Condition category
Circulatory System
Date applied
03/11/2008
Date assigned
12/11/2008
Last edited
15/08/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
The number of people worldwide diagnosed with diabetes is increasing rapidly every year. China has one of the highest rates of new onset type 2 diabetes (T2DM) in the world today. People with T2DM are at a greater risk of heart disease and stroke than the general population and have a reduced life expectancy. The purpose of the Acarbose Cardiovascular Evaluation (ACE) study is to determine if improving blood glucose control after meals using a drug called acarbose can reduce the risk of further heart disease or strokes in people who already have known heart disease. Acarbose is a licenced drug and is used worldwide for the treatment of diabetes. It is the most frequently prescribed treatment for diabetes in China. The study will also investigate whether this treatment can prevent or delay the onset of T2DM in people with above normal blood sugar levels who are at risk of developing diabetes. Approximately 6,500 patients will be recruited across China.

Who can participate?
Adults in China aged 50 years or older diagnosed with heart disease and who have an above normal blood sugar level.

What does the study involve?
The effectiveness of acarbose is being compared against a placebo. Each participant will receive either a 50mg acarbose tablet or a placebo three times a day.

What are the possible benefits and risks of participating?
Acarbose may help protect patients from developing heart related problems or strokes. It may also prevent or delay the development of T2DM. Taking the drug acarbose may cause some abdominal discomfort. Nausea has been reported with acarbose in <1% of patients, and in very rare cases (0.1%) acarbose may cause elevated liver enzyme levels. Taking blood samples at clinic visits may cause some discomfort and/or bruising or very rarely, a minor infection. The oral glucose tolerance test, which measures blood sugar levels before and after consumption of a sugary drink, may cause some nausea.

Where is the study run from?
The study is being sponsored and run by The University of Oxford, UK. It is being conducted in 176 hospitals in mainland China and Hong Kong. The participating hospitals are managed on a day-to-day basis through the University’s office in Beijing.

When is the study starting and how long is it expected to run for?
December 2008 to April 2017.

Who is the main contact?
Professor Rury Holman
ace@dtu.ox.ac.uk

Trial website

http://www.dtu.ox.ac.uk/ace

Contact information

Type

Scientific

Primary contact

Prof Rury Holman

ORCID ID

http://orcid.org/0000-0002-1256-874X

Contact details

Diabetes Trials Unit
Oxford Centre for Diabetes
Endocrinology and Metabolism (OCDEM)
Churchill hospital
Old Road
Headington
Oxford
OX3 7LJ
United Kingdom
+44 (0)1865 857240
ace@dtu.ox.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

NCT00829660

Protocol/serial number

11232

Study information

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

Acronym

ACE

Study hypothesis

To determine whether acarbose therapy can reduce cardiovascular-related morbidity and mortality in patients with impaired glucose intolerance (IGT) who have established coronary heart disease (CHD) or acute coronary syndrome (ACS). A secondary objective of the study is to determine if acarbose therapy can prevent or delay transition to type 2 diabetes mellitus (T2DM) in this patient population.

The first participant was enrolled on 17/02/2009 and randomised on 20/03/2009.

Please note that this trial was updated as of 02/03/2010, 21/09/2011 and 05/07/2017. All updates can be found in the relavent field with the above update date. Changes to the protocol were approved by OXTREC.

Ethics approval

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.

Study design

Phase IV multi-centre double-blind randomised controlled clinical outcome trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Coronary heart disease, acute coronary syndrome, impaired glucose tolerance, type 2 diabetes mellitus

Intervention

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 four years

Intervention type

Drug

Phase

Phase IV

Drug names

Acarbose

Primary outcome measures

Current 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 measures

Current 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.

Overall trial start date

15/12/2008

Overall trial end date

18/04/2017

Reason abandoned

Eligibility

Participant 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 during the run-in period
6. Provision of written informed consent

Previous inclusion criteria as of 02/03/10:

2.1. Previous myocardial infarction (MI), but not within the last 3 months, with at least two of the following:
2.2 Previous unstable angina, but not within the last 3 months, with all of the following:
2.2.1. Typical clinical presentation
2.2.2. Dynamic 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
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
3. Impaired glucose tolerance diagnosed on a single 75g anhydrous glucose 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

Previous inclusion criteria at time of registration:
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), but not within the last 3 months, with all of the following:
2.1.1. Typical clinical presentation
2.1.2. Confirmatory electrocardiogram (ECG) changes
2.1.3. Appropriate elevation of cardiac enzymes/biomarkers
2.2. Previous unstable angina, but not within the last 3 months, with all of the following:
2.2.1. Typical clinical presentation
2.2.2. Dynamic 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
2.3. Current stable angina with both of the following:
2.3.1. Current and typical clinical history
2.3.2. A >50% stenosis in >=1 major epicardial coronary artery shown on coronary
angiography
3. Impaired glucose tolerance diagnosed on a single 75 g anhydrous glucose 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
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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

6500

Participant 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 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

Recruitment start date

17/02/2009

Recruitment end date

10/09/2015

Locations

Countries of recruitment

China

Trial participating centre

Diabetes Trials Unit
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) Churchill hospital Old Road Headington
Oxford
OX3 7LJ
United Kingdom

Trial participating centre

176 hospitals in China
-
China

Sponsor information

Organisation

University of Oxford (UK)

Sponsor details

University Offices
Wellington Square
Oxford
OX1 2JD
United Kingdom
-
research.services@admin.ox.ac.uk

Sponsor type

University/education

Website

http://www.ox.ac.uk

Funders

Funder type

Industry

Funder name

Bayer

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

The primary results will be presented at the European Association of the Study of Diabetes in Lisbon on 13 September 2017 at 17.30 (WEST) and published in a high-impact peer reviewed journal shortly afterwards. Further results will be presented at the International Diabetes Federation World Diabetes Congress in Abu Dhabi in the week commencing 4 December 2017 and published in a high-impact peer reviewed journal early in 2018.

IPD sharing statement:
The current data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/03/2018

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

15/08/2017: Internal review. 01/08/2017: The scientific title has been changed from "The Acarbose Cardiovascular Evaluation (ACE) Trial: A 4-year, 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" to "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". The overall trial end date has been updated from 31/10/2014 to 18/04/2017. Outcome measures have been updated. Inclusion criteria and exclusion criteria have been updated. Target enrollment has changed from 7500 to 6500. Recruitment dates have been changed from 15/12/2008-31/10/2014 to 17/02/2009- 10/09/2015. Plain English summary has been added. Publication and dissemination plan, as well as the intention to publish date and participant level data sharing plan have been added. ORCID was added for study contact. Please note that the first participant was enrolled on 17/02/2009 and was randomised 20/03/2009. The last participant was enrolled on 10/09/2015 and was randomised on 13/10/2015. 14/06/2017: Inclusion criteria number 3 has been updated from "Impaired glucose tolerance diagnosed on a single 75g anhydrous glucose 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." Added a note to the exclusion criteria.