The International Polycap Study 3 (TIPS-3)

NCT01646437 | Completed Phase 3 DMC

• 1 other identifier: TIPS-3
• Study Type: interventional
• Target: 7,793
• Locations: 9 countries
• Sites: 9

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.

Conditions

Cardiovascular Disease; Fractures; Cancers

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (5)

• Polycap Secondary Objective

  Participants will be followed for an average of 4.25 years

• Aspirin Secondary Objective

  Participants will be followed for an average of 4.25 years

• Vitamin D Secondary Objective

  Participants will be followed for an average of 4.25 years

• Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome A

  Participants will be followed for an average of 4.25 years

• Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome B

  Participants will be followed for an average of 4.25 years

Other Outcomes (6)

• Total mortality

  Participants will be followed for an average of 4.25 years

• Incident and recurrent CV events

  Participants will be followed for an average of 4.25 years

• Long term safety

  Participants will be followed for an average of 4.25 years

Study Arms (3)

Polycap vs. matching placebo

EXPERIMENTAL

Polycap is a once daily capsule containing thiazide (25mg), atenolol (100mg), ramipril (10mg) and simvastatin (40mg) vs. matching placebo

Drug: Polycap; Drug: Matching Placebo

Aspirin vs. matching placebo

EXPERIMENTAL

Once daily 75mg tablet of Aspirin vs. matching placebo

Drug: Aspirin; Drug: Matching Placebo

Vitamin D vs. matching placebo

EXPERIMENTAL

Monthly oral dosage of 60,000IU vs. matching placebo

Drug: Vitamin D; Drug: Matching Placebo

Interventions

Polycap DRUG

Polycap (thiazide 25mg, atenolol 100mg, ramipril 10mg, simvastatin 40mg) taken once daily

Polycap vs. matching placebo

Aspirin DRUG

75 mg daily

Also known as: enteric coated aspirin

Aspirin vs. matching placebo

Vitamin D DRUG

60,000 IU monthly

Also known as: cholecalciferol

Vitamin D vs. matching placebo

Matching Placebo DRUG

Matching Placebo

Aspirin vs. matching placebo; Polycap vs. matching placebo; Vitamin D vs. matching placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Population Health Research Institute: lead
• Cadila Pharnmaceuticals: collaborator
• Wellcome Trust: collaborator
• Canadian Institutes of Health Research (CIHR): collaborator
• Heart and Stroke Foundation of Ontario: collaborator

Study Sites (9)

Eminence

Dhaka, Bangladesh

Location

Hamilton Health Sciences

Hamilton, Ontario, L8L 2X2, Canada

Location

Fundaction Oftamologica De Santander (FOSCAL)

Bucaramanga, Colombia

Location

St. John's Medical College Hospital

Bangalore, India

Location

Harapan Kita Hopsital

Jakarta, Indonesia

Location

Universiti Teknologi MARA (UiTM)

Shah Alam, Selangor, Malaysia

Location

Adult Medicine & Medical Research Unit, Philippine General Hospital

Manila, Philippines

Location

Pamoja Tunaweza Women's Centre

Moshi, Tanzania

Location

Fattouma Bourguiba University Hospital

Monastir, Tunisia

Location

Related Publications (3)

• Joseph P, Pais P, Gao P, Teo K, Xavier D, Lopez-Jaramillo P, Yusoff K, Santoso A, Gamra H, Talukder SH, Christou C, Dagenais G, Tyrwhitt J, Bosch J, Dans A, Yusuf S; International Polycap Study (TIPS)-3 Investigators. Vitamin D supplementation and adverse skeletal and non-skeletal outcomes in individuals at increased cardiovascular risk: Results from the International Polycap Study (TIPS)-3 randomized controlled trial. Nutr Metab Cardiovasc Dis. 2023 Feb;33(2):434-440. doi: 10.1016/j.numecd.2022.11.001. Epub 2022 Nov 15.

  PMID: 36604262 DERIVED

• 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.

  PMID: 33186492 DERIVED

• 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.

  PMID: 30342297 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Fractures, Bone; Neoplasms

Interventions

Aspirin; Vitamin D; Cholecalciferol

Condition Hierarchy (Ancestors)

Wounds and Injuries

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Secosteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholestenes; Cholestanes; Sterols; Membrane Lipids; Lipids

Study Officials

• Salim Yusuf

  Population Health Research Institute

  PRINCIPAL INVESTIGATOR

• Prem Pais

  St. John's Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Executive Director - Population Health Research Institute, Professor of Medicine - McMaster University

Study Record Dates

• First Submitted: July 10, 2012
• First Posted: July 20, 2012
• Study Start: June 1, 2012
• Primary Completion: June 30, 2020
• Study Completion: August 30, 2021
• Last Updated: September 16, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

BA (1); ID (1); CO (1); MY (1); PH (1); CA (1); IN (1); TA (1); TU (1)