Evaluation of the Precision and Sensitivity of Tilmanocept Uptake Value (TUV) on Tc 99m Tilmanocept Planar Imaging

Evaluation of the Precision and Sensitivity of Tilmanocept Uptake Value (TUV) on Tc 99m Tilmanocept Planar Imaging

Evaluation of the Precision and Sensitivity of Tilmanocept Uptake Value (TUV) on Tc 99m Tilmanocept Planar Imaging

This clinical trial will look at scans of the hands and wrists taken from healthy control subjects (HCs) and from subjects with rheumatoid arthritis (RA). Before each scan, subjects will be given an injection of Tc 99m tilmanocept to help the scan identify inflammation in the hand and wrist joints, which can be a part of the RA disease. Data from the scans will be used to calculate a number referred to as tilmanocept uptake value (or TUV) that is a measure of how much Tc 99m tilmanocept has located in the joints. The questions this trial aims to answer are: How consistent are the scan results (TUVs) when the scans are repeated over time? What are normal TUVs in healthy people? This will help define abnormally high values in people with RA. Are TUVs calculated early after a person starts a new drug to treat RA able to predict whether that person will have a good response to the drug later on (after it has had time to take full effect several weeks later)?

This trial is a prospective, open-label, multicenter, single and repeated-dose study designed to evaluate the reliability and sensitivity of TUV assessments in healthy control subjects and subjects with active RA. This study is stratified into 3 arms. The first 2 arms, consisting of [1] disease-free HCs and [2] clinically diagnosed RA subjects on stable treatment, respectively, are designed to evaluate the image re-image and/or test re-test (i.e., repeated dose) consistency of joint-specific and global TUVs across a variety of image acquisition intervals. The third arm consists of clinically-diagnosed subjects with active RA who are candidates for initiation of, or change to, a new anti-TNFα bDMARD therapy. This arm is designed to assess the efficacy of TUVglobal as an early predictor of response to the new anti-TNFα bDMARD therapy.

This is a prospective, open-label, multicenter, single and repeated-dose study designed to evaluate the reliability and sensitivity of TUV assessments in healthy controls and subjects with active RA.

Arm 1 includes inflammatory-disease-free HCs. Arm 1 was designed to evaluate image/re-image consistency (repeatability and stability) of joint-specific and global TUVs across a variety of image acquisition intervals and to collect normative HC data.

Arm 2 includes clinically-diagnosed RA subjects on stable treatment. Arm 2 was designed to evaluate image/re-image and test re-test (i.e., repeated dose) consistency of joint-specific and global TUVs across a variety of image acquisition intervals.

Arm 3 includes clinically-diagnosed RA subjects on stable treatment who are candidates for initiation of, or change to, new anti-TNFα therapy. Arm 3 was designed to assess the efficacy of global TUVs, obtained before and after initiation of a new anti-TNFα therapy, to predict future clinical responsiveness to the new therapy.

Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface.

The camera-specific precision of TUVjoint in subjects with active RA and Healthy Controls (HCs), which is described as the Root Mean Square Difference (RMSD) between the 15-minute planar images (referred to as A and B images at 60 and 180 minutes). The RMSD is calculated as the square root of the mean squared deviation from zero.

Day 0 tilmanocept injection followed by imaging at 60 minutes (60A) and 75 minutes (60B) and at 180 minutes (180A) and 195 minutes (180B).

The stability of the mean/variance relationship, which is assessed by comparing the Coefficient of Variation (CV) of TUVjoint and TUVglobal in subjects with active RA and in healthy control subjects at 60 and 180 minutes.

The Kendall rank correlation of the change in global TUV from baseline to 5 weeks (ΔTUVglobal[5w]) and response to new anti-TNFα bDMARD therapy defined by the change from baseline of CDAI to 12 ± 1 weeks and 24 ± 1 weeks (ΔCDAI12w and ΔCDAI24w).• The Kendall rank correlation of ΔTUVglobal[5w] and response to new anti-TNFα bDMARD therapy from baseline to 12 ± 1 weeks and 24 ± 1 weeks defined by ACR Response Criteria (ΔACR12w and ΔACR24w)

Imaging (60 minutes after tilmanocept injection) on Day 0 and at 5 weeks after new therapy initiation; Assessment of CDAI and ACR Response Criteria at 12 and 24 weeks after new therapy initiation.

Longitudinal (8-day) variation of TUV analyzed for each DAS28 joint, defined as the root mean square deviation (RMSD) and 95% confidence interval for the RMSD for each joint at Day 0 vs Day 8

The normal range of tilmanocept uptake values (TUVs) in hand and wrist joints of healthy control subjects, expressed as the mean and standard deviation. TUV is defined as the average pixel intensity of the region of interest (hand or wrist joint) divided by the average pixel intensity of the reference region (includes the region from one wrist region of interest diameter above the wrist region of interest down to the fingertips)

Qualitative Evaluations of SPECT/CT as an Indication of Bone Involvement Rather Than Localization Within the Synovial Space in the Hands and Wrists of Arm 2 Subjects

Percent of Arm 2 subjects who had SPECT/CT scans who were determined to have bone involvement rather than localization within the synovial space of the hands and wrists

A SPECT/CT scan was performed at approximately 210 minutes after the tilmanocept injection on Day 8 of the trial.

The correlation of the TUVglobal[baseline] and response to new anti-TNFα bDMARD therapy defined by the change from baseline (CFB) of CDAI to 12 ± 1 weeks and 24 ± 1 weeks (ΔCDAI12w and ΔCDAI24w, respectively) and by ACR Response Criteria (ACR12w and ACR24w, respectively).

Images were obtained 60 minutes after tilmanocept injection on Day 0. New anti-TNFα therapy was initiated after completion of Day 0 procedures. CDAI and ACR were assessed on Day 0 and again 12 and 24 weeks after initiation of new anti-TNFα therapy.

Inclusion Criteria: ALL SUBJECTS: The subject has provided written informed consent with HIPAA (Health Information Portability and Accountability Act) authorization before the initiation of any study-related procedures. ARMS 1 and 2 (only): The subject has agreed to not engage in any diet, lifestyle, or medication changes until study completion. HEALTHY CONTROL SUBJECTS The subject is between 18 and 80 years of age at the time of consent. The subject is deemed to be clinically free of any inflammatory disease(s) and has not experienced joint pain for at least 28 days prior to the consent date. The subject is not currently on anti-inflammatory drugs (including NSAIDs) and has not taken anti-inflammatories for at least 28 days prior to the consent date. For all ongoing concomitant medications, the subject has maintained a stable dose for at least 28 days prior to the consent date. CLINICALLY DIAGNOSED ACTIVE RA SUBJECTS: 3. The subject is at least 18 years of age and was ≥ 18 years of age at the time of RA diagnosis. 4. The subject has moderate to severe RA as determined by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria (score of ≥ 6/10). 5. The subject has a 28-joint disease activity score (DAS28) of ≥ 3.2 (includes the Erythrocyte Sedimentation Rate [ESR] test and Visual Analog Scale [VAS]). 6. Subjects receiving traditional DMARDs must have been on therapy for ≥ 90 days and at a stable dose for ≥ 30 days prior to the first imaging visit (Day 0). 7. If the subject is receiving bDMARD or janus kinase (JAK) inhibitor therapy, they have been at a stable dose > 180 days prior to the first imaging visit (Day 0). 8. If the subject is receiving NSAIDs or oral corticosteroids, the dose has been stable for > 28 days prior to first imaging visit (Day 1). The corticosteroid dose must be ≤ 10 mg/day of prednisone or an equivalent steroid dose. 9. ARM 3 (only): The subject is receiving anti-rheumatic treatment and is a candidate for initiation of, or change to, a new anti-TNFα bDMARD treatment. Exclusion Criteria: The subject is pregnant or lactating. The subject size or weight is not compatible with imaging per the investigator. The subject has had or is currently receiving radiation therapy or chemotherapy. The subject has renal insufficiency as demonstrated by a glomerular filtration rate of < 60 mL/min. The subject has hepatic insufficiency as demonstrated by ALT (alanine aminotransferase [SGPT]) or AST (aspartate aminotransferase [SGOT]) greater than 3 times the upper limit of normal. The subject has any severe, acute, or chronic medical conditions and/or psychiatric conditions and/or laboratory abnormalities that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration that would deem the subject inappropriate for study participation. The subject has a known allergy to or has had an adverse reaction to dextran exposure. The subject has received an investigational product within 30 days prior to the Tc 99m tilmanocept administration. The subject has received intra-articular corticosteroid injections ≤ 8 weeks prior to the first imaging visit (Day 0). The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior to the administration of Tc 99m tilmanocept.