Clinical trial NCT01646437: The International Polycap Study 3 (TIPS-3)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiovascular Disease
Fractures
Cancers
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: Cadila Pharnmaceuticals
name: Wellcome Trust
name: Canadian Institutes of Health Research (CIHR)
name: Heart and Stroke Foundation of Ontario
First posted: 2012-07-20
Enrollment: 7793
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

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.

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.

Eligibility 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.

Primary outcomes:
measure: Polycap Primary Objective
timeFrame: Participants will be followed for an average of 4.25 years
measure: Aspirin Primary Objective
timeFrame: Participants will be followed for an average of 4.25 years
measure: Vitamin D Primary Objective
timeFrame: Participants will be followed for an average of 4.25 years
measure: Combined Effects of Polycap and Aspirin on CVD Events
timeFrame: Participants will be followed for an average of 4.25 years
Secondary outcomes:
measure: Polycap Secondary Objective
timeFrame: Participants will be followed for an average of 4.25 years
measure: Aspirin Secondary Objective
timeFrame: Participants will be followed for an average of 4.25 years
measure: Vitamin D Secondary Objective
timeFrame: Participants will be followed for an average of 4.25 years
measure: Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome A
timeFrame: Participants will be followed for an average of 4.25 years
measure: Combined Effects of Polycap and Aspirin on CVD Events Secondary Outcome B
timeFrame: Participants will be followed for an average of 4.25 years
Other outcomes:
measure: Total mortality
timeFrame: Participants will be followed for an average of 4.25 years
measure: Incident and recurrent CV events
timeFrame: Participants will be followed for an average of 4.25 years
measure: Long term safety
timeFrame: Participants will be followed for an average of 4.25 years
measure: Visual acuity
timeFrame: Participants will be followed for an average of 4.25 years
measure: Cognitive Function
timeFrame: Participants will be followed for an average of 4.25 years
measure: Health Economics
timeFrame: Participants will be followed for an average of 4.25 years
Locations:
city: Dhaka
country: Bangladesh
facility: Eminence
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: Bucaramanga
country: Colombia
facility: Fundaction Oftamologica De Santander (FOSCAL)
city: Bangalore
country: India
facility: St. John's Medical College Hospital
city: Jakarta
country: Indonesia
facility: Harapan Kita Hopsital
city: Shah Alam
country: Malaysia
facility: Universiti Teknologi MARA (UiTM)
state: Selangor
city: Manila
country: Philippines
facility: Adult Medicine & Medical Research Unit, Philippine General Hospital
city: Moshi
country: Tanzania
facility: Pamoja Tunaweza Women's Centre
city: Monastir
country: Tunisia
facility: Fattouma Bourguiba University Hospital
Study officials:
affiliation: Population Health Research Institute
name: Salim Yusuf
role: PRINCIPAL_INVESTIGATOR
affiliation: St. John's Research Institute
name: Prem Pais
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.