The Effects of mETHotrexate Therapy on ST Segment Elevation MYocardial InfarctionS (TETHYS Trial) (TETHYS)

The Effects of mETHotrexate Therapy on ST Segment Elevation MYocardial InfarctionS: Randomized Double-blind, Placebo-controlled Trial (TETHYS Trial)

Experimental studies suggest that anti-inflammatory and immunomodulatory drugs could reduce the inflammatory profile in acute ischemic disease and reduce the area of ischemia. Methotrexate is a drug that has shown promise in ischemic disease in animal studies.

Study Overview

• Status: Unknown
• Conditions: Myocardial Infarction
• Intervention / Treatment: Drug: Methotrexate; Drug: Riboflavin

Detailed Description

Atherosclerosis and ischemic disease have clear association with inflammation. There is an anti-inflammatory action of methotrexate by increasing adenosine. Experimental studies demonstrate reduction of infarct induced in animals treated with methotrexate. We expect a reduction in the area under the curve of creatine kinase (CK), creatine kinase MB fraction (CK-MB) and Troponin I high sensitive, decreased levels of B-type natriuretic peptide (BNP) and improvement in left ventricular ejection fraction.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90620001
      • Instituto de Cardiologia do Rio Grande do Sul / Fundação Universitária de Cardiologia
  • Santa Catarina
    • São José, Santa Catarina, Brazil, 88103901
      • Instituto de Cardiologia de Santa Catarina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age over 18 years;
• Chest pain suggestive of acute myocardial infarction initiated within 12 hours;
• Electrocardiogram with ST-segment elevation greater than or equal to 0.2 mV in at least 2 contiguous leads;
• Choice of primary angioplasty

Exclusion Criteria:

• Prior acute myocardial infarction;
• Prior heart failure;
• Angioplasty in the last 3 months;
• Cardiac arrest or cardiogenic shock;
• History of renal insufficiency (serum creatinine greater than 2.0 mg/dl);
• History of alcohol abuse (consumption equal to or greater than 20 drinks per week);
• Illicit drug use;
• Evidence of rheumatoid arthritis;
• Neoplasia;
• Infectious diseases;
• Prior anemia (hematocrit below 30%);
• Use of anti-inflammatory hormonal or non-hormonal last week;
• Xanthines excessive consumption (more than two and a half cups of coffee or two and a half mate gourds);
• Pregnancy;
• Disagreement with the term of consent;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Methotrexate; Established treatment associated with methotrexate	Drug: Methotrexate; The treatment group will receive a bolus dose of 0.05 mg/kg of methotrexate before primary angioplasty followed by 0.05 mg/kg per hour for 6 hours; Other Names: MTX; Amethopterin; Rheumatrex®; Trexall®
PLACEBO_COMPARATOR: Placebo (Riboflavin); Established treatment associated with placebo (riboflavin sodium fosfate 0.1%). We use riboflavin in placebo group to remain the double-blind fashion: methotrexate has a yellow color and riboflavin in that concentration has the same color.	Drug: Riboflavin; We use riboflavin in placebo group to remain the double-blind fashion: methotrexate has a yellow color and riboflavin in that concentration has the same color.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve of creatine kinase	The primary end point was the reduction of the size of the infarct as assessed by the area under the curve (AUC) (expressed in arbitrary units) for creatine kinase (CK) during 72 hours after the infarct	During 72 hours after the infarct

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve for creatine kinase MB fraction and troponin I high sensitive	The primary end point was the reduction of the size of the infarct as assessed by the area under the curve (AUC) (expressed in arbitrary units) for creatine kinase MB fraction(CK-MB) and Troponin I high sensitive during 72 hours after the infarct	During 72 hours after the infarct
Compare the peaks of CK, CK-MB and troponin I ultra-sensitive	Compare the peaks of CK, CK-MB and troponin I ultra-sensitive	During 72 hours after the infarct
Compare the levels of high-sensitivity C-reactive protein at admission, after 72 hours and after 3 months	Compare the levels of high-sensitivity C-reactive at admission, after 72 hours and after 3 months	After 72 hours and after 3 months
Compare the levels of erythrocyte sedimentation rate on admission and after 72 hours	Compare the levels of erythrocyte sedimentation rate on admission and after 72 hours	On admission and after 72 hours
Compare B-type natriuretic peptide (BNP) levels on admission, after 72 hours and after 3 months	Compare B-type natriuretic peptide (BNP) levels on admission, after 72 hours and after 3 months	On admission, after 72 hours and after 3 months
Compare the "TIMI frame count" of the culprit artery	Compare the "TIMI frame count" of the culprit artery	On admission
Compare the Killip score on admission and after 72 hours	Compare the Killip score on admission and after 72 hours;	On admission and after 72 hours
Assess ventricular ejection fraction with transthoracic echocardiography during the first 72 hours after 3 months	Assess ventricular ejection fraction with transthoracic echocardiography during the first 72 hours after 3 months	During the first 72 hours after 3 months
Assess mortality at 3 months	Assess mortality at 3 months;	At 3 months;
Evaluate reinfarction in 3 months	Evaluate reinfarction in 3 months	In 3 months
Rate side effects	Evaluation in 72 hours the changes in the levels of hematocrit, hemoglobin, leukocytes and platelets, changes in the levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase and prothrombin Time; changes in the levels of plasma creatinine, gastrointestinal effects (oral ulcers, diarrhea, nausea and vomiting), skin changes (rash, pruritus, and alopecia) and pulmonary effects (pneumonitis and pneumonia).	In 72 hours

Collaborators and Investigators

• Sponsor: Instituto de Cardiologia do Rio Grande do Sul
• Collaborators: Instituto de Cardiologia de Santa Catarina
• Investigators: Study Chair: Daniel M. Moreira, MD. MSc., Instituto de Cardiologia do Rio Grande do Sul; Study Director: Daniel M. Moreira, MD. MSc, Instituto de Cardiologia do Rio Grande do Sul; Principal Investigator: Daniel M. Moreira, MD. MSc., Instituto de Cardiologia do Rio Grande do Sul; Study Director: Maria E. Lueneberg, MD., Instituto de Cardiologia de Santa Catarina; Study Director: Roberto L. da Silva, MD., Instituto de Cardiologia de Santa Catarina; Study Director: Tammuz Fattah, MD., Instituto de Cardiologia de Santa Catarina

Publications and helpful links

General Publications

• Moreira DM, Lueneberg ME, da Silva RL, Fattah T, Gottschall CAM. MethotrexaTE THerapy in ST-Segment Elevation MYocardial InfarctionS: A Randomized Double-Blind, Placebo-Controlled Trial (TETHYS Trial). J Cardiovasc Pharmacol Ther. 2017 Nov;22(6):538-545. doi: 10.1177/1074248417699884. Epub 2017 Mar 22.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (ANTICIPATED): August 1, 2014
• Study Completion (ANTICIPATED): December 1, 2014

Study Registration Dates

• First Submitted: December 3, 2012
• First Submitted That Met QC Criteria: December 3, 2012
• First Posted (ESTIMATE): December 5, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): April 9, 2013
• Last Update Submitted That Met QC Criteria: April 5, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: Inflammation; Methotrexate; Inflammation Mediators; Myocardial Infarction; Myocardial Ischemia; Anti-Inflammatory Agents
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Photosensitizing Agents; Dermatologic Agents; Micronutrients; Vitamins; Reproductive Control Agents; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Riboflavin
• Other Study ID Numbers: UP 4747/12; CAAE 04482712.3.0000.5333 (OTHER: Plataforma Brasil)