Novel PET Radioligands as Inflammatory Biomarkers in Rheumatoid Arthritis and Myositis

April 20, 2024 updated by: National Institute of Mental Health (NIMH)

Evaluation of a Novel PET Radioligand as an Inflammatory Biomarker in Musculoskeletal Conditions

Background:

Inflammation can play a role in diseases like heart disease and rheumatoid arthritis. PET scans can help detect inflammation. Two new drugs may create better PET images.

Objective:

To see if the drugs [11C]ER176 and [11C]MC1 can help image inflammation.

Eligibility:

People ages 18 and older with rheumatoid arthritis or idiopathic inflammatory myopathy (IIM).

Healthy volunteers enrolled in protocol 01-M-0254 or 17-M-0181 are also needed.

Design:

Healthy participants will be screened under protocol 01-M-0254 or 17-M-0181.

Participants with arthritis or IIM will have a screening visit. This will include:

Medical history

Physical exam

Blood and urine tests

Possible CT or X-ray: A machine will take pictures of the body.

Healthy participants will have 1 or 2 visits. They may have urine tests. They may take the drug celecoxib by mouth. They will have a PET scan. A small amount of one or both study drugs will be injected through a catheter: A needle will guide a thin plastic tube into an arm vein. Another catheter will draw blood. They will like on a bed that slides into a machine. Their vital signs and heart activity will be measured.

Participants with arthritis will have up to 2 visits after screening. They may take celecoxib and have PET scans.

Participants with IIM will have up to 3 visits after screening. At 1 or 2 visits, they will take celecoxib and have PET scans. They will have 1 visit where they have an MRI: They will lie on a table that slides into a machine. The machine takes pictures of the body.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

I. Objective

18-kDa translocator protein (TSPO) and cyclooxygenase-2 (COX-2) are both implicated in the pathophysiology of various inflammatory disorders, suggesting that both may serve as potential biomarkers of inflammation in brain as well as periphery. Our laboratory recently developed two new radioligands: [11C]ER176 to image TSPO and [11C]MC1 to image COX-2. Using wholebody imaging, this study seeks to determine whether PET imaging using these new radioligands can differentiate two inflammatory conditions-rheumatoid arthritis (RA) and idiopathic inflammatory myopathies (IIM)-from healthy conditions. To determine if [11C]MC1 uptake is specific to COX-2, we will also conduct a blocking study with a selective COX-2 inhibitor (celecoxib) in both [11C]MC1 and [11C]ER176 scans; celecoxib is expected to block uptake of [11C]MC1 but not [11C]ER176. Using brain-dedicated imaging, this seeks to determine whether RA patients and healthy volunteers have specific binding in brain - i.e., uptake that can be blocked celecoxib.

II. Study population

Healthy volunteers (n = 17), patients with RA (n = 15), and patients with IIM (n = 15) will undergo whole-body PET/CT. In addition, healthy volunteers (n = 22) and patients with RA (n =12) will have brain-dedicated imaging using [11C]MC1 concurrent with arterial blood sampling. Finally, 15 patients with RA will be imaged during a period of moderate to severe symptoms and after clinically-indicated treatment for two to four months.Thus, the entire population will be healthy volunteers (n = 39), patients with RA (n = 42), and patients with IIM (n = 15).

III. Design

  1. Phase 1: We will begin by injecting up to 10 mCi of [11C]MC1 in one healthy male and one healthy female and then conducting a whole body PET scan. Uptake will be measured in the ovaries and testes, and the dose of radioactivity will be calculated. We will proceed only if the dose to these organs with the higher injected activity proposed for Phase 2 will not exceed the limits specified by the Radioactive Drug Research Committee (RDRC).
  2. Phase 2: Fifteen RA patients, 15 IIM patients, and 15 age-, sex-, and genotypematched healthy subjects will undergo two whole-body PET/CT scans using 15 mCi of [11C]ER176 on one day and two whole-body PET/CT scans using 15 mCi of [11C]MC1 on another day. The first scan on each day will serve as the baseline scan for comparison; the second scan on each day will be a blocking study using celecoxib. The [11C]ER176 scans are not mandatory and will be requested at the discretion of the PI.
  3. Phase 3: Twelve RA patients and 22 age- and sex-matched healthy subjects will undergo two brain-dedicated PET/CT scans, each using 20 mCi [11C]MC1, and concurrent with arterial blood sampling. The first scan will be a baseline scan, and the second will be after blockade by celecoxib.
  4. Phase 4: Fifteen RA participantstients will be imaged twice with [11C]MC: while having moderate to severe symptoms and after clinically-indicated therapy for about two to four months. Participants will have can after injection of 15 mCi of [11C]MC1.

IV. Outcome measures

For whole body imaging, radioligand uptake in a selected region of interest will be quantified as a Standardized Uptake Value (SUV), which normalizes for injected activity and body weight. Possible differences in actual blood radioligand level will be adjusted by venous blood data obtained during the PET scan. Regional uptake after blockade with celecoxib will be expressed as a percentage of the baseline value. The baseline uptake and the percentage blockade by celecoxib of each radioligand will be compared between patients and healthy subjects as well as between inflamed and non-inflamed regions of the body in RA and IIM patients.

For brain-dedicated imaging, the density of COX-2 will be measured with pharmacokinetic modeling and expressed as distribution volume (VT).

Study Type

Interventional

Enrollment (Estimated)

111

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • Recruiting
        • National Institutes of Health Clinical Center
        • Contact:
          • For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
          • Phone Number: TTY8664111010 800-411-1222
          • Email: prpl@cc.nih.gov

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 99 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

  • INCLUSION CRITERIA:

    1) Healthy subjects

  • Age greater than or equal to 18.
  • Willing and able to complete all study procedures.
  • Able to give written informed consent.
  • Medically healthy.
  • Enrolled in protocol #01M0254 "The Evaluation of Participants with Mood and Anxiety Disorders and Healthy Volunteers" or # 17-M-0181 "Recruitment and Characterization of Healthy Research Volunteers for NIMH Intramural Studies".
  • Be age-, sex-, and genotype-matched with patient groups for the 15 subjects in the Phase 2.

  • If female, no plans for pregnancy within the ensuing 3 months in the Phase 2.

    2) RA patients

  • Age greater than or equal to 18.
  • Willing and able to complete all study procedures.
  • Able to give written informed consent.
  • Have been given a diagnosis of RA based on the published criteria
  • Have moderate to severe symptoms, as defined by a DAS28-ESR score >3.2, but RA patients may be in remission for the repeat scan in phase 4.

  • If female, no plans for pregnancy within the ensuing 3 months for studies using celecoxib and for five months for the longitudinal study (Phase 4).

    3) IIM patients

  • Age greater than or equal to 18.
  • Willing and able to complete all study procedures.
  • Able to give written informed consent.
  • Meets Bohan and Peter criteria for probable or definite DM or PM, or

  • Meets criteria for IBM as defined by Lloyd et al. : 1) finger flexor or quadriceps weakness, and 2) endomysial inflammation, and

    3) either invasion of non-necrotic muscle fibers or rimmed vacuoles.

  • If female, no plans for pregnancy within the ensuing 3 months.

EXCLUSION CRITIERIA:

  1. Common for all participants

    • Because non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2, subjects should not have taken NSAIDs or willow bark tea for two weeks prior to the PET scan.

    • For Phase 2, 3 and 4 *contraindications to taking COX-2 inhibitors include:

      • History of hypersensitivity reaction to COX inhibitors or History of aspirin- or NSAID-induced asthma;
      • History of upper or lower gastrointestinal bleeding, gastritis, peptic ulcer disease;
      • History of uncontrolled gastroesophageal reflux disease (GERD), but not medically-controlled GERD;
      • Coagulation disorder;
      • Thrombocytopenia;
      • G6PD deficiency;
      • History of gout;
      • History of hepatic or renal impairment;
      • History of cardiovascular disease or presence of cardiovascular risk factors such as uncontrolled or poorlycontrolled hypertension.
      • Current use of probenecid
      • Patients clinically in remission or who have low disease activity
    • Positive HIV test.
    • Any other history of severe medical illness or injury with the potential to affect study data interpretation or to be any medical contraindication to the procedures performed in the study, including active infection and untreated malignancy.
    • Unable to travel to NIH
    • Recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.
    • Inability to lie flat on camera bed for at least two hours, including claustrophobia and overweight greater than the maximum for the scanner (500 lb).
    • Current pregnancy or breastfeeding.
    • Participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not exclusion criteria, unless that use affects the function of daily life.

    • NIMH employees and staff or immediate family member of NIMH employee/staff.

      • These criteria will not be applied to the two healthy volunteers participating in the Phase 1 of this study.

  2. Healthy subjects

    -Clinically significant laboratory abnormalities based on tests performed under screening protocol 01-M-0254 or 17-M-0181.

  3. IIM patients

    • Unable to have an MRI scan (e.g., pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or shrapnel fragments, metal fragments in the eye).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Single arm
all groups get the same studies
Drug: Celecoxib
COX-2 inhibitor
Diagnostic test: 11C-MC1
PET radioligand for COX-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Uptake of the radioligands in the affected body area
Time Frame: 2 hours
Radioligand uptake in a selected region of interest will be quantified as a Standardized Uptake Value (SUV), which normalizes for injected activity and body weight. Possible differences in actual blood radioligand level will be adjusted by venous blood data obtained during the PET scan. Regional uptake after blockade with celecoxib will be expressed as a percentage of the baseline value. The baseline uptake and the percentage blockade by celecoxib of each radioligand will be compared between patients and healthy subjects as well as between inflamed and non-inflamed regions of the body in RA and IIM patients.
2 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Robert B Innis, M.D., National Institute of Mental Health (NIMH)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 14, 2019

Primary Completion (Estimated)

February 22, 2029

Study Completion (Estimated)

February 22, 2030

Study Registration Dates

First Submitted

April 10, 2019

First Submitted That Met QC Criteria

April 10, 2019

First Posted (Actual)

April 11, 2019

Study Record Updates

Last Update Posted (Actual)

April 23, 2024

Last Update Submitted That Met QC Criteria

April 20, 2024

Last Verified

April 18, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 190079
  • 19-M-0079

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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