Cardiovascular DiseaseTEMPUSNCT01506505
The Evening Versus Morning Polypill Utilization Study
A study testing Cardiovascular Agents in people with Cardiovascular Disease and Cerebrovascular Disease, run by UMC Utrecht at 1 site in Netherlands.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cardiovascular Disease, Cerebrovascular Disease, Peripheral Arterial Disease
- What is being tested?
- Cardiovascular Agents
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 1 siteNetherlands
- Study dates
- Jul 2012to Jul 2013
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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))
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomised Controlled Cross-over Trial to Evaluate Evening Versus Morning Administration of a Cardiovascular Polypill
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.
Read more
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.
Read the 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.
- Being tested
- Cardiovascular Agents
- Keywords
- Cardiovascular prevention, Polypill, Combination therapy
- Medical subject headings
- Cardiovascular Diseases, Cerebrovascular Disorders, Peripheral Arterial Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cardiovascular AgentsDrug
Also called Acetylsalicylic acid 80 mg, Simvastatin 40 mg, Lisinopril 10 mg, Hydrochlorothiazide 12,5 mg
Acetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg in individual agents or a combination pill
| Study group | Role | What they receive |
|---|---|---|
| Polypill in the morning | Experimental | 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) Receives: Drug: Cardiovascular Agents |
| Polypill in the evening | Experimental | 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) Receives: Drug: Cardiovascular Agents |
| Individual agents of the polypill) | Active comparator | 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. Receives: Drug: Cardiovascular Agents |
What is being measured
The primary outcome is the main question the study is designed to answer.
LDL cholesterol (polypill evening vs polypill morning)
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
Measured: 24 weeks
Mean 24 hour ambulatory systolic BP (polypill evening vs morning)
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
Measured: 24 weeks
Secondary outcomes (4)
Differences in ambulatory BP parameters after a mean of 7 week of treatment (polypill evening vs. morning, polypill vs regular care)
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.
Measured: 24 weeks
Differences in tolerability (adverse event, cessation of treatment)
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
Measured: Every 6-8 weeks
Adherence (polypill evening vs. morning, polypill vs regular care)
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
Measured: 24 weeks
Cholesterol fractions (polypill evening vs. morning, polypill vs regular care)
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
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jan 2012 (estimated)
- Study startJul 2012
- Primary completionJul 2013
- Study completionJul 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Cardiovascular DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 78 participants (actual)
Sponsor and investigators
- Lead sponsor
- UMC Utrecht
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, dr.Frank L.J. Visseren, UMC Utrecht
- Investigators
- W. Spiering, MD, PhD, Principal investigator, UMC Utrecht
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01506505
- Sponsor's protocol ID
- EudraCT 2011-001120-38
- Acronym
- TEMPUS
- Status last verified
- Aug 2013
- First submitted
- 23 Nov 2011
- Last updated
- 13 Aug 2013
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Lafeber M, Grobbee DE, Schrover IM, Thom S, Webster R, Rodgers A, Visseren FL, Bots ML, Spiering W. Comparison of a morning polypill, evening polypill and individual pills on LDL-cholesterol, ambulatory blood pressure and adherence in high-risk patients; a randomized crossover trial. Int J Cardiol. 2015 Feb 15;181:193-9. doi: 10.1016/j.ijcard.2014.11.176. Epub 2014 Dec 3.
PubMed 25528311Lafeber M, Grobbee DE, Bots ML, Thom S, Webster R, Rodgers A, Visseren FL, Spiering W. The evening versus morning polypill utilization study: the TEMPUS rationale and design. Eur J Prev Cardiol. 2014 Apr;21(4):425-33. doi: 10.1177/2047487313476961. Epub 2013 Feb 4.
PubMed 23382539
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised Controlled Cross-over Trial to Evaluate Evening Versus Morning Administration of a Cardiovascular Polypill
- ClinicalTrials.gov ID
- NCT01506505
- Acronym / sponsor ID
- TEMPUS / EudraCT 2011-001120-38
- Keywords
- Cardiovascular prevention, Polypill, Combination therapy
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 78 participants (actual)
- Lead sponsor
- UMC UtrechtUniversity, hospital or other
- Study start
- Jul 2012
- Primary completion
- Jul 2013 (actual)
- Study completion
- Jul 2013 (actual)
- First posted
- 10 Jan 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Polypill in the morning | Experimental | Drug: Cardiovascular AgentsCardiovascular 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) |
| Polypill in the evening | Experimental | Drug: Cardiovascular AgentsCardiovascular 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) |
| Individual agents of the polypill) | Active comparator | Drug: Cardiovascular AgentsCardiovascular 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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;
Key exclusion criteria (7 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cardiovascular AgentsAlso: Acetylsalicylic acid 80 mg, Simvastatin 40 mg, Lisinopril 10 mg, Hydrochlorothiazide 12,5 mgAcetylsalicylic acid 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorthiazide 12.5mg in individual agents or a combination pill | Drug | Individual agents of the polypill), Polypill in the evening, Polypill in the morning |
Primary outcome
LDL cholesterol (polypill evening vs polypill morning)
Time frame: 24 weeks
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
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
4 secondary outcomes
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
Differences in tolerability (adverse event, cessation of treatment)
Time frame: Every 6-8 weeks
Adherence (polypill evening vs. morning, polypill vs regular care)
Time frame: 24 weeks
Cholesterol fractions (polypill evening vs. morning, polypill vs regular care)
Time frame: 24 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2013.
- Derived from this study: PubMed 25528311Lafeber M, Grobbee DE, Schrover IM, Thom S, Webster R, Rodgers A, Visseren FL, Bots ML, Spiering W. Comparison of a morning polypill, evening polypill and individual pills on LDL-cholesterol, ambulatory blood pressure and adherence in high-risk patients; a randomized crossover trial. Int J Cardiol. 2015 Feb 15;181:193-9. doi: 10.1016/j.ijcard.2014.11.176. Epub 2014 Dec 3.
- Derived from this study: PubMed 23382539Lafeber M, Grobbee DE, Bots ML, Thom S, Webster R, Rodgers A, Visseren FL, Spiering W. The evening versus morning polypill utilization study: the TEMPUS rationale and design. Eur J Prev Cardiol. 2014 Apr;21(4):425-33. doi: 10.1177/2047487313476961. Epub 2013 Feb 4.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
W. Spiering, MD, PhD principal investigator
UMC Utrecht
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Cardiovascular Agents in people with Cardiovascular Disease and Cerebrovascular Disease, run by UMC Utrecht at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Aug 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
LDL cholesterol (polypill evening vs polypill morning) (time frame: 24 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01506505, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2013.