A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus (THEMIS)

• ClinicalTrials.gov Identifier: NCT01991795
• Recruitment Status: Completed
• First Posted: November 25, 2013
• Results First Posted: March 18, 2020
• Last Update Posted: March 18, 2020
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: November 18, 2013
• First Posted Date: November 25, 2013
• Results First Submitted Date: January 10, 2020
• Results First Posted Date: March 18, 2020
• Last Update Posted Date: March 18, 2020
• Actual Study Start Date: February 10, 2014
• Actual Primary Completion Date: January 25, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 4, 2020)

Composite of Cardiovascular (CV) Death, MI or Stroke [ Time Frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. ]

Participants with Cardiovascular (CV) death, myocardial infarction (MI) or stroke. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and non-CV death date.

• Original Primary Outcome Measures (submitted: November 18, 2013): Time from randomisation to first occurrence of any event from the composite of CV death, MI or stroke [ Time Frame: Up to 35 months ]

Current Secondary Outcome Measures (submitted: March 4, 2020)

• CV Death [ Time Frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. ]
  Participants with Cardiovascular (CV) death. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and non-CV death date.
• MI [ Time Frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. ]
  Participants with myocardial infarction. If no event, censoring occurs at the earliest of primary analysis censoring date (PACD), last endpoint assessment date and death date
• Ischaemic Stroke [ Time Frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. ]
  Participants with ischaemic stroke. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and death date.
• All-cause Death [ Time Frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. ]
  Participants with all-cause death. If no event, censoring occurs at the earliest of PACD and last endpoint assessment date. Includes deaths based on publically available vital status data in patients who have withdrawn consent.

Original Secondary Outcome Measures (submitted: November 18, 2013)

• Time from randomisation to first occurrence of any event from the composite of all-cause death, MI or stroke [ Time Frame: Up to 35 months ]
• Time from randomisation to death of CV cause [ Time Frame: Up to 35 months ]
• Time from randomisation to death of any cause [ Time Frame: Up to 35 months ]

Current Other Pre-specified Outcome Measures (submitted: March 4, 2020)

• TIMI Major Bleeding Event (Primary Safety Objective) [ Time Frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. ]
  Participants with TIMI major bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication
• TIMI Major or Minor Bleeding Event [ Time Frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. ]
  Participants with TIMI major or minor bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication
• PLATO Major Bleeding Event [ Time Frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. ]
  Participants with PLATO major bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication
• Permanent Discontinuation of Study Medication Due to Any Bleeding Event [ Time Frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. ]
  Participants with permanent discontinuation of study medication due to any bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and the date of last dose of study medication

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus
• Official Title: A Multinational, Randomised, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Ticagrelor Twice Daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Stroke in Patients With Type 2 Diabetes Mellitus (THEMIS - Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study).
• Brief Summary: The purpose of this study is to compare the effect of ticagrelor versus placebo in patients with Type 2 Diabetes Mellitus.
• Detailed Description: A multinational, randomised, double-blind, placebo-controlled phase IIIb trial to evaluate the effect of ticagrelor twice daily on the incidence of cardiovascular death, myocardial infarction or stroke in patients with type 2 diabetes mellitus
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Diabetes Mellitus, Type 2

Intervention

• Drug: Ticagrelor 60 mg
  Ticagrelor 60 mg bd taken orally as tablets
  Other Name: Brilinta/Brilique
• Drug: Ticagrelor placebo
  Ticagrelor placebo bd taken orally as tablets

Study Arms

• Experimental: Ticagrelor 60 mg
  Initially ticagrelor 90 mg or corresponding placebo was the selected dose, but reduced to ticagrelor 60 mg or corresponding placebo in Clinical Study Protocol Amendment No 1.
  Intervention: Drug: Ticagrelor 60 mg
• Placebo Comparator: Ticagrelor placebo
  Initially ticagrelor 90 mg or corresponding placebo was the selected dose, but reduced to ticagrelor 60 mg or corresponding placebo in Clinical Study Protocol Amendment No 1.
  Intervention: Drug: Ticagrelor placebo

Publications *

• Steg PG, Bhatt DL, Simon T, Fox K, Mehta SR, Harrington RA, Held C, Andersson M, Himmelmann A, Ridderstrale W, Leonsson-Zachrisson M, Liu Y, Opolski G, Zateyshchikov D, Ge J, Nicolau JC, Corbalan R, Cornel JH, Widimsky P, Leiter LA; THEMIS Steering Committee and Investigators. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med. 2019 Oct 3;381(14):1309-1320. doi: 10.1056/NEJMoa1908077. Epub 2019 Sep 1.
• Bhatt DL, Steg PG, Mehta SR, Leiter LA, Simon T, Fox K, Held C, Andersson M, Himmelmann A, Ridderstrale W, Chen J, Song Y, Diaz R, Goto S, James SK, Ray KK, Parkhomenko AN, Kosiborod MN, McGuire DK, Harrington RA; THEMIS Steering Committee and Investigators. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet. 2019 Sep 28;394(10204):1169-1180. doi: 10.1016/S0140-6736(19)31887-2. Epub 2019 Sep 1.
• Bhatt DL, Fox K, Harrington RA, Leiter LA, Mehta SR, Simon T, Andersson M, Himmelmann A, Ridderstrale W, Held C, Steg PG; THEMIS Steering Committee. Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study. Clin Cardiol. 2019 May;42(5):498-505. doi: 10.1002/clc.23164. Epub 2019 Apr 9.
• Abtan J, Bhatt DL, Elbez Y, Ducrocq G, Goto S, Smith SC Jr, Ohman EM, Eagle KA, Fox K, Harrington RA, Leiter LA, Mehta SR, Simon T, Petrov I, Sinnaeve PR, Pais P, Lev E, Bueno H, Wilson P, Steg PG; REACH Registry Investigators. External applicability of the Effect of ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) trial: An analysis of patients with diabetes and coronary artery disease in the REduction of Atherothrombosis for Continued Health (REACH) registry. Int J Cardiol. 2023 Jan 1;370:51-57. doi: 10.1016/j.ijcard.2022.10.132. Epub 2022 Oct 19.
• Wittbrodt E, Bhalla N, Sundell KA, Hunt P, Wong ND, Kuster M, Mellstrom C. Assessment of The High risk and unmEt Need in patients with CAD and type 2 diabetes (ATHENA): US healthcare resource use, cost, and burden of illness in a commercially insured population. J Diabetes Complications. 2021 Apr;35(4):107859. doi: 10.1016/j.jdiacomp.2021.107859. Epub 2021 Jan 20.
• Held P, Himmelmann A, Ditmarsch M. Ticagrelor for the treatment of atherosclerotic disease: insights from the PARTHENON clinical development program. Future Cardiol. 2016 Jul;12(4):405-18. doi: 10.2217/fca-2016-0028. Epub 2016 May 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2019): 19271
• Original Estimated Enrollment (submitted: November 18, 2013): 17000
• Actual Study Completion Date: January 25, 2019
• Actual Primary Completion Date: January 25, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Men or women ≥50 years of age with type 2 diabetes mellitus on treatment with a glucose lowering medication since at least 6 months, and either documented coronary artery occlusive disease or previous revascularization of a coronary artery.

Key Exclusion Criteria:

History of myocardial infarction or any stroke; planned treatment with agents inhibiting blood clotting; planned use of ASA/Aspirin at doses above 150 mg daily; planned coronary, cerebrovascular, or peripheral arterial revascularization; patients with known bleeding disorders and patients who need chronic oral anticoagulant therapy or chronic low-molecular-weight heparin; history of intracranial bleeding at any time, or a history of bleeding from the gastrointestinal tract within the last 6 months or a major surgery within the last 30 days; patients with known severe liver disease or with kidney failure requiring dialysis

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Puerto Rico, Romania, Russian Federation, Saudi Arabia, Slovakia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Vietnam
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01991795
• Other Study ID Numbers: D513BC00001
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Philippe Gabriel Steg, MD; Hôpital Bichat-Claude Bernard 46 Rue Henri Huchard, Paris
• Principal Investigator: Deepak L. Bhatt, MD; Brigham and Women's Hospital75 Francis Street, Boston

• PRS Account: AstraZeneca
• Verification Date: March 2020