The Evening Versus Morning Polypill Utilization Study (TEMPUS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
dr.Frank L.J. Visseren, UMC Utrecht
ClinicalTrials.gov Identifier:
NCT01506505
First received: November 23, 2011
Last updated: August 12, 2013
Last verified: August 2013
  Purpose

Background and rationale:

In clinical practice, antihypertensives are generally prescribed for use in the morning, whereas some statins are recommended for use in the evening. There is evidence that the reduction in LDL cholesterol achieved with some statins is superior when taken in the night, but it is unclear whether the additional reduction in LDL cholesterol(and the reported improvement in BP control when aspirin is taken in the evening) is offset by a reduction in adherence when taking medication in the evening. Current product labelling recommends night use for simvastatin and does not state a timing preference for aspirin or blood pressure lowering medicines. There is therefore uncertainty concerning the best timing of administration of the polypill. This uncertainty will be addressed by this trial.

Trial design:

Randomised, open label cross over trial (n=75) of the polypill in the morning compared with the evening administration compared with individual agent administration (acetylsalicylic acid and blood pressure lowering agents in the morning, and statin in the evening) in individuals at high risk of cardiovascular disease. Patients will be recruited to the RHP 2c (acetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg), and will be randomly allocated to the sequence of time of administration.


Condition Intervention
Cardiovascular Disease
Cerebrovascular Disease
Peripheral Arterial Disease
Drug: Cardiovascular Agents

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomised Controlled Cross-over Trial to Evaluate Evening Versus Morning Administration of a Cardiovascular Polypill

Resource links provided by NLM:


Further study details as provided by UMC Utrecht:

Primary Outcome Measures:
  • LDL cholesterol (polypill evening vs polypill morning) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

    Differences between polypill in the evening (after 8 weeks of evening treatment) and polypill in the morning (after 8 weeks of morning treatment) in:

    - Mean LDL cholesterol


  • Mean 24 hour ambulatory systolic BP (polypill evening vs morning) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

    Difference between the between polypill in the evening (after 8 weeks of evening treatment) and polypill in the morning (after 8 weeks of morning treatment) in:

    - Mean 24 hour ambulatory systolic BP



Secondary Outcome Measures:
  • Differences in ambulatory BP parameters after a mean of 7 week of treatment (polypill evening vs. morning, polypill vs regular care) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

    Differences between polypill in the evening (after 8 weeks of evening treatment) and polypill in the morning (after 8 weeks of morning treatment) and regular care (after 8 weeks of treatment with individual agents of the polypill) in:

    • Mean 24 hour ambulatory diastolic BP
    • Mean diurnal (awake) and nocturnal (asleep) systolic and diastolic BP.
    • Percentage of dipping of SBP.

  • Differences in tolerability (adverse event, cessation of treatment) [ Time Frame: Every 6-8 weeks ] [ Designated as safety issue: No ]

    Difference between polypill in the evening (after 8 weeks of evening treatment) and polypill in the morning (after 8 weeks of morning treatment) and regular care (after 8 weeks of treatment with individual agents of the polypill) in:

    • Patients' acceptability
    • Number of adverse events
    • Number of cessation of study treatment

  • Adherence (polypill evening vs. morning, polypill vs regular care) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

    Differences between polypill in the evening (after 8 of evening treatment) and polypill in the morning (after 8 weeks of morning treatment) and regular care (after 8 weeks of treatment with individual agents of the polypill) in:

    • Patients' adherence measured with electronic medication registration lids (MEM spots, AARDEX group)
    • Patients' self reported adherence

  • Cholesterol fractions (polypill evening vs. morning, polypill vs regular care) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

    Differences between polypill in the evening (after 8 of evening treatment) and polypill in the morning (after 8 weeks of morning treatment) and regular care (after 8 weeks of treatment with individual agents of the polypill) in:

    • Mean total cholesterol.
    • Mean HDL cholesterol.
    • Mean triglycerides.
    • Mean total:HDL ratio


Enrollment: 78
Study Start Date: July 2012
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Polypill in the morning
Cardiovascular agents in a polypill used from 05.00-11.00 in the morning (acetylsalicylic acid 75 mg, simvastatin 40 mg, lisinopril 10 mg, hydrochlorothiazide 12,5 mg)
Drug: Cardiovascular Agents
Acetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg in individual agents or a combination pill
Other Names:
  • Acetylsalicylic acid 80 mg
  • Simvastatin 40 mg
  • Lisinopril 10 mg
  • Hydrochlorothiazide 12,5 mg
Experimental: Polypill in the evening
Cardiovascular agents in a polypill used from 18.00-00.00 in the evening (acetylsalicylic acid 75 mg, simvastatin 40 mg, lisinopril 10 mg, hydrochlorothiazide 12,5 mg)
Drug: Cardiovascular Agents
Acetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg in individual agents or a combination pill
Other Names:
  • Acetylsalicylic acid 80 mg
  • Simvastatin 40 mg
  • Lisinopril 10 mg
  • Hydrochlorothiazide 12,5 mg
Active Comparator: Individual agents of the polypill)

Cardiovascular agents in as acetylsalicylic acid 75 mg, lisinopril 10 mg, hydrochlorothiazide 12,5 mg used 05.00-11.00 in the morning.

Simvastatin 40 mg used 18.00-00.00 in the evening.

Drug: Cardiovascular Agents
Acetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg in individual agents or a combination pill
Other Names:
  • Acetylsalicylic acid 80 mg
  • Simvastatin 40 mg
  • Lisinopril 10 mg
  • Hydrochlorothiazide 12,5 mg

Detailed Description:

Background and rationale:

In clinical practice, antihypertensives are generally prescribed for use in the morning, whereas some statins are recommended for use in the evening. There is evidence that the reduction in LDL cholesterol achieved with some statins is superior when taken in the night, but it is unclear whether the additional reduction in LDL cholesterol(and the reported improvement in BP control when aspirin is taken in the evening) is offset by a reduction in adherence when taking medication in the evening. Current product labelling recommends night use for simvastatin and does not state a timing preference for aspirin or blood pressure lowering medicines. There is therefore uncertainty concerning the best timing of administration of the polypill. This uncertainty will be addressed by this trial.

Trial design:

Randomised, open label cross over trial (n=75) of the polypill in the morning compared with the evening administration compared with individual agent administration (acetylsalicylic acid and blood pressure lowering agents in the morning, and statin in the evening) in individuals at high risk of cardiovascular disease. Patients will be recruited to the RHP 2c (acetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg), and will be randomly allocated to the sequence of time of administration.

Aim:

To measure whether there is a difference in LDL cholesterol levels or the 24 hour ambulatory blood pressure in individuals at high risk of cardiovascular disease when the polypill is taken in the morning compared to the evening.

Randomisation and trial treatment:

Eligible individuals willing to participate in the trial will receive the polypill for a total of 18 weeks and be randomised to the sequence of 6 weeks morning, 6 weeks evening administration and 6 weeks administration of the individual agents. The polypill will be provided by the investigator at the Trial Centre. Participants will also receive information about smoking cessation (if applicable) and how to follow a healthy heart diet. They will be advised to increase physical activity and lose weight if needed.

Data collection and follow-up:

Participants will be followed-up for 20 weeks. Ambulatory blood pressure will be measured at baseline and week 6, week 12 and week 18. Fasting lipids will be measured at baseline, weeks 6, 12 and 18. Tolerability will be assessed at weeks 6, 12, 18 and 20 as will adverse events. Participant acceptability will be measured at the end of the treatment period.

Primary outcome:

Difference in LDL cholesterol and mean 24 hour ambulatory systolic BP.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The participant is able to give informed consent.
  • The trial Investigator considers that each of the polypill components are indicated at the doses in the Red Heart Pill
  • Established atherothrombotic cardiovascular disease (CVD) or intermediate to high cardiovascular risk, defined as;

    • History of coronary heart disease (myocardial infarction, stable or unstable angina pectoris, or coronary revascularisation procedure), or
    • History of ischaemic cerebrovascular disease (ischaemic stroke or transient ischaemic attack), or
    • History of peripheral vascular disease (peripheral revascularisation procedure or amputation due to vascular disease or aortic reconstruction), or
    • For individuals without established cardiovascular disease, a calculated 5 year CVD risk of 5% or greater (calculated using the 1991 Anderson Framingham risk equation with adjustments as defined by the New Zealand Guidelines Group recommendations - (Appendix 1))

Exclusion Criteria:

  • Contraindication to any of the components of the polypill (e.g. known intolerance to aspirin, statins, or ACE inhibitors; pregnancy or likely to become pregnant or breastfeeding women during the treatment period). Such contraindications are fully listed in the Investigator Brochures.
  • The treating doctor considers that changing a participant's cardiovascular medications would put the participant at risk (e.g. symptomatic heart failure, high dose β-blocker required to manage angina or for rate control in atrial fibrillation, accelerated hypertension, severe renal insufficiency, a history of severe resistant hypertension).
  • Other potential reasons for exclusion include:
  • Known situation where medication regimen might be altered for a significant length of time, e.g. current acute cardiovascular event, planned coronary bypass graft operation.
  • Unlikely to complete the trial (e.g. life-threatening condition other than cardiovascular disease) or adhere to the trial procedures or attend study visits (e.g. major psychiatric condition, dementia).
  • Any reason, medical condition, ongoing medication or significant disability that would prevent the participant complying with trial consent, treatment and follow-up procedures or potentially jeopardise her / his medical care.
  • Night shift workers.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01506505

Locations
Netherlands
UMC Utrecht
Utrecht, Netherlands, 3508 GA
Sponsors and Collaborators
UMC Utrecht
Investigators
Principal Investigator: W. Spiering, MD, PhD UMC Utrecht
  More Information

No publications provided by UMC Utrecht

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: dr.Frank L.J. Visseren, Clinical Professor, UMC Utrecht
ClinicalTrials.gov Identifier: NCT01506505     History of Changes
Other Study ID Numbers: EudraCT 2011-001120-38
Study First Received: November 23, 2011
Last Updated: August 12, 2013
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by UMC Utrecht:
Cardiovascular prevention
Polypill
Combination therapy

Additional relevant MeSH terms:
Cardiovascular Diseases
Cerebrovascular Disorders
Peripheral Arterial Disease
Peripheral Vascular Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Aspirin
Cardiovascular Agents
Hydrochlorothiazide
Lisinopril
Simvastatin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Hematologic Agents

ClinicalTrials.gov processed this record on July 28, 2014