The International Polycap Study 3 (TIPS-3)

Study Overview
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Brief Summary
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The randomized 2x2x2 factorial design placebo controlled trial will enroll 5000 participants (women 60 years or older and men 55 years or older) without known heart disease or prior stroke and without a clear indication or contraindication to any of the study medications. Eligible and consenting individuals will be randomized to receive either the active study medications or placebo (dummy pills) and will be monitored for an average of 5 years. The study will include people from at 10 countries, will be conducted by an international group of scientists and physicians and will be coordinated by the Population Health Research Institute at Hamilton Health Sciences.

Detailed Description
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Cardiovascular disease (CVD), cancers and osteoporosis collectively make up the largest disease burden globally. CVD is the major cause of death and disability and affects about half of the population over their lifetimes. Cancers are a leading cause of death and it accounts for 13.0% of all deaths. The commonest forms include lung, breast, prostate, colorectum, stomach and liver cancer. It is estimated that over 200 hundred million people worldwide are living with osteoporosis. This is the underlying pathologic predisposition to fractures of the hip, vertebral body, and distal forearm. CVD, cancers and osteoporotic fractures increase with age and so their burden is expected to substantially increase over the next few decades. Simple, safe and effective preventive strategies which can reduce the incidence and prevalence of these 3 diseases are therefore urgently needed It is suggested that this polypill could be given to all individuals with a CVD event as well as to anyone over 55 years (primary prevention) without the need for any measurement of risk factors. The polypill contains 3 blood pressure lowing medications and a statin in a single tablet. This includes hydrochlorothiazide (25 mg), atenolol (100 mg), ramipril (10 mg) and simvastatin (40 mg). In addition, to the polypill (Polycap), participants will be randomized to receive aspirin (75mg) and vitamin D (60,000 IU monthly). This factorial design on 3 distinct treatment arms which could reduce CVD, fractures and cancers could have large implications for the prevention of several of the important chronic diseases in middle and old age, using safe and inexpensive medications/supplements.

Official Title
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The International Polycap Study 3 (TIPS-3) is a Randomized Double-blind Placebo-controlled Trial for the Evaluation of a Polycap, Low Dose Aspirin and Vitamin D Supplementation in Primary Prevention

Conditions
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Cardiovascular Disease, Fractures, Cancers

Intervention / Treatment
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* Drug: Polycap
* Drug: Aspirin
* Drug: Vitamin D
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged ≥ 50 years and women aged ≥ 55 years with an INTERHEART risk score ≥ 10 OR men and women aged ≥ 65 years with an INTERHEART risk score of ≥5. Provision of informed consent Exclusion Criteria Participants with a clear clinical indication, contraindication, preference for or intolerance to statin, beta blocker (e.g. bradycardia), ACE inhibitor, diuretic, aspirin or clopidogrel in the judgment of the physician. Regular use of vitamin D at doses higher than 400 IU per day. Hypercalcemia, hyperparathyroidism, osteomalacia or other contraindication or indication for vitamin D therapy. Peptic ulcer disease, frequent dyspepsia or bleeding. Expected long term use of anticoagulants Known vascular disease. (e.g., Stroke, TIA, Angina, MI, ACS, PVD including claudication and amputation). Mean systolic BP (using 2 automatic readings) below 120 mm Hg at run-in. Symptomatic hypotension (e.g., dizziness with SBP <110 mm Hg systolic) during the run-in phase. Chronic liver disease or abnormal liver function, i.e. ALT or AST > 3 x ULN. Inflammatory muscle disease (such as dermatomyositis or polymyositis) or creatine kinase (CK) > 3 x ULN. Severe renal impairment (serum creatinine >264 µmol/L). History of malignancy affecting any organ system, except basal cell carcinoma of the skin, within the previous 5 years. Other serious condition(s) likely to interfere with study participation or with the ability to complete the trial. Concurrent use of any experimental pharmacological agent. Inability to attend follow-up as required by the protocol for at least 5 years.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Polycap vs. matching placebo<br>Polycap is a once daily capsule containing thiazide (25mg), atenolol (100mg), ramipril (10mg) and simvastatin (40mg) vs. matching placebo | Drug: Polycap<br>* Polycap (thiazide 25mg, atenolol 100mg, ramipril 10mg, simvastatin 40mg) taken once daily<br>Drug: Matching Placebo<br>* Matching Placebo<br>|
| Experimental: Aspirin vs. matching placebo<br>Once daily 75mg tablet of Aspirin vs. matching placebo | Drug: Aspirin<br>* 75 mg daily<br>* Other names: enteric coated aspirin;Drug: Matching Placebo<br>* Matching Placebo<br>|
| Experimental: Vitamin D vs. matching placebo<br>Monthly oral dosage of 60,000IU vs. matching placebo | Drug: Vitamin D<br>* 60,000 IU monthly<br>* Other names: cholecalciferol;Drug: Matching Placebo<br>* Matching Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polycap Primary Objective | To determine whether the Polycap reduces the risk of the composite outcome of CVD events which includes major CVD (CV death, non-fatal stroke, non-fatal MI), plus heart failure, resuscitated cardiac arrest, or arterial revascularization compared to placebo. | Participants will be followed for an average of 4.25 years | 
| Aspirin Primary Objective | To determine whether aspirin reduces the risk of composite outcome of major CV events (CV death, non-fatal MI or non-fatal stroke,) compared to its placebo. | Participants will be followed for an average of 4.25 years | 
| Vitamin D Primary Objective | To determine whether vitamin D reduces the risk of fractures compared to its placebo. | Participants will be followed for an average of 4.25 years | 
| Combined Effects of Polycap and Aspirin on CVD Events | To determine the combined effect of aspirin and the Polycap (i.e. double treatment) on major CV events (CV death, non-fatal MI or non-fatal stroke), heart failure, resuscitated cardiac arrest, or arterial revascularization compared to double-placebo. | Participants will be followed for an average of 4.25 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polycap Secondary Objective | To determine whether the Polycap reduces the risk of the composite of CV death, non-fatal stroke, and non-fatal MI compared to its placebo.To determine whether the Polycap reduces the risk of the composite outcome of major CVD (CV death, non- fatal stroke, non-fatal myocardial infarction [MI]), heart failure, resuscitated cardiac arrest, arterial revascularization, or angina with evidence of ischemia. | Participants will be followed for an average of 4.25 years | 
| Aspirin Secondary Objective | To determine whether a daily aspirin reduces the risk of the composite outcome of major CV events (CV death, non-fatal MI or non-fatal stroke) and cancers compared to its placebo. | Participants will be followed for an average of 4.25 years | 
| Vitamin D Secondary Objective | To determine whether vitamin D reduces the risk of the composite outcome of CV events, fractures and cancers, and the risk of falls compared to its placebo. | Participants will be followed for an average of 4.25 years | 
| Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome A | To determine whether the Polycap and aspirin reduces the risk of the composite of CV death, non-fatal stroke, and non-fatal MI compared to double placebo. | Participants will be followed for an average of 4.25 years | 
| Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome B | To determine whether the Polycap and aspirin reduces the risk of the composite outcome of major CVD (CV death, non- fatal stroke, non-fatal myocardial infarction [MI]), heart failure, resuscitated cardiac arrest, arterial revascularization, or angina with evidence of ischemia, compared to double-placebo | Participants will be followed for an average of 4.25 years |