Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome (EXAMINE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00968708
First received: August 28, 2009
Last updated: April 15, 2014
Last verified: April 2014
Results First Received: March 8, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: Diabetes Mellitus, Type 2
Acute Coronary Syndrome
Interventions: Drug: Alogliptin
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the study at 898 investigative sites worldwide from 24 September 2009 to 18 June 2013.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with a diagnosis of type 2 diabetes mellitus and acute coronary syndrome were enrolled equally in 1 of 2 treatment groups, once a day placebo or alogliptin, in addition to receiving standard of care for cardiovascular disease and diabetes.

Reporting Groups
  Description
Placebo Alogliptin placebo matching tablets, orally, once daily. Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines.
Alogliptin Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min). Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines.

Participant Flow:   Overall Study
    Placebo     Alogliptin  
STARTED     2679     2701  
Treated     2676     2698  
COMPLETED     2361     2403  
NOT COMPLETED     318     298  
Adverse Event                 169                 150  
Major Protocol Deviation                 0                 1  
Lost to Follow-up                 19                 11  
Voluntary Withdrawal                 104                 101  
Investigator Discretion                 0                 1  
Other                 26                 34  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS) - all randomized participants who signed informed consent.

Reporting Groups
  Description
Placebo Alogliptin placebo matching tablets, orally, once daily.
Alogliptin Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min).
Total Total of all reporting groups

Baseline Measures
    Placebo     Alogliptin     Total  
Number of Participants  
[units: participants]
  2679     2701     5380  
Age  
[units: years]
Mean ± Standard Deviation
  60.7  ± 9.88     61.0  ± 9.96     60.9  ± 9.92  
Gender  
[units: participants]
     
Female     856     873     1729  
Male     1823     1828     3651  
Race/Ethnicity, Customized  
[units: participants]
     
American Indian or Alaska Native     54     56     110  
Asian     542     547     1089  
Black or African American     115     101     216  
Native Hawaiian or Other Pacific Islander     5     6     11  
White     1943     1966     3909  
More than one race     20     25     45  
Race/Ethnicity, Customized  
[units: participants]
     
Hispanic or Latino     764     773     1537  
Non-Hispanic or Latino     1915     1928     3843  
Region of Enrollment  
[units: participants]
     
Argentina     136     136     272  
Australia     7     8     15  
Austria     8     8     16  
Belgium     11     12     23  
Brazil     179     181     360  
Bulgaria     41     41     82  
Canada     54     55     109  
Chile     51     55     106  
Colombia     15     13     28  
Croatia     38     39     77  
Czech Republic     13     13     26  
Denmark     3     3     6  
Egypt     7     7     14  
Finland     12     10     22  
France     11     11     22  
Germany     26     27     53  
Greece     0     1     1  
Guatemala     25     24     49  
Hong Kong     11     12     23  
Hungary     60     59     119  
India     165     165     330  
Israel     100     101     201  
Italy     25     25     50  
Japan     105     104     209  
Kuwait     2     3     5  
Latvia     6     6     12  
Lithuania     16     20     36  
Malaysia     39     42     81  
Mexico     192     191     383  
New Zealand     13     13     26  
Peru     79     81     160  
Philippines     52     50     102  
Poland     121     118     239  
Portugal     13     16     29  
Puerto Rico     16     19     35  
Korea, Republic Of     61     62     123  
Romania     40     38     78  
Russian Federation     153     151     304  
Serbia     35     35     70  
Slovakia     46     49     95  
South Africa     39     41     80  
Spain     21     22     43  
Sweden     16     16     32  
Taiwan, Province Of China     14     13     27  
Thailand     57     58     115  
Ukraine     138     138     276  
United Arab Emirates     3     3     6  
United Kingdom     32     34     66  
United States     372     372     744  
Body Mass Index  
[units: kg/m^2]
Mean ± Standard Deviation
  29.53  ± 5.758     29.42  ± 5.422     29.48  ± 5.591  
Duration of Type 2 Diabetes Mellitus  
[units: years]
Mean ± Standard Deviation
  9.18  ± 8.121     9.13  ± 8.198     9.16  ± 8.159  
Smoking History  
[units: participants]
     
Never smoked     1144     1158     2302  
Current smoker     383     351     734  
Ex-smoker     1152     1192     2344  
Estimated Glomerular Filtration Rate (eGFR) [1]
[units: mL/min/1.73 m^2]
Mean ± Standard Deviation
  71.01  ± 21.541     70.86  ± 21.297     70.93  ± 21.417  
Renal Impairment Category [2]
[units: participants]
     
Normal Renal Function     440     399     839  
Mild Renal Impairment     1446     1530     2976  
Moderate Renal Impairment     714     694     1408  
Severe Renal Impairment/End-Stage Renal Disease     79     78     157  
Index Acute Coronary Syndrome (ACS) Event Type [3]
[units: participants]
     
Myocardial Infarction     2068     2084     4152  
Unstable Angina     605     609     1214  
Time From Index ACS Event to Randomization [3]
[units: days]
Mean ± Standard Deviation
  48.0  ± 21.95     47.6  ± 22.04     47.8  ± 22.00  
[1] Calculated using the Modification of Diet in Renal Disease (MDRD) formula
[2] Normal renal function: eGFR ≥90 mL/min/1.73 m^2; Mild renal impairment: eGFR ≥60 and <90 mL/min/1.73 m^2; Moderate renal impairment: eGFR ≥30 and <60 mL/min/1.73 m^2; Severe renal impairment: eGFR <30 mL/min/1.73 m^2; End-stage renal disease (ESRD): eGFR <15 mL/min/1.73 m^2
[3] Six participants in the placebo arm and 7 participants in the alogliptin arm are not included because they did not meet the ACS requirements for study inclusion.



  Outcome Measures
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1.  Primary:   Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)   [ Time Frame: From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). ]

Measure Type Primary
Measure Title Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)
Measure Description Primary Major Adverse Cardiac Events were defined as a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee.
Time Frame From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months).  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set (all randomized participants)

Reporting Groups
  Description
Placebo Alogliptin placebo matching tablets, orally, once daily.
Alogliptin Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min).

Measured Values
    Placebo     Alogliptin  
Number of Participants Analyzed  
[units: participants]
  2679     2701  
Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)  
[units: percentage of participants]
  11.8     11.3  


Statistical Analysis 1 for Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Cox proportional hazards
P Value [4] 0.315
Hazard Ratio (HR) [5] 0.962
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Statistical analyses of the primary MACE composite endpoint was based on sequences of 1-sided repeated confidence intervals (CIs) to assess non-inferiority or statistical superiority with respect to the null hypotheses. Each sequence of repeated CIs was constructed using critical values from a 1-sided stopping boundary for a group sequential design (GSD), to preserve an overall false-rejection rate of 2.5%. Each sequence of 1-sided repeated CIs had a simultaneous coverage probability of 97.5%.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If after accrual of 550 participants with MACE events, the upper bound of a 1-sided repeated CI for the hazard ratio (alogliptin to placebo) was <1.0, superiority of alogliptin to placebo for the primary MACE composite would be concluded. If the upper bound of the 1-sided repeated CI for the hazard ratio of the primary MACE composite was <1.3 but ≥1.0 then non-inferiority but not superiority of alogliptin to placebo was to be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Cox proportional hazards
P Value [4] 0.332
Hazard Ratio (HR) [5] 0.965
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Stratified by endpoint renal function and geographic region
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If after accrual of 550 participants with MACE events, the upper bound of a 1-sided repeated CI for the hazard ratio (alogliptin to placebo) was <1.0, superiority of alogliptin to placebo for the primary MACE composite would be concluded. If the upper bound of the 1-sided repeated CI for the hazard ratio of the primary MACE composite was <1.3 but ≥1.0 then non-inferiority but not superiority of alogliptin to placebo was to be concluded.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified by endpoint renal function (defined as the last observed postbaseline renal function (normal renal function/mild renal impairment vs moderate/severe renal impairment including end-stage renal disease)) and geographic region.
[5] Other relevant estimation information:
  No text entered.



2.  Secondary:   Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE)   [ Time Frame: From randomization until the adjudication cut-of date of May 31 2013 (maximum time on study was 41 months). ]

Measure Type Secondary
Measure Title Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE)
Measure Description Secondary MACE composite consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina; these events were adjudicated by an independent cardiovascular endpoint committee.
Time Frame From randomization until the adjudication cut-of date of May 31 2013 (maximum time on study was 41 months).  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set

Reporting Groups
  Description
Placebo Alogliptin placebo matching tablets, orally, once daily.
Alogliptin Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and <60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR <30 mL/min).

Measured Values
    Placebo     Alogliptin  
Number of Participants Analyzed  
[units: participants]
  2679     2701  
Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE)  
[units: percentage of participants]
  13.4     12.7  


Statistical Analysis 1 for Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE)
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Hazard Ratio (HR) [3] 0.952
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  If the upper bound of the confidence interval for the primary MACE composite was <1.0, then statistical superiority of alogliptin to placebo for the secondary MACE composite would be demonstrated.
[3] Other relevant estimation information:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director
Organization: Takeda
phone: 800-778-2860
e-mail: clinicaltrialregistry@tpna.com


No publications provided by Takeda

Publications automatically indexed to this study:

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00968708     History of Changes
Other Study ID Numbers: SYR-322_402, U1111-1111-6825, 2009-011222-34, JapicCTI-101246, DOH-27-0310-3047, 09/H0709/63, CTRI/2010/091/000046, 2009-011222-34, 2009-011222-34, NMRR-09-872-4471
Study First Received: August 28, 2009
Results First Received: March 8, 2014
Last Updated: April 15, 2014
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Argentina: Human Research Bioethics Committee
Austria: Agency for Health and Food Safety
Austria: Ethikkommission
Austria: Federal Ministry for Health and Women
Austria: Federal Office for Safety in Health Care
Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: Human Research Ethics Committee
Australia: National Health and Medical Research Council
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Belgium: Federal Agency for Medicinal Products and Health Products
Belgium: Institutional Review Board
Belgium: Ministry of Social Affairs, Public Health and the Environment
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Brazil: Ministry of Health
Brazil: National Committee of Ethics in Research
Brazil: National Health Surveillance Agency
Bulgaria: Bulgarian Drug Agency
Bulgaria: Ministry of Health
Canada: Canadian Institutes of Health Research
Canada: Ethics Review Committee
Canada: Health Canada
Canada: Ministry of Health & Long Term Care, Ontario
Chile: Comisión Nacional de Investigación Científica y Tecnológica
Chile: Instituto de Salud Pública de Chile
Costa Rica: Ministry of Health Costa Rica
Czech Republic: Ethics Committee
Czech Republic: State Institute for Drug Control
Denmark: Danish Dataprotection Agency
Denmark: Danish Medicines Agency
Denmark: Ethics Committee
Denmark: National Board of Health
Denmark: The Danish National Committee on Biomedical Research Ethics
Denmark: Ministry of Health
Denmark: The Regional Committee on Biomedical Research Ethics
European Union: European Medicines Agency
Finland: Ethics Committee
Finland: Ministry of Social Affairs and Health
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Direction Générale de la Santé
France: French Data Protection Authority
France: Institutional Ethical Committee
France: Ministry of Health
France: National Consultative Ethics Committee for Health and Life Sciences
Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices
Germany: Federal Ministry of Education and Research
Germany: Federal Ministry of Food, Agriculture and Consumer Protection
Germany: German Institute of Medical Documentation and Information
Germany: Ministry of Health
Germany: Paul-Ehrlich-Institut
Guatemala: Ministry of Public Health and Social Assistance
Hong Kong: Department of Health
Hong Kong: Ethics Committee
Hong Kong: Joint CUHK-NTEC Clinical Research Ethics Committee
Hungary: National Institute of Pharmacy
India: Central Drugs Standard Control Organization
India: Department of Atomic Energy
India: Drugs Controller General of India
India: Indian Council of Medical Research
India: Institutional Review Board
India: Ministry of Health
India: Ministry of Science and Technology
India: Science and Engineering Research Council
Israel: The Israel National Institute for Health Policy Research and Health Services Research
Israel: Ethics Commission
Israel: Israeli Health Ministry Pharmaceutical Administration
Israel: Ministry of Health
Italy: Ethics Committee
Italy: Ministry of Health
Italy: National Bioethics Committee
Italy: National Institute of Health
Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
Italy: The Italian Medicines Agency
Korea: Food and Drug Administration
Latvia: State Agency of Medicines
Lithuania: Bioethics Committee
Lithuania: State Medicine Control Agency - Ministry of Health
Malaysia: Ministry of Health
Mexico: Ethics Committee
Mexico: Federal Commission for Protection Against Health Risks
Mexico: Federal Commission for Sanitary Risks Protection
Mexico: Ministry of Health
Mexico: National Council of Science and Technology
Mexico: National Institute of Public Health, Health Secretariat
Netherlands: Dutch Health Care Inspectorate
Netherlands: Medical Ethics Review Committee (METC)
Netherlands: Medicines Evaluation Board (MEB)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
New Zealand: Food Safety Authority
New Zealand: Health Research Council
New Zealand: Health and Disability Ethics Committees
New Zealand: Institutional Review Board
New Zealand: Medsafe
Peru: Ethics Committee
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs
Peru: Ministry of Health
Philippines: Department of Health
Philippines: Bureau of Food and Drugs
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Poland: Ministry of Health
Poland: Ministry of Science and Higher Education
Portugal: Ethics Committee for Clinical Research
Portugal: Health Ethic Committee
Portugal: National Pharmacy and Medicines Institute
Romania: Ministry of Public Health
Romania: National Medicines Agency
Romania: State Institute for Drug Control
Russia: Ethics Committee
Russia: Ministry of Health of the Russian Federation
Russia: Pharmacological Committee, Ministry of Health
Serbia: Ethics Committee
Slovakia: State Institute for Drug Control
South Africa: Department of Health
South Africa: Medicines Control Council
South Africa: National Health Research Ethics Council
South Korea: Institutional Review Board
South Korea: Korea Food and Drug Administration (KFDA)
Spain: Comité Ético de Investigación Clínica
Spain: Ethics Committee
Spain: Ministry of Health
Spain: Ministry of Health and Consumption
Spain: Spanish Agency of Medicines
Sweden: Institutional Review Board
Sweden: Medical Products Agency
Sweden: Regional Ethical Review Board
Sweden: Swedish National Council on Medical Ethics
Sweden: Swedish Research Council
Sweden: The National Board of Health and Welfare
Thailand: Ethical Committee
Thailand: Food and Drug Administration
Thailand: Khon Kaen University Ethics Committee for Human Research
Thailand: Ministry of Public Health
Turkey: Ethics Committee
Turkey: Ministry of Health
Ukraine: Ministry of Health
Ukraine: State Pharmacological Center - Ministry of Health
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United Kingdom: Research Ethics Committee
United States: Federal Government
United States: Institutional Review Board