METhotrexate Therapy Effects in the Physical Capacity of Patients With ISchemic Heart Failure (METIS Trial)

• Sponsor: Instituto de Cardiologia do Rio Grande do Sul (Other)
• Overall Status: Completed
• CT.gov ID: NCT00759811
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 2
• Duration (Months): 11
• Patients Per Site Per Month: 4.5

Study Details

Study Description

Brief Summary

The aim of the study is to evaluate the efficacy of methotrexate to improve physical capacity in patients with symptomatic ischemic heart failure.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure; Myocardial Ischemia	Drug: Methotrexate; Drug: Placebo	Phase 2/Phase 3

Detailed Description

Recent studies have showed the importance of proinflammatory mediators in the heart failure. However, there is a lack of benefit of therapies that tried to neutralize these mediators.

Methotrexate has adenosine-mediated anti-inflammatory effects in rheumatoid arthritis and psoriasis. Methotrexate limits infarct size via this adenosine-dependent mechanisms in heart of dogs (J Cardiovasc Pharmacol. 2004 Apr;43(4):574-9). A recent trial showed that this drug reduced proinflammatory mediators in patients with heart failure (Am Heart J. 2006 Jan;151(1):62-8).

These data suggest that methotrexate may improve physical capacity in patients ischemic heart failure reducing inflammation, but a randomized clinical trial is necessary to prove it.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: METhotrexate Therapy Effects in the Physical Capacity of Patients With ISchemic Heart Failure: Randomized Double-blind, Placebo-controlled Trial (METIS Trial)
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methotrexate Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks.	Drug: Methotrexate; Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks. All patients will have evaluated at the baseline and after 12 weeks: physical capacity by the 6-minutes walk test, quality of life by the Brazilian edition SF-36 and inflammatory marker by C-reactive protein. They also will be tested for ALT, AST, blood cell count, creatinine, and prothrombin time at baseline, after 6 weeks and after 12 weeks.; Other Names: Rheumatrex Trexall
Placebo Comparator: Placebo Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks.	Drug: Placebo; Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks. All patients will have evaluated at the baseline and after 12 weeks: physical capacity by the 6-minutes walk test, quality of life by the Brazilian edition SF-36 and inflammatory marker by C-reactive protein. They also will be tested for ALT, AST, blood cell count, creatinine, and prothrombin time at baseline, after 6 weeks and after 12 weeks.; Other Names: Control

Outcome Measures

Primary Outcome Measures

1. Change in Physical Capacity Measured Using the 6-minute Walk Test Distance [Baseline and 12 weeks]

   The primary outcome of the study was the difference in 6MWT distance before and after the treatment (change in meters evaluated by t test).

Secondary Outcome Measures

1. Improve in Heart Failure Functional Class Measured Using New York Heart Association [12 weeks]

2. Improve in Quality of Life Measured Using the Brazilian Edition SF-36 [12 weeks]

3. Reduction of Inflammatory Marker Measured Using C-reactive Protein Blood Levels [12 weeks]

4. Incidence of All Cause Mortality, Hospitalization for Worsening Heart Failure, Myocardial Infarct, Stroke or Myocardial Revascularization Need [12 weeks]

5. Incidence of Adverse Effects of the Treatment [12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Heart failure functional class measured using the New York Heart Association classification class II, III or IV

• Left ventricular fraction <0.45 at the ventriculography

• Angiographic coronary lesions higher than 50% or coronary lesion revascularized (coronary artery bypass or percutaneous transluminal coronary angioplasty)

Exclusion Criteria:

• Myocardial infarction in the past four months

• Coronary artery bypass or percutaneous transluminal coronary angioplasty in the past four months

• Left ventricular disfunction diagnosed during a acute coronary syndrome

• Those who require revascularization in the following 12 weeks

• Hepatic disease (ALT and AST higher than the upper limit of the reference value)

• Renal failure (plasma creatinine higher than 2.0mg/dl)

• Alcoholism (20 doses per week or more)

• Illegal drug use

• Rheumatoid arthritis or other inflammatory diseases

• Infectious disease

• Neoplasm

• Anemia (hematocrit lower than 30%)

• Currently on any anti-inflammatory drugs

• Difficulty in walking

• Unable to understand/complete the 36-item Short Form health survey (SF-36)

• Those who do not give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Instituto de Cardiologia do Rio Grande do Sul / Fundação Universitária de Cardiologia	Porto Alegre	Rio Grande do Sul	Brazil	90620001

Sponsors and Collaborators

• Instituto de Cardiologia do Rio Grande do Sul

Investigators

• Study Director: Carlos AM Gottschall, MD MSc PhD, Instituto de Cardiologia do Rio Grande do Sul
• Principal Investigator: Daniel M Moreira, MD, Instituto de Cardiologia do Rio Grande do Sul
• Study Director: Jefferson L Vieira, MD, Instituto de Cardiologia do Rio Grande do Sul

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daniel Medeiros Moreira, MSc., Instituto de Cardiologia do Rio Grande do Sul
• ClinicalTrials.gov Identifier: NCT00759811
• Other Study ID Numbers: UP4062
• First Posted: Sep 25, 2008
• Last Update Posted: May 8, 2013
• Last Verified: Mar 1, 2013

• Keywords provided by Daniel Medeiros Moreira, MSc., Instituto de Cardiologia do Rio Grande do Sul: Heart Failure; Myocardial Ischemia; Methotrexate; Inflammation; Anti-Inflammatory Agents; Inflammation Mediators
• Additional relevant MeSH terms: Heart Failure; Myocardial Ischemia; Coronary Artery Disease; Ischemia; Methotrexate

Study Results

Participant Flow

Arm/Group Title	Methotrexate	Placebo
Arm/Group Description	Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks.	Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks.
Period Title: Overall Study
STARTED	25	25
COMPLETED	23	24
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Methotrexate	Placebo	Total
Arm/Group Description	Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks.	Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks.	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 64%	18 72%	34 68%
>=65 years	9 36%	7 28%	16 32%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (10.3)	58.2 (8.0)	59.5 (9.2)
Sex: Female, Male (Count of Participants)
Female	7 28%	4 16%	11 22%
Male	18 72%	21 84%	39 78%
Region of Enrollment (participants) [Number]
Brazil	25 100%	25 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Change in Physical Capacity Measured Using the 6-minute Walk Test Distance
Description	The primary outcome of the study was the difference in 6MWT distance before and after the treatment (change in meters evaluated by t test).
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methotrexate	Placebo
Arm/Group Description	Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks.	Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks.
Measure Participants	25	25
Mean (Standard Deviation) [meters]	24.5 (39.5)	21.3 (43.7)

2. Secondary Outcome

Title	Improve in Heart Failure Functional Class Measured Using New York Heart Association
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Improve in Quality of Life Measured Using the Brazilian Edition SF-36
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Reduction of Inflammatory Marker Measured Using C-reactive Protein Blood Levels
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Incidence of All Cause Mortality, Hospitalization for Worsening Heart Failure, Myocardial Infarct, Stroke or Myocardial Revascularization Need
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Incidence of Adverse Effects of the Treatment
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Methotrexate		Placebo
Arm/Group Description	Patients receiving conventional treatment to heart failure who will receive methotrexate 7.5mg oral plus folic acid 5mg oral once a week for 12 weeks.		Patients receiving conventional treatment to heart failure who will receive placebo oral plus folic acid 5mg oral once a week for 12 weeks.
All Cause Mortality
	Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/23 (30.4%)		9/24 (37.5%)
Cardiac disorders
sustained ventricular tachycardia	1/23 (4.3%)		0/24 (0%)
Gastrointestinal disorders
nausea	2/23 (8.7%)		2/24 (8.3%)
Nervous system disorders
lipothymia	1/23 (4.3%)		2/24 (8.3%)
dizziness	3/23 (13%)		5/24 (20.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.