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

• ClinicalTrials.gov Identifier: NCT01646437
• Recruitment Status: Completed
• First Posted: July 20, 2012
• Last Update Posted: September 16, 2021
• Sponsor: Population Health Research Institute
• Collaborators: Cadila Pharnmaceuticals; Wellcome Trust; Canadian Institutes of Health Research (CIHR); Heart and Stroke Foundation of Ontario
• Information provided by (Responsible Party): Salim Yusuf's office, Population Health Research Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cardiovascular Disease; Fractures; Cancers	Drug: Polycap; Drug: Aspirin; Drug: Vitamin D; Drug: Matching Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7793 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: 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
• Study Start Date: June 2012
• Actual Primary Completion Date: June 30, 2020
• Actual Study Completion Date: August 30, 2021

Arms and Interventions

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: Polycap; Polycap (thiazide 25mg, atenolol 100mg, ramipril 10mg, simvastatin 40mg) taken once daily; Drug: Matching Placebo; Matching Placebo
Experimental: Aspirin vs. matching placebo; Once daily 75mg tablet of Aspirin vs. matching placebo	Drug: Aspirin; 75 mg daily; Other Name: enteric coated aspirin; Drug: Matching Placebo; Matching Placebo
Experimental: Vitamin D vs. matching placebo; Monthly oral dosage of 60,000IU vs. matching placebo	Drug: Vitamin D; 60,000 IU monthly; Other Name: cholecalciferol; Drug: Matching Placebo; Matching Placebo

Outcome Measures

Primary Outcome Measures :

1. Polycap Primary Objective [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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.
2. Aspirin Primary Objective [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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.
3. Vitamin D Primary Objective [ Time Frame: Participants will be followed for an average of 4.25 years ]
   To determine whether vitamin D reduces the risk of fractures compared to its placebo.
4. Combined Effects of Polycap and Aspirin on CVD Events [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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.

Secondary Outcome Measures :

1. Polycap Secondary Objective [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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.
2. Aspirin Secondary Objective [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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.
3. Vitamin D Secondary Objective [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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.
4. Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome A [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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.
5. Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome B [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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

Other Outcome Measures:

1. Total mortality [ Time Frame: Participants will be followed for an average of 4.25 years ]
   To assess the effect of each of the 3 treatments on total mortality.
2. Incident and recurrent CV events [ Time Frame: Participants will be followed for an average of 4.25 years ]
   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)).
3. Long term safety [ Time Frame: Participants will be followed for an average of 4.25 years ]
   To assess the long-term safety of each treatment (Polycap, Aspirin or Vitamin D) versus their respective placebo on safety and tolerability.
4. Visual acuity [ Time Frame: Participants will be followed for an average of 4.25 years ]
   To assess the effect of the Polycap and Aspirin on visual acuity change from baseline and onset of age-related macular degeneration.
5. Cognitive Function [ Time Frame: Participants will be followed for an average of 4.25 years ]
   To assess the effect of each of the 3 treatments on cognitive function
6. Health Economics [ Time Frame: Participants will be followed for an average of 4.25 years ]
   To assess the economic impact of the Polycap

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

Bangladesh

Eminence

Dhaka, Bangladesh

Canada, Ontario

Hamilton Health Sciences

Hamilton, Ontario, Canada, L8L 2X2

Colombia

Fundaction Oftamologica De Santander (FOSCAL)

Bucaramanga, Colombia

India

St. John's Medical College Hospital

Bangalore, India

Indonesia

Harapan Kita Hopsital

Jakarta, Indonesia

Malaysia

Universiti Teknologi MARA (UiTM)

Shah Alam, Selangor, Malaysia

Philippines

Adult Medicine & Medical Research Unit, Philippine General Hospital

Manila, Philippines

Tanzania

Pamoja Tunaweza Women's Centre

Moshi, Tanzania

Tunisia

Fattouma Bourguiba University Hospital

Monastir, Tunisia

Sponsors and Collaborators

Population Health Research Institute

Cadila Pharnmaceuticals

Wellcome Trust

Canadian Institutes of Health Research (CIHR)

Heart and Stroke Foundation of Ontario

Investigators

• Principal Investigator: Salim Yusuf; Population Health Research Institute
• Principal Investigator: Prem Pais; St. John's Research Institute

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yusuf S, Joseph P, Dans A, Gao P, Teo K, Xavier D, López-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.

• Responsible Party: Salim Yusuf's office, Executive Director - Population Health Research Institute, Professor of Medicine - McMaster University, Population Health Research Institute
• ClinicalTrials.gov Identifier: NCT01646437
• Other Study ID Numbers: TIPS-3
• First Posted: July 20, 2012
• Last Update Posted: September 16, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Cardiovascular Diseases; Aspirin; Vitamin D; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics; Calcium-Regulating Hormones and Agents