RHYTHM (Formerly Escape II Myocardium)

Sponsor
Columbia University (Other)
Overall Status
Completed
CT.gov ID
NCT01548768
Collaborator
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
149
1
3
94.7
1.6

Study Details

Study Description

Brief Summary

For aim 1, the proposed studies will be performed in 150 patients with RA and 25 subjects without RA (healthy volunteers) who will function as controls.

For aim 2, 25 of the patients enrolled in aim 1 (who are in need for further treatment due to increased RA activity despite their current treatment) will be recruited to continue in the study for an additional 24 (+/- 2) weeks (or 6 months). These patient will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care.

The investigators hypothesize that anti-TNF agents in RA patients without heart disease will not adversely affect the heart (will not cause a detrimental change in heart structure or its function).

Condition or Disease Intervention/Treatment Phase
Phase 4

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, 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 it is unknown 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 RA 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. Data in non-RA patients with advanced heart failure suggest that anti-TNF agents may not help heart failure and may even be harmful. However, the effect of these agents on the hearts of RA patients has never been directly studied. Some observational studies suggest 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
149 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Prevention
Official Title:
RHYTHM (RHeumatoid Arthritis studY of THe Myocardium): How Rheumatoid Arthritis (RA) and Tumor Necrosis Factor (TNF) Inhibitors Affect the Myocardial Structure and Function.
Actual Study Start Date :
Oct 10, 2011
Actual Primary Completion Date :
Sep 1, 2019
Actual Study Completion Date :
Sep 1, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Patients - DMARDs + TNF Inhibitors

Patients will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care.

Drug: TNF inhibitors
TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA. The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi.
Other Names:
  • Anti-TNF drugs
  • Drug: DMARDs
    Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.
    Other Names:
  • Disease-modifying antirheumatic drugs
  • Active Comparator: Patients - DMARDs only

    Patients will receive their current treatment in an open label protocol in the context of standard of care.

    Drug: DMARDs
    Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs.
    Other Names:
  • Disease-modifying antirheumatic drugs
  • No Intervention: Healthy Volunteers

    Subjects without RA who will function as controls.

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Myocardial FDG Uptake [Baseline]

      This is designed to evaluate the baseline characteristics of the cross sectional RA cohort to understand the correlation of disease activity measured by the Clinical Disease Activity Index (CDAI) with myocardial inflammation measured by fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) scan at the baseline visit. Myocardial FDG uptake is classified as "diffuse" or "focal."

    Secondary Outcome Measures

    1. Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy [Baseline, 6-Month Follow-up]

      This is designed to measure the myocardial inflammation, and its association with change in CDAI, after ramp-up of RA therapy over 6 months. Measurements are taken at baseline and 6-months post treatment escalation. Myocardial FDG uptake is classified as "diffuse" or "focal."

    2. LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake [Baseline]

      This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) structure measured by 2D/3D echocardiogram at the baseline visit.

    3. LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake [Baseline]

      This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) function measured by 2D/3D echocardiogram at the baseline visit.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    For RA patients (150 patients):

    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 Clinical Disease Activity Index (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

    • Current treatment with "Triple Therapy" or within the last 2 months

    • Untreated positive purified protein derivative (PPD) tuberculosis skin test 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 non-RA subjects (25 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

    Locations

    Site City State Country Postal Code
    1 Columbia University Medical Center New York New York United States 10032

    Sponsors and Collaborators

    • Columbia University
    • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

    Investigators

    • Principal Investigator: Joan M Bathon, MD, Columbia University

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Joan M. Bathon, Professor Medicine, Rheumatology, Columbia University
    ClinicalTrials.gov Identifier:
    NCT01548768
    Other Study ID Numbers:
    • AAAI1026
    • 7R01AR050026-07
    First Posted:
    Mar 8, 2012
    Last Update Posted:
    Nov 27, 2020
    Last Verified:
    Nov 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Joan M. Bathon, Professor Medicine, Rheumatology, Columbia University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Patients - DMARDs + TNF Inhibitors Patients - DMARDs Only Healthy Volunteers Patients - Cross Sectional (RA)
    Arm/Group Description Patients will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care. TNF inhibitors: TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA. The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi. DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. Patients will receive their current treatment in an open label protocol in the context of standard of care. DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. Subjects without RA who will function as controls. A cohort of patients with Rheumatoid Arthritis will undergo the baseline study visit only (no randomization to treatment). Note, that those who were randomized, their data will be utilized in the full cross sectional analysis.
    Period Title: Overall Study
    STARTED 8 4 16 121
    COMPLETED 7 2 15 117
    NOT COMPLETED 1 2 1 4

    Baseline Characteristics

    Arm/Group Title Patients - DMARDs + TNF Inhibitors Patients - DMARDs Only Healthy Volunteers Patients - Cross Sectional (RA) Total
    Arm/Group Description Patients will receive a TNF inhibitor in addition to their current treatment in an open label protocol for increased disease activity and in the context of standard of care. TNF inhibitors: TNF inhibitors are an FDA approved class of medications indicated for the treatment of RA when initial treatment (usually with methotrexate) has failed to achieve remission of RA disease activity. TNF inhibitors are part of the standard of care management of RA. The possible TNF inhibitors are: Remicade, Humira, Enbrel, Cimzia, Simponi. DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. Patients will receive their current treatment in an open label protocol in the context of standard of care. DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. Subjects without RA who will function as controls. A cohort of patients with Rheumatoid Arthritis will undergo the baseline study visit only (no randomization to treatment). Note, that those who were randomized, their data will be utilized in the full cross sectional analysis. Total of all reporting groups
    Overall Participants 8 4 16 121 149
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    8
    100%
    2
    50%
    15
    93.8%
    105
    86.8%
    130
    87.2%
    >=65 years
    0
    0%
    2
    50%
    1
    6.3%
    16
    13.2%
    19
    12.8%
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    55.125
    56
    52
    55.6
    54.38
    Sex: Female, Male (Count of Participants)
    Female
    6
    75%
    4
    100%
    12
    75%
    105
    86.8%
    127
    85.2%
    Male
    2
    25%
    0
    0%
    4
    25%
    16
    13.2%
    22
    14.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    3
    37.5%
    1
    25%
    4
    25%
    52
    43%
    60
    40.3%
    Not Hispanic or Latino
    5
    62.5%
    3
    75%
    12
    75%
    69
    57%
    89
    59.7%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    12.5%
    0
    0%
    0
    0%
    4
    3.3%
    5
    3.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    25%
    1
    25%
    5
    31.3%
    28
    23.1%
    36
    24.2%
    White
    5
    62.5%
    3
    75%
    11
    68.8%
    53
    43.8%
    72
    48.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    36
    29.8%
    36
    24.2%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Myocardial FDG Uptake
    Description This is designed to evaluate the baseline characteristics of the cross sectional RA cohort to understand the correlation of disease activity measured by the Clinical Disease Activity Index (CDAI) with myocardial inflammation measured by fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) scan at the baseline visit. Myocardial FDG uptake is classified as "diffuse" or "focal."
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    2 RA patients and 1 healthy volunteer (control subject) were not included in this analysis population because the subjects withdrew study participation prior to scan (no data were collected).
    Arm/Group Title Patients - Cross Sectional (RA) Healthy Volunteers
    Arm/Group Description A cohort of patients with Rheumatoid Arthritis who underwent the baseline visit analysis and completed the visit in the full cross sectional analysis. A cohort of healthy volunteers (those without an autoimmune or history of cardiac illness) was utilized. n=16 were recruited directly, while n=11 were recruited via the CUIMC Nuclear Cardiology archive.
    Measure Participants 119 15
    Diffuse FDG Uptake
    21
    262.5%
    4
    100%
    Focal FDG Uptake
    25
    312.5%
    1
    25%
    No FDG Uptake
    73
    912.5%
    10
    250%
    2. Secondary Outcome
    Title Number of Participants With Myocardial FDG Uptake After Escalation of RA Pharmacotherapy
    Description This is designed to measure the myocardial inflammation, and its association with change in CDAI, after ramp-up of RA therapy over 6 months. Measurements are taken at baseline and 6-months post treatment escalation. Myocardial FDG uptake is classified as "diffuse" or "focal."
    Time Frame Baseline, 6-Month Follow-up

    Outcome Measure Data

    Analysis Population Description
    2 TNFi, and 2 DMARDs and 1 healthy volunteer (control subject) were not included in this analysis population because the subjects withdrew participation prior to study completion or scan (no data were collected).
    Arm/Group Title RA Patients - Pharmacotherapy Escalation (TNFi) RA Patients - Pharmacotherapy Escalation (DMARD) Healthy Volunteers
    Arm/Group Description Participants were randomized to TNFi or DMARD therapy. Patients will receive their current treatment in an open label protocol in the context of standard of care. TNFi: biologic treatment for RA, such as Humira, Enbrel, Remicade, Participants were randomized to TNFi or DMARD therapy. Patients will receive their current treatment in an open label protocol in the context of standard of care. DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. A cohort of healthy volunteers (those without an autoimmune or history of cardiac illness) was utilized. n=16 were recruited directly, while n=11 were recruited via the CUIMC Nuclear Cardiology archive.
    Measure Participants 6 2 15
    Focal Baseline FDG Uptake
    1
    12.5%
    1
    25%
    1
    6.3%
    Focal Follow-up FDG Uptake
    1
    12.5%
    0
    0%
    NA
    NaN
    Diffuse Baseline FDG Uptake
    4
    50%
    1
    25%
    4
    25%
    Diffuse Follow-up FDG Uptake
    2
    25%
    0
    0%
    NA
    NaN
    3. Secondary Outcome
    Title LV Structure (Mean EDVI) in Association With Myocardial FDG Uptake
    Description This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) structure measured by 2D/3D echocardiogram at the baseline visit.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    Only 119 out of 121 subjects had data analyzed due to 2 subject withdrawals prior to scan.
    Arm/Group Title Patients - Cross Sectional (RA) Healthy Volunteers
    Arm/Group Description A cohort of patients with Rheumatoid Arthritis who underwent the baseline visit analysis and completed the visit in the full cross sectional analysis. A cohort of healthy volunteers (those without an autoimmune or history of cardiac illness) was utilized. n=16 were recruited directly, while n=11 were recruited via the CUIMC Nuclear Cardiology archive
    Measure Participants 119 16
    Mean (Standard Deviation) [ml/m^2]
    53.8
    (11)
    49.1
    (12.9)
    4. Secondary Outcome
    Title LV Function (Mean Stroke Volume Index) in Association With Myocardial FDG Uptake
    Description This is designed to evaluate the baseline characteristics of the entire RA cohort to understand the association of myocardial inflammation measure by FDG uptake with measures of left ventricular (LV) function measured by 2D/3D echocardiogram at the baseline visit.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    Only 119 out of 121 subjects had data analyzed due to 2 subject withdrawals prior to scan.
    Arm/Group Title Patients - Cross Sectional (RA) Healthy Volunteers
    Arm/Group Description A cohort of patients with Rheumatoid Arthritis who underwent the baseline visit analysis and completed the visit in the full cross sectional analysis. A cohort of healthy volunteers (those without an autoimmune or history of cardiac illness) was utilized. n=16 were recruited directly, while n=11 were recruited via the CUIMC Nuclear Cardiology archive
    Measure Participants 119 16
    Mean (Standard Deviation) [ml/m^2]
    58.6
    (13.9)
    31.3
    (7.5)

    Adverse Events

    Time Frame For those who underwent the baseline scans only (RA cross-sectional cohort, Healthy Controls), the gathering of adverse events were determined from the events from the visit alone (either acute, or patient-reported follow-up); For the group escalated in treatment therapy (n=12), adverse events were collected from baseline visit/randomization to the end-of-study safety visit conducted 6-8 weeks after the 6-month study visit.
    Adverse Event Reporting Description An adverse event (AE) is any undesirable sign, symptom or medical condition occurring after starting study drug (or therapy). Medical conditions/diseases present before starting study treatment are only considered adverse events if they worsen after starting study therapy. In addition all adverse events regardless of whether they constitute unanticipated problems as well as AEs thought to be possibly related to study procedures will also be reported to IRB, safety officer, SMC, and NIH/NIAMS.
    Arm/Group Title RA Patients - Pharmacotherapy Escalation (TNFi) RA Patients - Pharmacotherapy Escalation (DMARD) Healthy Volunteers Patients - Cross Sectional (RA)
    Arm/Group Description Participants were randomized to TNFi or DMARD therapy. Patients will receive their current treatment in an open label protocol in the context of standard of care. TNFi: biologic treatment for RA, such as Humira, Enbrel, Remicade, Participants were randomized to TNFi or DMARD therapy. Patients will receive their current treatment in an open label protocol in the context of standard of care. DMARDs: Standard of care treatment for RA, such as Methotrexate or other disease-modifying antirheumatic drugs. Subjects without RA who will function as controls. A cohort of patients with Rheumatoid Arthritis will undergo the baseline study visit only (no randomization to treatment). Note, that those who were randomized, their data will be utilized in the full cross sectional analysis.
    All Cause Mortality
    RA Patients - Pharmacotherapy Escalation (TNFi) RA Patients - Pharmacotherapy Escalation (DMARD) Healthy Volunteers Patients - Cross Sectional (RA)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/8 (0%) 0/4 (0%) 0/16 (0%) 0/121 (0%)
    Serious Adverse Events
    RA Patients - Pharmacotherapy Escalation (TNFi) RA Patients - Pharmacotherapy Escalation (DMARD) Healthy Volunteers Patients - Cross Sectional (RA)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/8 (12.5%) 0/4 (0%) 0/16 (0%) 0/121 (0%)
    Respiratory, thoracic and mediastinal disorders
    Shortness Of Breath 1/8 (12.5%) 1 0/4 (0%) 0 0/16 (0%) 0 0/121 (0%) 0
    Other (Not Including Serious) Adverse Events
    RA Patients - Pharmacotherapy Escalation (TNFi) RA Patients - Pharmacotherapy Escalation (DMARD) Healthy Volunteers Patients - Cross Sectional (RA)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/8 (12.5%) 0/4 (0%) 0/16 (0%) 6/121 (5%)
    Cardiac disorders
    Mobitz II Heart Block 0/8 (0%) 0 0/4 (0%) 0 0/16 (0%) 0 1/121 (0.8%) 1
    Atrial Tachycardia 0/8 (0%) 0 0/4 (0%) 0 0/16 (0%) 0 1/121 (0.8%) 1
    General disorders
    Worsening Migraine 0/8 (0%) 0 0/4 (0%) 0 0/16 (0%) 0 1/121 (0.8%) 1
    Angina 0/8 (0%) 0 0/4 (0%) 0 0/16 (0%) 0 1/121 (0.8%) 1
    Psychiatric disorders
    Panic Attack 0/8 (0%) 0 0/4 (0%) 0 0/16 (0%) 0 1/121 (0.8%) 1
    Skin and subcutaneous tissue disorders
    Thrombophlebitis 0/8 (0%) 0 0/4 (0%) 0 0/16 (0%) 0 1/121 (0.8%) 1
    Eczema 1/8 (12.5%) 1 0/4 (0%) 0 0/16 (0%) 0 0/121 (0%) 0

    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.

    Results Point of Contact

    Name/Title Dr. Joan Bathon, MD
    Organization Columbia University Irving Medical Center
    Phone 212-305-6327
    Email jmb2311@cumc.columbia.edu
    Responsible Party:
    Joan M. Bathon, Professor Medicine, Rheumatology, Columbia University
    ClinicalTrials.gov Identifier:
    NCT01548768
    Other Study ID Numbers:
    • AAAI1026
    • 7R01AR050026-07
    First Posted:
    Mar 8, 2012
    Last Update Posted:
    Nov 27, 2020
    Last Verified:
    Nov 1, 2020