Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Determine Whether, in Patients With Type 2 Diabetes at High Risk for Cardiovascular and Renal Events, Aliskiren, on Top of Conventional Treatment, Reduces Cardiovascular and Renal Morbidity and Mortality
Brief Summary: The purpose of this study was to determine whether, in patients with type 2 diabetes and pre-existing disease of the heart and the circulatory system and/or the kidney, aliskiren at a target dose of 300 mg once daily (compared to placebo), on top of conventional treatment, reduces death and disease caused by the heart, the circulatory system and the kidney.

AMENDMENT 4 RATIONALE (MARCH 2012) :

Protocol amendment 4 served to address the data monitoring committee recommendation dated 14 Dec 2011 to discontinue study treatment in all participating patients. It also addressed the subsequent Health Authorities request to implement a 12 month safety follow-up period (actual duration was 9 months in average) post study drug discontinuation.


Options:
A: Inclusion Criteria:

* Male and female outpatients 18 years of age and older
* Patients who are eligible and able to participate in the study

Exclusion Criteria:

* Severe hypertension
* History or evidence of a secondary form of hypertension
* History of hypertensive encephalopathy or cerebrovascular accident.

Other protocol-defined inclusion/exclusion criteria may apply
B: Inclusion Criteria:

Systolic blood pressure 130 - 159 mmHg with any one of the following (1, 2 or 3):

1. Men and women aged ≥ 65 years if they have at least one of the following: (secondary prevention) Coronary heart disease

   * Previous myocardial infarction or
   * Stable angina or unstable angina with documented multi-vessel coronary artery disease, \> 50% stenosis in at least 2 major coronary arteries on coronary angiography, or positive stress test (ECG or nuclear perfusion scintogram), or
   * Multi-vessel PCI, or
   * Multi-vessel CABG surgery \> 4 years prior to informed consent, or with recurrent angina or ischemia following surgery Stroke/TIA Previous documented stroke or documented TIA \< 1 year before informed consent Peripheral artery disease
   * Previous limb bypass surgery or percutaneous transluminal angioplasty, or
   * Previous limb or foot amputation, or
   * History of intermittent claudication, with an ankle:arm BP ratio ≤ 0.80 on at least one side, or significant peripheral artery stenosis (\> 50%) documented by angiography or non-invasive testing
   * Diabetes mellitus: High-risk diabetics with evidence of end-organ damage
2. Men and women aged ≥ 65 years with no history of CVD, and with at least 1 CV risk factor (primary prevention):

   * History of dyslipidemia, defined as LDL cholesterol \> 3.5 mmol/L (135 mg/dL) or HDL\< 1.3 mmol/L (50 mg/dL) in women or \< 1.0 mmol/L (39 mg/dL) in men or total cholesterol/HDL ratio \> 5
   * History of current or recent smoking (regular tobacco use within 5 years)
   * Abdominal adiposity defined as waist/hip ratio ≥ 0.90 in women and ≥ 0.95 in men
   * History of dysglycemia defined as impaired fasting glucose (IFG - fasting plasma glucose 5.6 to 6.9 mmol/L \[101 to 124 mg/dL\]), or impaired glucose tolerance (IGT - fasting plasma glucose \< 7 mmol/L \[126 mg/dL\] but 2 hour glucose 7.8 to 11.0 mmol/L \[140 to 198 mg/dL\]) or type 2 diabetes
   * Renal dysfunction: eGFR\< 60 ml/min/1.73m2 but \> 30 ml/min/1.73m2 (MDRD formula) and/or microalbuminurea/macroalbuminurea
   * Clinical evidence of left ventricular hypertrophy
3. Men and women aged ≥ 70 years if they do not have any of the above (primary prevention)

Exclusion Criteria:

1. Current treatment with aliskiren, an ACE-inhibitor, an ARB or an aldosterone antagonist and unable to discontinue this therapy in those without clinical vascular disease. Individuals with CVD or type 2 diabetes and/or renal dysfunction may receive an ACE-inhibitor or an ARB, but not both, contraindications to Aliskiren, Amlodipine or Hydrochlorothiazide.
2. Use of both thiazide diuretic and amlodipine or another calcium channel blocker. Patients on only one of these two classes of drugs are eligible
3. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg)
4. Symptomatic heart failure, requiring the use of loop diuretics
5. Hemodynamically significant primary valvular or outflow tract obstruction (e.g. aortic or mitral valve stenosis, asymmetric septal hypertrophy, malfunctioning prosthetic valve). Constrictive pericarditis. Complex congenital heart disease.
6. Acute stroke \< 3 months or TIA ≤ 7 days before informed consent, acute coronary syndrome \< 1 months before informed consent
7. Planned cardiac surgery or angioplasty \< 3 months after informed consent or having had the procedure \< 3 months before informed consent
8. Severe renal impairment eGFR ≤ 30 ml/min/1.73m2 (MDRD formula); known renal artery stenosis ; serum potassium ≥ 5.3 mmol/L
9. Chronic liver disease (i.e. cirrhosis, esophageal varices, portocaval shunt or persistent hepatitis) or abnormal liver function, i.e., alanine transaminase (ALT) or AST \> 3x upper limit of normal (ULN)
10. Concurrent treatment with cyclosporine or quinidine; chronic use of non-steroidal anti-inflammatory drug (NSAIDs) or cyclooxygenase-2 (COX 2) inhibitors in patients with eGFR \< 60 ml/min/1.73m2 (MDRD formula)
11. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years regardless of whether there is evidence of local recurrence or metastases
12. Other serious condition(s) likely to interfere with study participation or with the ability to complete the study. Significant psychiatric illness, senility, dementia, alcohol or substance abuse, which could impair the ability to provide informed consent and to adhere to the study procedures
C: Inclusion Criteria:

* Type 2 diabetes and at least one of the following:

  * Macroalbuminuria and an eGFR ≥30 mL/min/1.73 m2
  * Microalbuminuria and a reduced kidney function (eGFR eGFR ≥30 and \<60 mL/min/1.73 m2)
  * A history of CV disease (previous MI, previous stroke, heart failure, coronary artery disease, history of percutaneous coronary intervention, angiography proven stenosis ≥50% in at least one coronary artery and a reduced kidney function (eGFR ≥30 and \<60 mL/min/1.73 m2)
* Concomitant treatment should follow national guidelines and must include either an Angiotensin-converting-enzyme-inhibitor (ACEi) or an Angiotensin-receptor-blocker (ARB) but not both.

Exclusion Criteria:

* Type 1 diabetes mellitus
* Cardiovascular event or procedure ≤ 3 months prior to Visit 1
* Unstable serum creatinine
* Hypertension: Mean sitting systolic blood pressure (msSBP) ≥ 135 and \< 170 mmHg or Mean sitting diastolic blood pressure (msDBP) ≥ 85 and \< 110 mmHg unless treated with at least 3 anti-hypertensive medications
* Hypertension msSBP ≥ 170 or msDBP ≥ 110 mmHg
* Baseline Serum Potassium \> 5.0 mmol/L
* Patients who are treated with two renin-angiotensin-aldosterone-system-blockers
* Patients with NYHA class III or IV heart failure
* Known renal artery stenosis
* Previous randomization into the AVOID trial (CSPP100C2201)

EXCLUSION SPECIFIC TO THE SAFETY FOLLOW-UP PERIOD:

- Aliskiren or aliskiren containing fixed combination products must not be used

Other protocol-defined inclusion/exclusion criteria applied
D: Inclusion Criteria:

* Patients with CAD who have blood pressure in the pre-hypertensive range defined as a msSBP ≥ 125 and ≤ 139mmHg and a msDBP \< 90mmHg.
* Patients with or without current treatment for hypertension
* Angiographic evidence of coronary artery disease
* At least 2 qualifying Cardiovascular risk factors at Visit 1

Exclusion Criteria:

* Baseline IVUS determined unacceptable
* Patients requiring treatment with disallowed study medications
* Patients with clinically significant heart disease
* Previous or current diagnosis of heart failure (NYHA Class IV) or a documented left ventricular ejection fraction of \< 25%
* Patients requiring treatment with any 2 of the following classes of medication at Visit 1 or Visit 2:

  * Angiotensin converting enzyme inhibitors
  * Angiotensin receptor blockers
  * aldosterone receptor blockers or a direct renin inhibitor.
* Other conditions may apply

Answer: C