Acarbose Cardiovascular Evaluation Trial

• Register: ISRCTN
• Last refreshed on: 13 November 2023
• Main ID: ISRCTN91899513
• Date of registration: 12/11/2008
• Prospective Registration: Yes
• Primary sponsor: University of Oxford (UK)
• Public title: Acarbose Cardiovascular Evaluation Trial
• Scientific title: The Acarbose Cardiovascular Evaluation (ACE) Trial: A long-term, multicentre, double-blind, randomised parallel-group trial to determine whether reducing post-prandial glycaemia can reduce cardiovascular-related morbidity and mortality in patients with established coronary heart disease or acute coronary syndrome who have impaired glucose tolerance
• Date of first enrolment: 17/02/2009
• Target sample size: 6500
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN91899513
• Study type: Interventional
• Study design: Phase IV multi-centre double-blind randomized controlled clinical outcome trial (Treatment)
• Phase: Phase IV

Countries of recruitment

China, England, United Kingdom

Contacts

• Name: Rury Holman

Key inclusion & exclusion criteria

Inclusion criteria: Current inclusion criteria as of 31/07/2017:
1. Male or female, aged 50 years or more
2. Definite CHD, defined as a, b or c below:
a) Previous myocardial infarction (MI), or Acute Coronary Syndrome (ACS), but not within the last 3 months, with any two of the following:
i) Typical clinical presentation
ii) Confirmatory ECG changes
iii) Appropriate elevation of cardiac enzymes/biomarkers
If original reports are unavailable then alternative documentation e.g. discharge summary or a clinical note from the study Investigator describing the evidence for a previous MI will be accepted.
Note: Patients with stents are eligible.
b) Previous unstable angina (UA) or Acute Coronary Syndrome (ACS), but not within the last 3 months, with any two of the following:
i) Typical clinical presentation
ii) Confirmatory ECG changes
iii) Either elevation of a cardiac biomarker or a >50% stenosis in =1 major epicardial coronary artery shown on coronary angiography or CT angiography. Where stenosis is reported in a qualitative manner, the categories “moderate” and “severe” will be taken as equating to >50% stenosis.
c) Current stable angina defined as:
i) Typical clinical history with symptoms occurring within the last month, and
ii) A >50% stenosis in =1 major epicardial coronary artery shown on coronary angiography or CT angiography. Where stenosis is reported in a qualitative manner, the categories “moderate” and “severe” will be taken as equating to >50% stenosis.
3. Impaired glucose tolerance diagnosed on a single standard OGTT, defined as a 2- hour plasma glucose (2HPG) value =7.8 but <11.1 mmol/l and a fasting plasma glucose(FPG) <7.0 mmol/l within six months prior to enrollment.
4. Optimised cardiovascular drug therapy.
5. At least 80% adherent to single blind placebo Study Medication during the run-in period.
6. Provision of written informed consent.

Correct inclusion criteria as of 14/06/2017:
1. Male or female, aged 50 years or more
2. Definite CHD, defined as a, b or c below:
2.1 Previous myocardial infarction (MI) or Acute Coronary Syndrome (ACS), but not within the last 3 months, with any two of the following:
2.1.1. Typical clinical presentation
2.1.2. Confirmatory ECG changes
2.1.3. Appropriate elevation of cardiac enzymes/biomarkers
Note: Patients with stents are eligible.
2.2 Previous unstable angina (UA) or Acute Coronary Syndrome (ACS), but not within the last 3 months, with any two of the following:
2.2.1. Typical clinical presentation
2.2.2.Confirmatory ECG changes
2.2.3.Either elevation of a cardiac biomarker or a >50% stenosis in =1 major epicardial coronary artery shown on coronary angiography or CT angiography. Where stenosis is reported in a qualitative manner, the categories ?moderate? and ?severe? will be taken as equating to >50% stenosis.
2.3. Current stable angina defined as:
2.3.1. Typical clinical history with symptoms occurring within the last month, and
2.3.2. A >50% stenosis in =1 major epicardial coronary artery shown on coronary angiography or CT angiography. Where stenosis is reported in a qualitative manner, the categories ?moderate? and ?severe? will be taken as equating to >50% stenosis.
3. Impaired glucose tolerance diagnosed on a single standard OGTT, defined as a 2-hour plasma glucose (2HPG) value =7.8 but <11.1 mmol/l and a fasting plasma glucose(FPG) <7.0 mmol/l within six months prior to enrollment.
4. Optimised cardiovascular drug therapy
5. At least 80% adherent to single blind placebo Study Medication
Exclusion criteria: Current information as of 01/08/2017:
1. Previous history of diabetes, other than gestational diabetes.
2. MI, unstable angina, stroke or a transient ischaemic attack (TIA) within the previous three months.
3. Planned or anticipated coronary, cerebrovascular or peripheral arterial revascularisation or other major surgical intervention, at the time of randomisation.
4. NYHA class III or IV heart failure.
5. Evidence of severe hepatic disease.
6. Evidence of severe renal impairment or an eGFR <30 ml/min/1.73m2 (derived using the MDRD Chinese equation).
7. Any other condition likely to reduce adherence to the protocol e.g. alcoholism, major active psychiatric disorder, cognitive impairment or a condition likely to markedly limit life expectancy e.g. malignancy.
8. Pregnancy (or planned pregnancy within the next five years).
9. Concurrent participation in any other clinical interventional trial. Note: Patients who were treated previously with an alphaglucosidase inhibitor must have at least a three-month washout period before being randomised into the ACE trial.
10. Known intolerance to alpha glucosidase inhibitors or gastrointestinal problems.
11. Thought by the investigator for any reason to be unsuitable for participation in this clinical study.

previous exclusion criteria as of 02/03/10:
1. Previous history of diabetes, other than gestational diabetes.
2. MI, unstable angina, stroke or a transient ischaemic attack (TIA) within the previous three months.
3. Planned or anticipated coronary, cerebrovascular or peripheral arterial revascularisation or other major surgical intervention.
4. New York Heart Association (NYHA) class III or IV heart failure.
5. Evidence of severe hepatic disease.
6. Evidence of severe renal impairment or an eGFR <30 ml/min/1.73m2 (derived using the MDRD Chinese equation)
7. Any other condition likely to reduce adherence to the protocol e.g. alcoholism, major active psychiatric disorder, cognitive impairment or a condition likely to markedly limit life expectancy e.g. malignancy.
8. Pregnancy (or planned pregnancy within the next five years).
9. Concurrent participation in any other clinical interventional trial. Added 14/06/2017: Note: Patients who were treated previously with an alphaglucosidase inhibitor must have at least a three-month washout period before being randomised into the ACE trial.
10. Known intolerance to alpha glucosidase inhibitors or gastrointestinal problems.
11. Thought by the investigator for any reason to be unsuitable for participation in this clinical study.

Initial information at time of registration:
1. Previous history of diabetes, other than gestational diabetes
2. MI, stroke or a transient ischaemic attack (TIA) within the previous three months
3. Planned or anticipated coronary, cerebrovascular or peripheral arterial revascularisation or other major surgical intervention
4. New York Heart Association (NYHA) class III or IV heart failure
5. Evidence of severe hepatic disease
6. Evidence of severe renal impairment or an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m^2 (derived using the MDRD Chinese equation)
7. Any other condition likely to reduce adherence to the protocol e.g., alcoholism, major active psychiatric disorder, cognitive impairment or a condition likely to markedly limit life expectancy e.g., malignancy
8. Pregnancy (or planned pregnancy within the next five years)
9. Concurrent participation in any other clinical interventional trial
10. Known i

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Coronary heart disease, acute coronary syndrome, impaired glucose tolerance, type 2 diabetes mellitus
Circulatory System
Chronic ischaemic heart disease

Intervention(s)

Current interventions as of 01/08/2017:
Acarbose (oral) vs placebo

The participants in the intervention group were given one tablet (50 mg) of acarbose per day to be taken with a meal during the first week (7 days). During the second week, the dose was increased to two tablets/day (50 mg twice a day; 100 mg/day), and then three tablets/day (50 mg three times a day; 150 mg/day) thereafter. The maximum tolerated dose was taken for the duration of the trial (maximum dose is 150 mg/day).

Total duration of interventions
Median duration of 3.0 years

Previous interventions:
Acarbose (oral) vs placebo.

The participants in the intervention group will be given one tablet (50 mg) of acarbose per day to be taken with a meal during the first week (7 days). During the second week, the dose is increased to two tablets/day (50 mg twice a day; 100 mg/day), and then three tablets/day (50 mg three times a day; 150 mg/day) thereafter. The maximum tolerated dose will be taken for the duration of the trial (maximum dose is 150 mg/day).

Total duration of interventions: Approximately 4 years

Primary Outcome(s)

Current primary outcome measure as of 20/04/2018:
Major cardiovascular events (defined as: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for unstable angina or hospitalisation for heart failure [MACE5]) occurring after randomisation (baseline) were identified through patient interviews at study visits, physician and/or family member reports and by searches of local or national electronic health records, death registries, or other publicly available sources (where permitted by local ethics approvals). All events were adjudicated by an independent Clinical Events Committee, blinded to therapy allocation.

Previous primary outcome measures as of 01/08/2017:
A composite cardiovascular outcome defined as the time after randomization to the first occurrence of any one of the following:
1. Cardiovascular death
2. Non-fatal MI
3. Non-fatal stroke
4. Hospitalisation for unstable angina
5. Hospitalisation for heart failure

Previous primary outcome measures:
Occurrence of any one of the following:
1. Cardiovascular death
2. Non-fatal MI
3. Non-fatal stroke

The primary and secondary outcomes will be monitored for a minimum of 4 years/participant. The outcomes will be assessed at 1, 2 and 4 months post-randomisation, and then every 4 months thereafter for the remainder of the trial.

Secondary Outcome(s)

Current secondary outcome measures as of 20/04/2018:
1. Individual MACE5 components and all-cause mortality were ascertained as for the primary outcome measure.
2. Transition to type 2 diabetes was ascertained from four-monthly study visit fasting plasma glucose values and by annual study visit 75g oral glucose tolerance tests, or by non-study physician reports adjudicated by an independent Clinical Events Committee, blinded to therapy allocation.
3. Transition to impaired renal function (defined as: eGFR <30 ml/min/1.73 m2, doubling of baseline serum creatinine concentration, or halving of baseline eGFR) was ascertained from annual study visit plasma creatinine measurements.
4. Medical resource use data were collected at 4-monthly study visits.

Previous secondary outcome measures as of 01/08/2017:
1. Transition to type 2 diabetes confirmed by two successive diagnostic plasma glucose values (FPG =7.0 mmol/l and/or 2HPG =11.1 mmol/l), with no intervening non-diagnostic values.
2. All-cause mortality.
3. Each of the components of the primary composite cardiovascular outcome will also be
analysed individually, both as first and as total events.
4. MACE composite cardiovascular outcome, defined as the time after randomisation to the first
occurrence of any one of the following:
• Cardiovascular death
• Non-fatal MI
• Non-fatal stroke
5.Proportion of patients with an impaired renal function as evidenced by:
• A reduced eGFR (<30 ml/minute/ 1.73 m2) estimated using the Chinese MDRD formula
• A doubling of the baseline plasma creatinine level
• A halving of the baseline eGRF.
6. Resource use, costs and cost effectiveness.

Previous as of 02/03/10:
1. Transition to type 2 diabetes confirmed by two successive diagnostic plasma glucose values (FPG =7.0 mmol/l and/or 2HPG =11.1 mmol/l), with no intervening non-diagnostic values
2. All cause mortality
3. Composite endpoint of cardiovascular death, non-fatal MI, non-fatal stroke, hospitalisation for heart failure or hospitalisation for unstable angina. Each of the components of this composite will also be analysed individually, both as first and as total events.
4. Proportion of patients with evidence of non-alcoholic fatty liver disease (NAFLD) as judged by changes in ALT levels
5. Proportion of patients with an impaired renal function as evidenced by:
A reduced eGFR (<30 ml/minute/ 1.73 m2) estimated using the Chinese MDRD formula, or a doubling of the baseline plasma creatinine level, or a halving of the baseline eGRF

The primary and secondary outcomes will be monitored for a minimum of 4 years/participant. The outcomes will be assessed at 1, 2 and 4 months post-randomisation, and then every 4 months thereafter for the remainder of the trial.

Initial information at time of registration:
1. Transition to type 2 diabetes confirmed by two successive diagnostic plasma glucose values (FPG >=7.0 mmol/l and/or 2HPG >=11.1 mmol/l), with no intervening non-diagnostic values
2. All cause mortality
3. Composite endpoint of cardiovascular death, non-fatal MI, non-fatal stroke, hospitalisation for heart failure or hospitalisation for unstable angina. Each of the components of this composite will also be analysed individually, both as first and as total events.
4. Proportion of patients with evidence of non-alcoholic fatty liver disease (NAFLD) as judged by changes in alanine aminotransferase (ALT) levels
5. Proportion of patients with an impaired renal function as evidenced by a reduced eGFR (<60 ml/minute/1.73 m^2) estimated using the Chinese MDRD formula, or a doubling of the baseline plasma creatinine level

The primary and secondary outcomes will be monitored for a minimum of 4 years/participant. The outcomes will be assessed at 1, 2 and 4 months post-randomisation, and then every 4 months thereafter for the remainder of the trial.

Secondary ID(s)

Nil known

11232

NCT00829660

Source(s) of Monetary Support

Bayer

Ethics review

Status:
Approval date:
Contact:

Old ethics approval format; Oxford Tropical Research Ethics Committee (OXTREC) on 28/10/2008 (ref: 51 08). Amendments to protocol were approved on the 17/02/2010. Further amendments to protocol approved on 18/08/2011. Added 01/08/2017: Amendments to the protocol were approved on the 17/02/2010, 18/08/2011, 20/03/2012, 04/02/2014, 03/11/2015, 27/06/2016, 03/08/2016.

Results

• Results available: Yes
• Date Completed: 18/04/2017