Escape II Myocardium

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by Columbia University
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Joan M. Bathon, Columbia University
ClinicalTrials.gov Identifier:
NCT01548768
First received: March 6, 2012
Last updated: January 14, 2013
Last verified: January 2013
  Purpose

Data on a small number of patients with Rheumatoid Arthritis (RA) show that patients with RA may have a smaller heart size and altered heart function. There is limited evidence that general inflammation due to RA and inflammation within the heart may lead to a smaller heart size which may precede heart failure in RA. Preliminary data show that all these may improve with treatment with a specific class of medications called Tumor Necrosis Factor (TNF) inhibitors. The investigators hypothesize that RA affects the size and function of the heart via inflammation and that treatment with TNF inhibitors may improve the heart size and function and possibly prevent the development of heart failure in RA.

In order to investigate these hypotheses the investigators are going to identify 50 patients who have joint inflammation that has not responded to treatment with methotrexate. As it would happen under standard of care (even without participation in the study) these patients will receive additional treatment to control their joint disease. The investigators will randomly assign these patients to receive one of two equivalent treatments that are commonly prescribed in clinical practice and in the context of standard of care: either a TNF inhibitor OR the medications sulfasalazine and hydroxychloroquine will be added to methotrexate after randomization. It is known that these two different treatments are equivalent in controlling joint inflammation but is not known if one or the other has a more favorable effect on the heart size and function. The patients will be evaluated at baseline and return 6 months after randomization and will have imaging of their heart with PET scanning and echocardiogram at both time points. Participants will also provide information about their RA, other diseases and will offer blood for testing. The investigators assume (hypothesize) that patients randomly assigned to TNF inhibitor will have improved heart size and better heart function and less inflammation in the heart compared to patients assigned to take the oral medications sulfasalazine and hydroxychloroquine.


Condition Intervention
Rheumatoid Arthritis
Drug: Triple Therapy
Drug: TNF inhibitors

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: ESCAPE II MYOCARDIUM: How Rheumatoid Arthritis (RA) and Tumor Necrosis Factor (TNF) Inhibitors Affect the Myocardial Structure and Function.

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • Improvement of left ventricular mass [ Time Frame: 6 months after treatment with TNF inhibitors versus triple therapy ] [ Designated as safety issue: No ]
    We will evaluate the differential effect TNF inhibitors vs "triple therapy" on LV mass after 6 months of treatment.

  • Improvement of Left Ventricular Ejection Fraction. [ Time Frame: After 6 months of treatment with TNF inhibitor versus triple therapy ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Improvement in the degree of myocardial inflammation (as indicated by FDG uptake in PET scanning) [ Time Frame: 6 months after treatment with TNF inhibitor versus triple therapy ] [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: October 2011
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: TNF Inhibitors Drug: TNF inhibitors

Patients will receive one of the FDA approved TNF inhibitors at the approved dosage regimen.

Patients will be evaluated during safety visits scheduled every 8 weeks between the 0 and 6 month study visits. At the time of the first safety visit medication tolerability and safety will be evaluated. At the time of the second safety visit if joint disease activity is still moderate or high an increase in the dose or frequency of the TNF inhibitor or a switch to treatment to an alternative/equivalent TNF inhibitor will take place ( there are 5 TNF inhibitors approved at the moment).

Other Names:
  • Infliximab
  • Adalimumab
  • Etanercept
  • Certolizumab pegol
  • Golimumab
  • Remicade
  • Humira
  • Enbrel
  • Cimzia
  • Simponi
Active Comparator: Triple Therapy (SSZ+MTX+Plaquenil) Drug: Triple Therapy

Patients on triple therapy will be started on 1 gram of sulfasalazine twice daily along with weight adjusted daily Hydroxychloroquine. MTX treatment will be continued.

Patients will be evaluated during safety visits scheduled every 8 weeks between the 0 and 6 month study visits.

In the first safety visit if joint disease activity is still moderate or high sulfasalazine will be increased to 3 grams daily. At the time of the second safety visit if disease activity remains moderate or high, SSZ and Hydroxychloroquine will be stopped and patients will be switched to Leflunomide (Arava) 10 mg plus methotrexate.

Other Names:
  • Sulfasalazine
  • Hydroxychloroquine
  • Leflunomide
  • Arava
  • Methotrexate
  • Plaquenil
  • MTX
  • SSZ
  • Azulfidine

  Hide Detailed Description

Detailed Description:

Patients with Rheumatoid Arthritis (RA) have a shortened life expectancy compared to the general population. Cardiovascular disease (CVD), including heart failure (HF), is the primary cause of the extra deaths in RA. HF, in general, results from failure of the heart muscle to pump adequately. In other words the heart muscle in HF becomes "weak". In patients without RA, the heart muscle gets larger before symptoms of HF appear. Contrary to that, we found that patients with RA have reduced heart size and reduced heart strength. This may mean that in RA the pathway to heart failure may be different compared to what happens in patients without RA. It is possible - for example - that in RA the heart muscle becomes smaller before it becomes weak ( while in non-RA patients the heart muscle becomes larger before it becomes weak). It is possible that cells that create inflammation in the joints may also do the same in the heart muscle making it smaller, thinner and eventually weaker.

Patients with RA nowadays can be treated with a variety of medications for their joint inflammation. These medications are powerful and have reduced the risk of permanent joint damage and disability. However we don't know what is the effect of these medications on the heart size and strength and whether they increase or decrease the risk for cardiovascular disease and heart failure.

Among the medications used for Rheumatoid Arthritis are medications called TNF inhibitors. They are usually prescribed to patients who have joint inflammation that has not responded to treatment with the first line medication Methotrexate. We have observed in few patients with RA that when they received treatment with medications called TNF inhibitors (in order to control the joint inflammation) their heart size and strength improved along with the improvement in their joint inflammation. However when these medications were used in trials for the treatment of advanced heart failure in patients without RA they were not helpful and it was thought that they may be harmful. Some studies have shown that RA patients treated with TNF inhibitors have a lower risk of developing heart disease. Overall the knowledge regarding the effect of TNF inhibitors on RA patients heart function is limited.

In this study the investigators propose to expand on the evidence suggesting that TNF inhibitors may be beneficial in terms of heart disease risk and heart function. We are going to only enroll patients with RA who do not have any prior heart disease. Specifically we are going to enroll 50 patients who have active joint disease and have not responded to treatment with methotrexate. These patients will be evaluated at baseline and 6 months later after randomization to different therapies. Normally, even if these patients did not participate in this ( or any) study, would have to take an additional medication along with methotrexate. Among the FDA approved options most rheumatologists would choose to add a TNF inhibitor to Methotrexate or proceed with what is called triple therapy (Methotrexate, Sulfasalazine, Plaquenil) . Both options are considered equivalent in terms of their ability to control joint inflammation. However nobody knows whether one or the other has a more beneficial influence on heart size function and degree of inflammation. We believe that TNF inhibitors will be more beneficial compared to triple therapy in terms of heart function.

In order to prove that the investigators are going randomly split the aforementioned 50 patients to receive one of the two treatments (TNF inhibitor vs triple therapy).

All these patients will come to our research facilities at Columbia university and will undergo a series of tests at baseline and 6 months later. These will include imaging of the heart with PET scanning and echocardiography. The later will tell us the size of the heart muscle. The former will tell us how strongly the heart muscle pumps the blood. PET scanning can also quantify the degree of inflammation within the heart. Patients will complete questionnaires about their RA their other diseases, their quality of life. Their joints will be examined by a rheumatologist and patients will provide some blood for research and clinical tests.

These will allow the investigators to compare the two treatments and see whether TNF inhibitors truly have a beneficial effect on the heart function and how much more beneficial it is compared to triple therapy. A different effect of the two regimens will allow us to understand how heart disease starts in RA, what is the role of inflammation and which inflammatory pathways are responsible for heart disease in patients with RA.

In between the two study visits the patients participating in the study will return every 6-8 weeks for what we call safety visits. During these visits they will be evaluated for the need to increase the dose of their medications or switched to a different but similar drug, they will be asked whether they can tolerate their drugs and in summary we will ensure their well-being and improvement of their joint inflammation. Overall this study will parallel/mirror what would happen even if the patients did not participate in research. The only difference from "real life clinical practice" is that the patients will have to undergo imaging and other research tests and also that the treatment will be randomly assigned.

Other pertinent to heart function evaluations will take place during this study such as weight measurement , blood pressure, heart rate, and a walk test.

In addition to the above: our previous studies have shown that RA patients have more fat than non RA individuals and that fat accumulates in the body in a different way than non RA people. This differential fat amount and distribution is thought to increase the amount of inflammation in the body and is thought to further increase the risk of heart disease in RA. In order to measure the amount of fat and how it is distributed across the body, patients will undergo whole body DEXA scans and three CT slices (two abdominal and one thigh), which will be obtained concurrently with the PET-CT imaging. Then these data will be analyzed in order to find out whether there is any differential effect between treatment with TNF inhibitors and triple therapy on fat distribution.

In order to be certain that the results of this study will not be the result of what is called random variation we are going to enroll 15 healthy subjects. These subjects will also be evaluated 6 months apart with the same evaluations mentioned above. Obviously the 15 healthy enrolled individuals will not receive any treatment. The results of heart imaging for these healthy participants will allow us to "standardize" the results for the RA patients enrolled.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

INCLUSION CRITERIA

  • Diagnosis of Rheumatoid Arthritis by 2010 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) diagnostic criteria
  • Age>18 years old
  • Moderate to high RA disease activity defined by a CDAI of >10
  • Stable dose of Methotrexate for 6 weeks prior to enrollment;
  • Stable doses of Nonsteroidal anti-inflammatory drug (NSAID) and prednisone (if already taking these medications) for 2 weeks prior to study

EXCLUSION CRITERIA

  • Prior self reported or physician diagnosed CV event (MI; angina; stroke or Transient Ischemic Attach (TIA); Heart Failure (HF); prior CV procedure (e.g., coronary artery bypass graft, angioplasty, valve replacement, pacemaker);
  • Contraindications to having a PET-CT scan or receive adenosine or Fludeoxyglucose (FDG).
  • Active treatment for Cancer
  • Uncontrolled hypertension
  • Diabetes
  • Smoking
  • Treatment with a TNF inhibitor or other biologic currently or within the last 6 months
  • Treatment with any non-biologic disease-modifying antirheumatic drug (DMARD) other than MTX in the past two months;
  • Untreated positive (tuberculosis skin test) PPD or active tuberculosis
  • History of Lymphoma and Melanoma
  • Ejection Fraction (EF) < 40% (if not known in advance then the Study Visit I Echocardiogram results will be used to exclude the patient from randomization and follow up)
  • Change in NSAID/Prednisone dosage in last 2 weeks
  • Participation in other research studies involving imaging/radiation exposure

For control participation (15 controls):

INCLUSION CRITERIA

  • Age>18 years old
  • Absence of diagnosis of RA. EXCLUSION CRITERIA
  • Prior self reported or physician diagnosed CV event (MI; angina; stroke or Transient Ischemic Attach (TIA); Heart Failure (HF); prior CV procedure (e.g., coronary artery bypass graft, angioplasty, valve replacement, pacemaker);
  • Contraindications to having a PET-CT scan or receive adenosine or FDG.
  • Uncontrolled hypertension.
  • Participation in other research studies involving imaging/radiation exposure
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01548768

Contacts
Contact: Afshin Zartoshti, MS 2123054114 az2200@columbia.edu
Contact: Dimitrios Pappas, MD 2123056327 dp2544@columbia.edu

Locations
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Afshin Zartoshti, MS    212-305-4114    az2200@columbia.edu   
Contact: Dimitrios Pappas, MD    2123056327    dp2544@columbia.edu   
Principal Investigator: Joan M Bathon, MD         
Sponsors and Collaborators
Columbia University
Investigators
Principal Investigator: Joan M Bathon, MD Columbia University
  More Information

Additional Information:
No publications provided

Responsible Party: Joan M. Bathon, Professor Medicine, Rheumatology, Columbia University
ClinicalTrials.gov Identifier: NCT01548768     History of Changes
Other Study ID Numbers: AAAI1026, 7R01AR050026-07
Study First Received: March 6, 2012
Last Updated: January 14, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Columbia University:
Rheumatoid Arthritis
Cardiovascular disease
Myocardium
TNF-alpha inhibitors
ESCAPE
Co-morbidities

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Hydroxychloroquine
Certolizumab pegol
Sulfasalazine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antimalarials

ClinicalTrials.gov processed this record on September 16, 2014