Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000535471
Ethics application status
Approved
Date submitted
30/03/2016
Date registered
27/04/2016
Date last updated
27/04/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Long Term Intervention with Pravastatin in Ischaemic Disease
Scientific title
Effect of long term pravastatin treatment on mortality due to coronary heart disease in patients who have suffered a recent acute myocardial infarction or have a diagnosis of unstable angina pectoris.
Secondary ID [1] 288834 0
Nil known
Universal Trial Number (UTN)
Trial acronym
LIPID
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coronary heart disease 298115 0
Condition category
Condition code
Cardiovascular 298280 298280 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
20mg pravastatin oral tablet twice daily for 6 years. Dosage will be halved if total cholesterol falls below 3.0 mmol/L on two successive follow-up visits.
Compliance will be assessed by site staff at follow up visits and subjects encouraged to take tablets as directed.
Intervention code [1] 294323 0
Treatment: Drugs
Comparator / control treatment
Matching placebo, microcellulose tablet
Control group
Placebo

Outcomes
Primary outcome [1] 297790 0
Mortality due to coronary heart disease.
Assessed by submission of death certificate and hospital case notes for adjudication by an Outcomes Committee.
Timepoint [1] 297790 0
6 years. Subsequent assessment by periodic linkage with central death registries to 16 years
Secondary outcome [1] 322260 0
Mortality due to any cause
Assessed by submission of death certificate and hospital case notes for adjudication by an Outcomes Committee
Timepoint [1] 322260 0
6 years. Subsequent assessment by periodic linkage with central death registries to 16 years
Secondary outcome [2] 322261 0
Combined incidence of non-fatal myocardial infarction and fatal coronary heart disease
Assessed by submission of death certificate, hospital case notes, ECGs and laboratory reports for adjudication by an Outcomes Committee
Timepoint [2] 322261 0
6 years. Subsequent assessment by periodic linkage with central death registries to 16 years
Secondary outcome [3] 322262 0
Combined incidence of total stroke and non-haemorrhagic stroke
Assessed by submission of hospital case notes and CT or MRI scans for adjudication by a Stroke Assessment Committee
Timepoint [3] 322262 0
6 years
Secondary outcome [4] 322263 0
Mortality due to a cardiovascular condition
Assessed by submission of death certificate and hospital case notes for adjudication by an Outcomes Committee
Timepoint [4] 322263 0
6 years. Subsequent assessment by periodic linkage with central death registries to 16 years
Secondary outcome [5] 322264 0
Incidence of revascularisation procedures
Assessed by submission of hospital operation report
Timepoint [5] 322264 0
6 years
Secondary outcome [6] 322267 0
Total days of hospitalisation
Assessed by dates of hospital admission and discharge entered on Serious Adverse Event forms submitted by study sites
Timepoint [6] 322267 0
6 years
Secondary outcome [7] 322636 0
Effects of treatment on total cholesterol using serum samples submitted to a central lipid laboratory.
Timepoint [7] 322636 0
6 years
Secondary outcome [8] 322637 0
Effects of treatment on LDL cholesterol using serum samples submitted to a central lipid laboratory.
Timepoint [8] 322637 0
6 years
Secondary outcome [9] 322638 0
Effects of treatment on HDL cholesterol using serum samples submitted to a central lipid laboratory.
Timepoint [9] 322638 0
6 years
Secondary outcome [10] 322639 0
Effects of treatment on triglycerides using serum samples submitted to a central lipid laboratory.
Timepoint [10] 322639 0
6 years
Secondary outcome [11] 322640 0
Effects of treatment on apoprotein A1 using serum samples submitted to a central lipid laboratory.
Timepoint [11] 322640 0
6 years
Secondary outcome [12] 322641 0
Effects of treatment on apoprotein B using serum samples submitted to a central lipid laboratory.
Timepoint [12] 322641 0
6 years
Secondary outcome [13] 322839 0
Cost-effectiveness of pravastatin treatment assessed by self completed questionnaire designed for this trial: Utility-Based Quality-of-Life Questionnaire (UBQ)
Timepoint [13] 322839 0
6 years
Secondary outcome [14] 322840 0
Psychological well-being assessed by self completed questionnaire consisting of:
1. General Health Questionnaire (GHQ)
2. Spielberger Anger Expression Scale
3. Barratt Impulsiveness Scale
Timepoint [14] 322840 0
6 years

Eligibility
Key inclusion criteria
1. ENTRY DIAGNOSIS:
A. Patients who have suffered an acute myocardial infarction in the period three months to three years prior to screening, where acute myocardial infarction satisfies the following criteria:
1) Discharge diagnosis of acute myocardial infarction in hospital records, OR
2) Any 2 of the following 3:
a. History of typical ischaemic pain lasting for at least 15 minutes and unresponsive to sublingual nitrates
b. Elevation of CK enzymes to more than twice the upper limit of normal
c. Development of new Q-Waves and/or evolutionary ST-T wave changes lasting at least one day.

OR

B. Patients who have been discharged from hospital with a diagnosis of unstable angina pectoris three months to three years prior to assessment, where unstable angina pectoris is defined as definite ischaemic pain increasing in frequency and duration, and/or angina occurring at rest.

2. SERUM CHOLESTEROL:
Total cholesterol between 4.0 and 7.0 mmol/L, measured by the Central Lipid Laboratory in the 4 weeks prior to randomisation
Minimum age
31 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who are unlikely to be available for the duration of follow-up:
i) patients with life threatening illnesses other than coronary artery disease, who are not expected to survive for six years (such as organ transplants), or
ii) those who are unreliable including those with known drug or alcohol related problems.

2. Any cardiac surgery, angioplasty, major surgery or major illness within the past three months.

3. Severely compromised cardiac function (whether due to ischaemic heart disease or not), manifest by either:
i) New York Heart Association (NYHA) Class III or IV congestive heart failure (at the time of assessment).
ii) Left ventricular ejection fraction less than 25% (if measured).

4. History of cerebrovascular disease, including completed stroke or transient ischaemic attack within three months.

5. Significant renal or hepatic disease (such as serum creatinine > 160 micromol/L, serum albumin <3.0 g/dl; bilirubin >30 micromol/L, serum ALT or AST >1.5x the upper limit of normal).

6. Any uncontrolled endocrine disease (particularly if likely to require hospitalisation); chronic pancreatitis; dysproteinaemia; porphyria; systemic lupus erythematosus.

7. Treatment with :
(a) other lipid-lowering agents;
(b) cyclosporin;
(c) other investigational drugs.

8. Known hypersensitivity to HMG-CoA reductase inhibitors or serious adverse reactions from prior administration of HMG-CoA reductase inhibitors.

9. Significant gastrointestinal disease or surgery which might interfere with drug absorption.

10. Women of child-bearing potential (ie pre-menopausal, unless surgically sterilised) and lactating women.

11. Fasting triglyceride (as measured by the Central Lipid Laboratory) of greater than 5mmol/L

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central allocation by phone
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomised block design
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
From an overview of previous studies, for every 1% reduction in cholesterol there may be expected a 2% reduction in cardiac events and a 1% reduction in deaths due to coronary disease over a five-year period. We may assume a 25% reduction in cholesterol with treatment given optimally. With 80% compliance amongst attenders we should realise around 20% reduction in cholesterol. Hence a 20% reduction in deaths due to coronary heart disease over a five to six year treatment period might be expected. Assuming 80% compliance amongst those taking medication with a 10% drop-out rate and a 10% drop-in rate, a sample size of about 9,000 would be required to detect reliably a reduction in mortality due to coronary heart disease of 25%. This would also provide reasonable statistical power to detect a reduction in total mortality of 20%.
Analysis will be of time to study outcome, with allowance for covariates, using the proportional hazards model, if appropriate.
Potential covariates include age, gender, smoking, other diseases, level of entry lipids, MI/unstable angina, time from MI/angina attack until enrolled.

All analyses will be performed on the groups as originally randomised (ie, the "intention-to-treat" principle). Any subgroup analyses (eg, patients with myocardial infarction versus those with unstable angina) will be performed only on the combined outcome of CHD death and non-fatal myocardial infarction, as this is the only outcome for which there is any reasonable probability of distinguishing reliably between the size of treatment effects in different patient groups.

Three interim analyses are planned at approximately 2, 3, and 4 years after accrual ceases. The events to be used for these analyses will be counts of deaths. The occurrence of serious clinical and adverse events will be kept continuously under surveillance.

Should there be a difference in mortality rate or the incidence rate of major adverse reactions between the treatment groups of at least three standard deviations, then the Safety and Data Monitoring Committee will be informed, so that it may advise the Management Committee appropriately.

The use of this stringent nominal significance level of 0.003 (3 SD) would cover the reasonable number of interim analyses planned and still preserve an overall type I error probability of 0.05.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
1/03/1990
Date of last participant enrolment
Anticipated
Actual
18/12/1992
Date of last data collection
Anticipated
Actual
Sample size
Target
9000
Accrual to date
Final
9014
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 7751 0
New Zealand
State/province [1] 7751 0

Funding & Sponsors
Funding source category [1] 293221 0
Charities/Societies/Foundations
Name [1] 293221 0
National Heart Foundation of Australia
Country [1] 293221 0
Australia
Funding source category [2] 293299 0
Commercial sector/Industry
Name [2] 293299 0
Bristol-Myers Squibb Pharmaceuticals
Country [2] 293299 0
Australia
Primary sponsor type
University
Name
NHMRC Clinical Trials Centre, The University of Sydney
Address
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 292105 0
None
Name [1] 292105 0
Address [1] 292105 0
Country [1] 292105 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294701 0
Central Sydney Area Health Service
Ethics committee address [1] 294701 0
Ethics committee country [1] 294701 0
Australia
Date submitted for ethics approval [1] 294701 0
Approval date [1] 294701 0
01/02/1990
Ethics approval number [1] 294701 0
N/A

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64642 0
Prof Andrew Tonkin
Address 64642 0
Department of Epidemiology and Preventative Medicine
Monash University
99 Commercial Road
Melbourne VIC 3004
Country 64642 0
Australia
Phone 64642 0
+61 3 9903 0044
Fax 64642 0
Email 64642 0
[email protected]
Contact person for public queries
Name 64643 0
Helen Pater
Address 64643 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 64643 0
Australia
Phone 64643 0
+61 2 9562 5000
Fax 64643 0
Email 64643 0
[email protected]
Contact person for scientific queries
Name 64644 0
John Simes
Address 64644 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 64644 0
Australia
Phone 64644 0
+61 2 9562 5000
Fax 64644 0
Email 64644 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseChanges in plasma lipids predict pravastatin efficacy in secondary prevention.2019https://dx.doi.org/10.1172/jci.insight.128438
EmbaseCirculating Cystatin C Is an Independent Risk Marker for Cardiovascular Outcomes, Development of Renal Impairment, and Long-Term Mortality in Patients With Stable Coronary Heart Disease: The LIPID Study.2022https://dx.doi.org/10.1161/JAHA.121.020745
EmbaseCommon genetic variants do not predict recurrent events in coronary heart disease patients.2022https://dx.doi.org/10.1186/s12872-022-02520-0
EmbaseDistributional regression in clinical trials: treatment effects on parameters other than the mean.2022https://dx.doi.org/10.1186/s12874-022-01534-8
N.B. These documents automatically identified may not have been verified by the study sponsor.