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 or female outpatients ≥ 18 years of age
* Participants with essential hypertension:

  * Naive participants must have a mean sitting Systolic Blood Pressure (msSBP) ≥ 150 mmHg and \< 180 mmHg at Visit 1 and Visit 2. (Participants are considered 'naïve' if they have never been treated with any antihypertensive medication.)
  * All participants must have a msSBP ≥ 150 mmHg and \< 180 mmHg at Visit 2
* Written informed consent to participate in this study prior to any study procedures

Exclusion Criteria:

* Severe hypertension
* Pregnant or nursing (lactating) women
* Pre-menopausal women not taking accepted form of birth control
* Serum potassium ≥ 5.5 mEq/L (mmol/L) at Visit 1
* History of cardiovascular conditions
* Uncontrolled Type 1 or Type 2 diabetes mellitus
* Hypersensitivity to renin inhibitors, calcium channel blockers, or to drugs with similar chemical structures

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

Coronary Artery Disease: Previous Myocardial infarction(\> 2 days prior to informed consent), or stable or previous unstable angina (\> 30 days prior to informed consent) with documented multivessel coronary artery disease or a positive stress test, or multivessel Percutaneous Transluminal Coronary Angioplasty (\> 30 days prior to informed consent), or previous multivessel Coronary Artery Bypass Grafting without angina (if surgery performed \> 4 years prior to informed consent) or with recurrent angina after surgery.

Other High Risk:

1. Peripheral Arterial Disease: Previous limb bypass surgery or angioplasty or amputation, intermittent claudication on history with ankle/arm Blood Pressure ratio \< 0.8 on at least one side, or significant stenosis by angiography or non-invasive testing
2. Previous stroke
3. Transient ischemic Attack \> 7 days and \< 1 year prior to informed consent
4. Diabetes Mellitus (types I or II): with evidence of end-organ damage (retinopathy, Left ventricular hypertrophy, micro or macro albuminuria), or any evidence of previous cardiac or vascular disease.

No definite and specific indication or contraindication for any of the study treatments. Written informed consent.

Exclusion Criteria:

A. Medication use:

1. Inability to discontinue Angiotension Converting Enzyme (ACE) inhibitors or Angiotension 2 receptor antagonists (AIIAs).
2. Patients with known hypersensitivity or intolerance to Angiotension 2 receptor antagonists (AIIAs) or Angiotension Converting Enzyme (ACE)inhibitors.

NOTE: Patients with known intolerance to Angiotension Converting Enzyme inhibitor intolerance ( ACE-I) can be enrolled in the TRANSCEND study.

B. Cardiovascular disease:

1. Symptomatic congestive heart failure.
2. Hemodynamically significant primary valvular or outflow tract obstruction (e.g. aortic or mitral valve stenosis, asymmetric septal hypertrophy, malfunctioning prosthetic valve).
3. Constrictive pericarditis.
4. Complex congenital heart disease.
5. Syncopal episodes of unknown etiology \< 3 months before informed consent.
6. Planned cardiac surgery or angioplasty within three months.
7. Uncontrolled hypertension on treatment (i.e.Blood pressure ( BP) \> 160/100).
8. Heart transplant recipient.
9. Strokes due to subarachnoid hemorrhage

C. Other conditions:

1. Significant renal disease defined as:

   1. Renal artery stenosis;
   2. Creatinine clearance \< 0.6 ml/min or serum creatinine \> 265 umol/L (\> 3.0 mg/dL);
   3. Hyperkalemia: potassium \> 5.5 mmol/L.
   4. Proteinuria\* (for TRANSCEND only).
2. Hepatic dysfunction as defined by the following laboratory parameters: Serum Glutamate Pyruvate Transaminase( SGPT) Alaninaminotransferase (ALT) or Serum Glutamic Oxaloacetic Transaminase (SGOT) Aspartate aminotransferase (AST) \> than 4 times upper limit of normal or additional criteria for hepatic impairment the upper limit of normal range, total Bilirubin \> 20 umol/L, biliary obstructive disorders.
3. Uncorrected volume depletion or sodium depletion.
4. Primary aldosteronism.
5. Hereditary fructose intolerance.
6. Any other major non-cardiac illness expected to reduce life expectancy or interfere with study participation.
7. Patient is simultaneously taking another experimental drug.
8. Patient with significant disability that precludes regular attendance at clinic for follow-up.
9. Patient has sufficient disability or other incapacity that precludes regular attendance at clinic for follow-up.
10. Unable or unwilling to provide written informed consent.
D: Patients must meet ALL inclusion criteria

1. Aged 18-79
2. Male subjects or female subjects taking adequate contraception such as the oral contraceptive pill, an intra uterine device or who are surgically sterilised or postmenopausal Females
3. BP ≥150 mmHg (systolic) OR ≥ 95 mmHg (diastolic). Patients may be included if the PI anticipates BP criteria for inclusion will be met at randomisation
4. Either never-treated or received a maximum of one antihypertensive drug class in the previous year

Patients will be excluded for ANY ONE of the following reasons

1. Clinic SBP \> 200 mmHg or DBP \> 120 mmHg, with PI discretion to override if home BP measurements are lower
2. Secondary or accelerated phase hypertension
3. eGFR \< 45 mls/min
4. Contra-indication or previous intolerance to any trial therapy
5. Failure to record required home BP readings during placebo run-in.
6. Significant co-morbidity (investigator opinion but to include alcoholism, terminal illness, documented non-attendance at clinics etc)
7. Diabetes type 1
8. Plasma K+ outside normal range on two successive measurements during screening
9. Requirement for treatment with ≥2 drugs (which can be a CCB and/or {ACEi OR ARB OR direct renin inhibitor OR β-blocker}) in order to reduce blood pressure to ≤180/120 mmHg
10. Requirement for diuretic therapy (other than for hypertension)
11. Requirement for ACE inhibitor (or ARB) therapy (other than for hypertension)
12. Absolute contra-indications to any of the study drugs (listed on their data-sheet)
13. Current therapy for cancer
14. Anticipation of change in medical status during course of trial (e.g. planned surgical intervention requiring \>2 weeks convalescence , actual or planned pregnancy)
15. Inability to give informed consent
16. Participation in a clinical study involving an investigational drug or device within 4 weeks of screening.
17. Any concomitant condition that, in the opinion of the investigator, may adversely affect the safety and/or efficacy of the study drug or severely limit the subject's lifespan or ability to complete the study (eg, alcohol or drug abuse, disabling or terminal illness, mental disorders).
18. Treatment with any of the following prohibited medications:

    1. Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation.

       Chronic stable or unstable use of non-steroidal anti-inflammatory drugs (NSAIDs) other than acetylsalicylic acid is prohibited. Chronic use is defined as \>3 consecutive or nonconsecutive days of treatment per week. In addition, the intermittent use of NSAIDs is strongly discouraged throughout the duration of this study. If intermittent treatment is required, NSAIDs must not be used for more than a total of 2 days. For all subjects requiring analgesic or anti-pyretic agents, the use of paracetamol is recommended during study participation.
    2. The use of short-acting oral nitrates (eg, sublingual nitroglycerin) is permitted; however, subjects should not take short-acting oral nitrates within 4 hours of screening or any subsequent study visit.
    3. The use of long-acting oral nitrates (eg, Isordil) is permitted; however, the dose must be stable for at least 2 weeks prior to screening and randomisation.
    4. The use of sympathomimetic decongestants is permitted; however, not within 1 day prior to any clinic visit/BP assessment.
    5. The use of theophylline is permitted; however, the dose must be stable for at least 4 weeks prior to screening and throughout study participation.
    6. The use of phosphodiesterase (PDE) type V inhibitors is permitted; however, subjects must refrain from taking these medications within 1 day of screening or any subsequent study visit.
    7. The use of alpha-blockers is not permitted - with the exception of afluzosin and tamsulosin for prostatic symptoms

Answer: B