Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised Controlled Cross-over Trial to Evaluate Evening Versus Morning Administration of a Cardiovascular Polypill
Brief Summary: Background and rationale:

In clinical practice, antihypertensives are generally prescribed for use in the morning, whereas some statins are recommended for use in the evening. There is evidence that the reduction in LDL cholesterol achieved with some statins is superior when taken in the night, but it is unclear whether the additional reduction in LDL cholesterol(and the reported improvement in BP control when aspirin is taken in the evening) is offset by a reduction in adherence when taking medication in the evening. Current product labelling recommends night use for simvastatin and does not state a timing preference for aspirin or blood pressure lowering medicines. There is therefore uncertainty concerning the best timing of administration of the polypill. This uncertainty will be addressed by this trial.

Trial design:

Randomised, open label cross over trial (n=75) of the polypill in the morning compared with the evening administration compared with individual agent administration (acetylsalicylic acid and blood pressure lowering agents in the morning, and statin in the evening) in individuals at high risk of cardiovascular disease. Patients will be recruited to the RHP 2c (acetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg), and will be randomly allocated to the sequence of time of administration.


Options:
A: Inclusion Criteria:

* The participant is able to give informed consent.
* The trial Investigator considers that each of the polypill components are indicated at the doses in the Red Heart Pill
* Established atherothrombotic cardiovascular disease (CVD) or intermediate to high cardiovascular risk, defined as;

  * History of coronary heart disease (myocardial infarction, stable or unstable angina pectoris, or coronary revascularisation procedure), or
  * History of ischaemic cerebrovascular disease (ischaemic stroke or transient ischaemic attack), or
  * History of peripheral vascular disease (peripheral revascularisation procedure or amputation due to vascular disease or aortic reconstruction), or
  * For individuals without established cardiovascular disease, a calculated 5 year CVD risk of 5% or greater (calculated using the 1991 Anderson Framingham risk equation with adjustments as defined by the New Zealand Guidelines Group recommendations - (Appendix 1))

Exclusion Criteria:

* Contraindication to any of the components of the polypill (e.g. known intolerance to aspirin, statins, or ACE inhibitors; pregnancy or likely to become pregnant or breastfeeding women during the treatment period). Such contraindications are fully listed in the Investigator Brochures.
* The treating doctor considers that changing a participant's cardiovascular medications would put the participant at risk (e.g. symptomatic heart failure, high dose β-blocker required to manage angina or for rate control in atrial fibrillation, accelerated hypertension, severe renal insufficiency, a history of severe resistant hypertension).
* Other potential reasons for exclusion include:
* Known situation where medication regimen might be altered for a significant length of time, e.g. current acute cardiovascular event, planned coronary bypass graft operation.
* Unlikely to complete the trial (e.g. life-threatening condition other than cardiovascular disease) or adhere to the trial procedures or attend study visits (e.g. major psychiatric condition, dementia).
* Any reason, medical condition, ongoing medication or significant disability that would prevent the participant complying with trial consent, treatment and follow-up procedures or potentially jeopardise her / his medical care.
* Night shift workers.
B: Inclusion Criteria:

* Estimated 10-year total CVD risk score \> 20%. The total CVD risk assessment will be based on the recently developed WHO CVD risk prediction charts
* No contraindication for treatment with aspirin, angiotensin converting enzyme inhibitors, low-dose diuretics, or statins
* Informed consent given

Exclusion Criteria:

* Patients with established angina pectoris, coronary heart disease, myocardial infarction, transient ischemic attacks, stroke, peripheral vascular disease, coronary revascularization and/or carotid endarterectomy Left ventricular hypertrophy (on ECG) or hypertensive retinopathy (grade III or IV)
* Patients with secondary hypertension
* Patients with diabetes type 1 or 2 with overt neuropathy or other significant renal disease.
* Known renal failure or impairment
* Atrial fibrillation
* ALT \> 1.5 times the upper limit of normal
* History of liver cirrhosis or hepatitis
* History of recent gastrointestinal bleeding (within the last year)
* Women in child bearing period
* History of life-limiting diseases or events
* Unwillingness to sign informed consent.
C: Inclusion Criteria:

* Age between 45 and 80 years
* At least any one of the following CVD risk factors:

  * Stable type 2 diabetes mellitus or
  * Hypertension or
  * Current smoker or
  * A waist to hip ratio \> 0.85 for women and \>0.9 for men or
  * Elevated lipids.
* Informed consent.

Exclusion Criteria:

* On any of the study medications,
* Uncontrolled blood pressure,
* Symptomatic hypotension,
* Any clear indication or a contraindication to the use of any of the study medications,
* History of coronary/cerebrovascular events,
* Pregnancy or lactating or women of child-bearing potential with inadequate contraception and / or an inability to attend follow up visits.
D: Inclusion Criteria:

* Demonstrable hypertension defined as mean sitting trough cuff blood pressure ≥ 140/100 mmHg (SeSBP ≥ 140 mmHg and SeDBP ≥ 100mmHg) or mean sitting trough cuff BP ≥ 160/90 mmHg (SeSBP ≥ 160 mmHg and SeDBP ≥ 90mmHg).
* Male or female newly diagnosed hypertensive subjects or currently on hypertension medication.

  * Negative urine pregnancy test at screening
  * Not lactating
  * Do not plan to become pregnant during the study
  * Will practice birth control throughout the study by the following: oral or patch contraceptive, injectable or implantable contraceptive medication, intrauterine device, diaphragm or female condom plus spermicide

    * Non childbearing potential must be classified by one of the following criteria
    * Had a hysterectomy or tubal ligation at least 6 months prior to consent
    * Has been postmenopausal for a least 1 year

Exclusion Criteria:

* Mean sitting trough cuff DBP \<90 mmHg or mean sitting trough cuff SBP \<140 mmHg (off antihypertensive medication).
* Subjects with uncontrolled hypertension taking multiple antihypertensive therapies (at the discretion of the investigator).
* Signs or symptoms which could exacerbate the occurrence of hypotension such as volume and salt depletion.
* History of hypertensive encephalopathy, stroke or transient ischemic attack (TIA).
* Participation in another clinical trial involving an investigational drug within one month prior to screening.
* History of myocardial infarction, percutaneous transluminal coronary revascularization, coronary artery bypass graft, and/or unstable angina within the past 6 months.
* Any history of New York Heart Association Class III or IV congestive heart failure (CHF). A history of New York Heart Association Class I or II CHF may be exclusionary at the discretion of the investigator.
* History of secondary hypertension including renal disease, pheochromocytoma, or Cushing's syndrome.
* Uncorrected coarctation of the aorta, bilateral renal artery stenosis, or unilateral renal artery stenosis in a solitary kidney.
* Evidence of symptomatic resting bradycardia.
* Evidence of hemodynamically significant cardiac valvular disease.
* Presence of heart block greater than first degree atrioventricular block, chronic atrial fibrillation or flutter.
* Uncontrolled Type I or Type II diabetes defined as HbA1c \>9.0%. Diabetics must have documentation of HbA1c within 6 months of the Screening Visit. Undocumented subjects must have their HbA1c assessed prior to randomization. Note: Subjects with Type I or Type II diabetes controlled with insulin, diet or oral hypoglycemic agents on a stable dose for at least 30 days may be included.
* Evidence of liver disease as indicated by ALT and AST and/or total bilirubin \>3 times the upper limit of normal.
* Severe renal insufficiency defined as a creatinine clearance (based on the Cockcroft-Gault formula) of \<30 mL/min.
* Clinically significant laboratory elevations at Visit 1 that compromise subject safety, based on the investigator's judgment. Consideration should take into account the potential laboratory effects of the component blinded therapies.
* Positive for any one of the following tests: hepatitis B surface antigen, hepatitis C antibody (confirmed by radio immunobinding assay, RIBA) or HIV antibody (confirmed by western blot assay).
* Subjects with malignancy during the past 2 years excluding squamous cell or basal cell carcinoma of the skin.
* Known allergy to any of the medications used in the study.
* Subjects who require or are taking any concomitant medication, which may interfere with the objectives of the study (Refer to Section 5.2 for a listing of excluded medications).
* Pregnant or lactating females.
* Current history of drug or alcohol abuse.
* A subject with any medical condition, which in the judgment of the Investigator would jeopardize the evaluation of efficacy or safety and/or constitute a significant safety risk to the subject.

Answer: A