The International Polycap Study 3 (TIPS-3) (TIPS-3)

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Fractures; Cancers
• Intervention / Treatment: Drug: Matching Placebo; Drug: Polycap; Drug: Aspirin; Drug: Vitamin D

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 7793
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh
    • Eminence
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton Health Sciences
• Colombia
  • Bucaramanga, Colombia
    • Fundaction Oftamologica De Santander (FOSCAL)
• India
  • Bangalore, India
    • St. John's Medical College Hospital
• Indonesia
  • Jakarta, Indonesia
    • Harapan Kita Hopsital
• Malaysia
  • Selangor
    • Shah Alam, Selangor, Malaysia
      • Universiti Teknologi Mara (UiTM)
• Philippines
  • Manila, Philippines
    • Adult Medicine & Medical Research Unit, Philippine General Hospital
• Tanzania
  • Moshi, Tanzania
    • Pamoja Tunaweza Women's Centre
• Tunisia
  • Monastir, Tunisia
    • Fattouma Bourguiba University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total mortality	To assess the effect of each of the 3 treatments on total mortality.	Participants will be followed for an average of 4.25 years
Incident and recurrent CV events	To determine whether the Polycap reduces the risk of incident and recurrent CV events (which is comprised of major CVD (CV death, non- fatal stroke, non-fatal myocardial infarction [MI]), plus heart failure, resuscitated cardiac arrest or arterial revascularization)).	Participants will be followed for an average of 4.25 years
Long term safety	To assess the long-term safety of each treatment (Polycap, Aspirin or Vitamin D) versus their respective placebo on safety and tolerability.	Participants will be followed for an average of 4.25 years
Visual acuity	To assess the effect of the Polycap and Aspirin on visual acuity change from baseline and onset of age-related macular degeneration.	Participants will be followed for an average of 4.25 years
Cognitive Function	To assess the effect of each of the 3 treatments on cognitive function	Participants will be followed for an average of 4.25 years
Health Economics	To assess the economic impact of the Polycap	Participants will be followed for an average of 4.25 years

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Wellcome Trust; Heart and Stroke Foundation of Ontario; Cadila Pharnmaceuticals
• Investigators: Principal Investigator: Salim Yusuf, Population Health Research Institute; Principal Investigator: Prem Pais, St. John's Research Institute

Publications and helpful links

General Publications

• Yusuf S, Joseph P, Dans A, Gao P, Teo K, Xavier D, Lopez-Jaramillo P, Yusoff K, Santoso A, Gamra H, Talukder S, Christou C, Girish P, Yeates K, Xavier F, Dagenais G, Rocha C, McCready T, Tyrwhitt J, Bosch J, Pais P; International Polycap Study 3 Investigators. Polypill with or without Aspirin in Persons without Cardiovascular Disease. N Engl J Med. 2021 Jan 21;384(3):216-228. doi: 10.1056/NEJMoa2028220. Epub 2020 Nov 13.
• Joseph P, Pais P, Dans AL, Bosch J, Xavier D, Lopez-Jaramillo P, Yusoff K, Santoso A, Talukder S, Gamra H, Yeates K, Lopez PC, Tyrwhitt J, Gao P, Teo K, Yusuf S; TIPS-3 Investigators. The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct. Am Heart J. 2018 Dec;206:72-79. doi: 10.1016/j.ahj.2018.07.012. Epub 2018 Aug 2.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): August 30, 2021

Study Registration Dates

• First Submitted: July 10, 2012
• First Submitted That Met QC Criteria: July 19, 2012
• First Posted (Estimate): July 20, 2012

Study Record Updates

• Last Update Posted (Actual): September 16, 2021
• Last Update Submitted That Met QC Criteria: September 14, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Aspirin; Vitamin D; Cholecalciferol
• Other Study ID Numbers: TIPS-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No