusion Criteria:

  • a history of hypoglycemic coma / seizure within last 12 months;
  • confirmed diagnosis of type 1 diabetes mellitus;
  • alanine-aminotransferase (ALT) or aspartate-aminotransferase (AST) over two times the upper limit of normal;
  • serum creatinine >150 μmol/L;
  • a ratio of urinary albumin (in mg/L) to urinary creatinine (in g/L) (ACR) > 30 mg/g;
  • coronary artery disease requiring beta-blockers, renin-angiotensin system (RAS) blockers for secondary prevention within one year prior to randomization;
  • congestive heart failure requiring treatment with digitalis, diuretics, beta-blockers, aldosterone antagonists, RAS blockers, and/or vasodilators within one year prior to randomization;
  • acute on-set of myocardial infarction, heart failure or stroke within 6 months prior to randomization;
  • a history of psychological or mental disorder;
  • severe non-cardiovascular diseases that are life threatening, potentially limit follow-up to less than the projected duration (3 years);
  • pregnancy or currently planning to have babies or lactation;
  • known contraindications for the active study medications;
  • a malignancy that clinical investigators consider as unsuitable to participate;
  • any organ transplant;
  • currently participating in another clinical trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03264352


Contacts
Contact: Jiyan Chen, MD 86-13802911148 chen-jiyan@163.com

Locations
China, Guangdong
Guangdong General Hospital
Guangzhou, Guangdong, China, 501080
Sponsors and Collaborators
Jiyan Chen
Investigators
Principal Investigator: Jiyan Chen, MD Guangdong General Hospital

Responsible Party: Jiyan Chen, chairman of the cardiology department, Guangdong General Hospital
ClinicalTrials.gov Identifier: NCT03264352     History of Changes
Other Study ID Numbers: GDREC2017192H
First Posted: August 29, 2017    Key Record Dates
Last Update Posted: January 12, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Antihypertensive Agents
Diabetes Mellitus
Diabetes Mellitus, Type 2
Prehypertension
Hypertension
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Vascular Diseases
Cardiovascular Diseases
Amlodipine
Hydrochlorothiazide
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors