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Rheumatoid ArthritisPhase 4NCT02659150

Effect of Subcutaneous ACTEMRA on Inflamed Atherosclerotic Plaques in Patients With Rheumatoid Arthritis

A Phase 4 study testing tocilizumab in people with Rheumatoid Arthritis, run by Massachusetts General Hospital.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The purpose of this study is to test the hypothesis that anti-IL-6 therapy is effective for reducing plaque inflammation as measured by fluorine-2-deoxy-D-glucose positron emission tomography (FDG-PET) in patients with rheumatoid arthritis (RA) who are synthetic disease-modifying antirheumatic drugs (dMARD) inadequate… Read more about this study

Who is it for?
Ages 50 to 75 years, women only
Conditions the study is for
Rheumatoid Arthritis
What is being tested?
tocilizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
No sites listed yet
Study dates
18 May 2016to 16 Nov 2019
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 to 75 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Adults aged 50-75
  • Diagnosis of RA according to the revised 1987 American College of Rheumatology (ACR; formerly American Rheumatism Association), criteria.
  • Patients who have had an inadequate response to non-biologic disease-modifying anti-rheumatic drug (DMARD) and are naïve to biologic agents.
  • Presence of plaque inflammation, identified during secondary screening, defined as a target to baseline (TBR ratio) ≥ 1.7 in the carotid artery or ascending aorta.
  • Not wheelchair or bedbound.
  • At screening, active RA consisting of ≥4 swollen joints (28 joint count) and ≥ 4 tender joints (28 joint count) and any one of the following criteria:
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  • Erythrocyte sedimentation rate (ESR) (Westergren) ≥ upper limit normal
  • CRP ≥ upper limit normal
  • If using other non-biologic DMARDS, (ex: methotrexate, sulfasalazine, hydroxychloroquine, azathioprine, cyclosporine, leflunomide), patient must demonstrate inadequate response, be on stable dose(s) for at least 4 weeks prior to baseline visit. For methotrexate: patients must be on methotrexate for at least 3 months with 4 weeks stable dose, and will stay on stable dose during the study.
  • taking corticosteroids, must be on stable doses of oral corticosteroids (≤ 10mg/day prednisone or equivalent) for at least 4 weeks prior to the baseline visit. Dose should remain stable throughout the study.
  • Any investigational treatment not mentioned elsewhere must be discontinued for 4 weeks or 5 half lives, whichever is longer, prior to the baseline visit. Exposure to any investigational biologics should be discussed with the Sponsor.
  • Signed informed consent (and informed assent of minor, if applicable).
  • Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.
  • Subject has provided written informed consent

Who cannot join

  • Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
  • Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening.
  • Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20.
  • Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
  • Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.
  • Previous treatment with TCZ or other biologics (an exception to this criterion may be granted for single dose exposure upon application to the PI on a case-by-case basis).
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  • Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
  • Currently taking a statin
  • An intra-articular injection of steroids within 6 weeks of imaging
  • Exclusions for General Safety:
  • History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
  • Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, Crohn's disease, or other symptomatic lower GI conditions that might predispose to perforations.)
  • Diagnosis of liver disease or elevated hepatic enzymes, as defined by ALT, AST, or both > 1.5 x the upper limit of age-determined normal (ULN) or total bilirubin > ULN.
  • Serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 mg/dL (168 µmol/L) in male patients. Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30
  • Any history of recent serious bacterial, viral, fungal, mycobacterial or other opportunistic infections.
  • Have serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C.
  • Positive QuantiFERON TB test , history of tuberculosis, or active TB infection without at least 4 weeks of adequate therapy for TB.
  • Active infection with EBV as defined by EBV viral load ≥ 10,000 copies per mL of whole blood.
  • Active infection with CMV as defined by CMV viral load ≥ 10,000 copies per mL of whole blood.
  • Any of the following hematologic abnormalities, confirmed by repeat tests:
  • White blood count <3,000/μL or >14,000/μL;
  • Lymphocyte count <500/μL;
  • Platelet count <100,000 /μL;
  • Hemoglobin <8.0 g/dL; or
  • Neutrophil count <2,000 cells/μL.
  • Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.
  • Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.
  • Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial.
  • History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer.
  • Pregnant women or nursing (breast feeding) mothers.
  • Patients with reproductive potential not willing to use an effective method of contraception.
  • History of alcohol, drug or chemical abuse within 1 year prior to screening.
  • Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation.
  • Rheumatic autoimmune disease other than RA, including SLE, MCTD, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty's Syndrome). Secondary Sjogrens syndrome with RA is allowable.
  • Prior history of, or current inflammatory joint disease other than RA (e.g., gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease).
  • Relatively significant radiation exposure over the course of the year prior to randomization. Significant exposure is defined as:
  • More than 2 PCI within 12 months of randomization ii) More than 2 myocardial perfusion studies within the past 12 months iii) More than 2 CT angiograms within the past 12 months iv) Any subjects with history of radiation therapy.
  • Prior history of diverticulitis
  • Contra-indications to MRI Imaging:
  • Cardiac pacemaker that is not MRI compatible
  • Surgical aneurysm clips
  • Neurostimulator
  • Implanted pumps
  • Metal fragments in body / eyes
  • Nitroglycerin patch that cannot be removed
  • Colored contact lenses should not be worn in scanner
  • Certain cochlear implants

About this study

Official title: A Multicenter, Open-Label, Proof-of-Activity Study of the Effect of Subcutaneous ACTEMRA on Inflamed Atherosclerotic Plaques in Patients With Rheumatoid Arthritis

The purpose of this study is to test the hypothesis that anti-IL-6 therapy is effective for reducing plaque inflammation as measured by fluorine-2-deoxy-D-glucose positron emission tomography (FDG-PET) in patients with rheumatoid arthritis (RA) who are synthetic disease-modifying antirheumatic drugs (dMARD) inadequate responders and are naive to biologic therapy.

Read the detailed description

This multi-center study will recruit 21 subjects to undergo an open-label tocilizumab treatment for 13-18 weeks in order to examine the efficacy of tocilizumab on plaque inflammation in RA patients. This multi-center study will employ PET/MR imaging of the carotid and coronary arteries and aorta to assess the effect of anti-IL-6 therapy on arterial inflammation in patients with RA who are synthetic dMARD inadequate responders and are naive to biologic therapy.

Secondary, exploratory evaluation will also examine correlations between atherosclerotic plaque inflammation and the inflammatory activity of the rheumatoid joint measured by PET-MR imaging, as well as how the changes in inflammation correlate with lipid and inflammatory biomarkers, and how stress levels are associated with inflammatory activity.

Adults between 50 and 75 years old diagnosed with RA will come in for an initial screening visit to assess for clinical eligibility criteria (visit 1). During the screening period, patient acceptability for the study will be assessed on the basis of medical history, concomitant medications, physical examination, and clinical laboratory test results. The study doctor will review the screening test results and procedures to determine the subject eligibility prior to imaging. Women able to become pregnant will be excluded due to teratogenic side effects.

A FDG-PET/MR imaging study will be performed at a second screening visit (visit 2) to assess for the presence of arterial, plaque and joint inflammation. A serum pregnancy test will be drawn and confirmed to be negative prior to imaging for female subjects of childbearing potential. Acceptability for study participants will be confirmed on the basis of a tissue-to-background ratio (TBR) of greater than or equal to 1.7 in qualifying vessel (calculated using the mean of the maximum SUV) as measured from FDG-PET/MR imaging. Participants who meet clinical and imaging eligibility criteria will be enrolled into the study (visit 3). Subjects will receive first dose of tocilizumab subcutaneously, on subsequent weeks, subjects will be instructed to self-administer tocilizumab at a dose of 162mg every week for a 12 week period. 4 weeks post-initiation, participants will return for a clinical safety follow-up (visit 4). Final evaluation will include physical exams, clinical assessments and carotid IMT test. A second FDG-PET/MR imaging session will take place 12 weeks post-administration (visit 5).

Effect of tocilizumab on arterial plaque inflammation will be examined by measuring the change in FDG uptake in the carotid arteries, coronary arteries and aorta between the baseline and 12 week FDG-PET/MRI.

Being tested
tocilizumab
Keywords
tocilizumab, subcutaneous injection, rheumatoid arthritis, plaque inflammation, atherosclerotic plaque, joint inflammation, FDG-PET, PET-MR, ACTEMRA
Medical subject headings
Arthritis, Rheumatoid, Plaque, Atherosclerotic, Arthritis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • tocilizumabDrug

    Also called ACTEMRA

    subjects will be treated with 162mg of weekly subcutaneous tocilizumab in an open-label manner, this will be done addition to MTX or monotherapy. On subsequent weeks after the first dose of tocilizumab, subjects will be instructed to inject the full amount of syringe according to the directions provided in the Instructions For Use (IFU).

Study groups in NCT02659150
Study groupRoleWhat they receive
Open-Label tocilizumabOthertocilizumab will be given to rheumatoid arthritis patients at a dose of 162 mg subcutaneously a week
Receives: Drug: tocilizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Arterial Inflammation in the Carotids

    The change in the target-to-background ratio of FDG uptake of the carotid, measured on PET-MR imaging before vs after 12 weeks of tocilizumab treatment. FDG uptake is calculated as Target to background values (TBR) . TBR, in turn, is calculated as the mean arterial standardized uptake value (SUV) divided by background blood pool SUV.

    Measured: Baseline and 13-18 weeks follow-up

Secondary outcomes (5)

  1. Association Between Change in Arterial Inflammation and Change in Articular Inflammation

    Change in FDG uptake in joints over the treatment period will be compared to the change in FDG uptake in arteries over the same period. FDG uptake is calculated as Target to background values (TBR)) . TBR, in turn, is calculated as the mean arterial standardized uptake value (SUV) divided by background blood pool SUV.

    Measured: Baseline and 13-18 weeks follow-up

  2. Change in Target to Background Ratio Within Carotid Artery Plaques

    Changes of Target to Background Ratio within the most diseased segment of the carotid arteries( a plaque-based analysis) before vs. after 12 weeks treatment

    Measured: Baseline and 13-18 weeks follow-up

  3. Association Between Change in Arterial Inflammation and Change in LDL

    Change in LDL over the treatment period will be compared to the change in FDG uptake in arteries over the same period. FDG uptake is calculated as Target to background values (TBR)) . TBR, in turn, is calculated as the mean arterial standardized uptake value (SUV) divided by background blood pool SUV.

    Measured: Baseline and 13-18 weeks follow-up

  4. Association Between Change in Arterial Inflammation and Change in CRP

    Change in CRP (C-reactive protein) over the treatment period will be compared to the change in FDG uptake in arteries over the same period. FDG uptake is calculated as Target to background values (TBR)) . TBR, in turn, is calculated as the mean arterial standardized uptake value (SUV) divided by background blood pool SUV.

    Measured: Baseline and 13-18 weeks follow-up

  5. Correlation Between Change in BOLD Signals in the Amygdala and Anterior Cingulate Cortex With Atherosclerotic Plaque FDG Uptake

    Correlation coefficients cannot be calculated. The BOLD imaging was optional. Only one subject produced measurable BOLD imaging at baseline and follow-up. Thus while the data are analyzed, correlation coefficients cannot be calculated.

    Measured: Baseline to 13-18 weeks follow-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Jan 2016 (estimated)
  2. Study start18 May 2016
  3. Primary completion16 Nov 2019
  4. Study completion16 Nov 2019

Why it stopped: Terminated by sponsor owing to slow enrollment

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02659150
Sponsor's protocol ID
ML29520
Status last verified
Feb 2021
First submitted
21 Dec 2015
Last updated
23 Feb 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing tocilizumab in people with Rheumatoid Arthritis, run by Massachusetts General Hospital.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 47 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 23 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Arterial Inflammation in the Carotids (time frame: Baseline and 13-18 weeks follow-up). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02659150.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2021.

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