Evaluating Safety of Escalating Doses of Tilmanocept by IV Injection and SPECT Imaging in Subjects With and Without RA

Navidea Biopharmaceuticals39 enrolled

Overview

Prospective, open-label, multicenter, dose escalation, safety with pharmacokinetics (PK) and dosimetry study of injected Tc 99m tilmanocept in the detection of and assessment of localization to skeletal joints in subjects with and without active RA by SPECT imaging.

A Manocept Platform prospective, open-label, multicenter, dose escalation, safety with PK and dosimetry study of injected Tc 99m tilmanocept in the detection of and assessment of localization to skeletal joints in subjects with and without active RA by SPECT imaging. All subjects will receive IV administration at one of 3 mass doses: 50 µg, 200 µg, or 400 µg. Within each mass dose group, subjects will receive Tc 99m tilmanocept labeled with one of 3 radiolabel doses: 1 mCi, 5 mCi, or 10 mCi. All subjects will have a whole body planar SPECT scan. Subjects enrolled in Groups 1-9 will receive a whole body and planar hands scan followed by SPECT/CT scans on areas of interest post injection at 60 minutes ± 15 minutes and 180 minutes ± 15 minutes. Subjects enrolled in Groups 10-11 will receive a whole body planar SPECT scan performed at 4 specified time points post injection: 15 ± 5 minutes, 60 ± 15 minutes, 180 ± 15 minutes and 18-20 hours. Planar hand scans will be collected at 60 ± 15 minutes and 180 ± 15 minutes post-injection. PK blood sampling will be performed before injection (within 15 minutes), immediately following injection (within 5 minutes) and at each scanning timepoint. Dosimetry tests will be performed at each scanning timepoint. PK of urine will be assessed through counts of the bladder wall obtained from cumulative quantitative planar imaging from radiation dosimetry.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Enrollment

Conditions

Arthritis, Rheumatoid

Interventions

Tc99m-tilmanoceptDRUG

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

SPECT Imaging (60 Minutes post-injection)PROCEDURE

Subjects enrolled in Groups 1-9 will receive whole body planar SPECT imaging with 3D SPECT or SPECT/CT for targeted joints of interest 60 Minutes post-injection.

SPECT Imaging (180 Minutes post-injection)PROCEDURE

Subjects enrolled in Groups 1-9 will receive whole body planar SPECT imaging with 3D SPECT or SPECT/CT for targeted joints of interest 180 Minutes post-injection.

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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. * Has a negative urine drug screening for illicit or unprescribed drugs suggestive of drug abuse. * All subjects shall be ≥18 years of age at the time of consent. CONTROL SUBJECTS: * The subject is deemed to be clinically free of any inflammatory disease (s) and has not experienced joint pain for at least 4 weeks prior to the consent date. ACTIVE RHEUMATOID ARTHRITIS SUBJECTS: * The subject has moderate to severe RA as determined by the 2010 ACR/EULAR (score of ≥ 6/10). * The subject has a DAS28 of ≥ 3.2 (includes the Erythrocyte Sedimentation Rate \[ESR\] test and Visual Analog Scale \[VAS\]) . * If the subject is receiving methotrexate, they have been at a stable dose for \> 4 weeks prior to the Baseline Visit 2 (Day 1). * If the subject is receiving biologic therapy, they have been at a stable dose \> 8 weeks prior to the Baseline Visit 2 (Day 1). * If the subject is receiving NSAIDS or oral corticosteroids, the dose has been at a stable dose for \> 4 weeks prior to the Baseline Visit 2 (Day 1). The corticosteroid dose should be ≤ 10mg/day of prednisone or an equivalent steroid dose. 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 for a condition other than rheumatoid arthritis. * The subject has renal insufficiency as demonstrated by serum creatinine clearance of \< 60 mL/min. * The subject has hepatic insufficiency as demonstrated by ALT or AST greater than two times the upper limit of normal. * The subject has a chronic or persistent infection or has any condition that would, in the opinion of the examining physician, preclude their 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 any radiopharmaceutical within 7 days prior to the administration of Tc 99m tilmanocept.

Locations (1)

Kettering Medical Center

Kettering, Ohio, United States

Outcomes

Primary Outcomes

Incidence of Adverse Drug Reaction

Number of participants that experienced pharmacologic activity or ADR in each dose group.

Time frame: From Enrollment to termination, up to 53 days

Secondary Outcomes

Per Subject Localization Rate of Tc 99m Tilmanocept by SPECT Imaging

Tc 99m Tilmanocept localization is defined as the visually (i.e., qualitatively) determined binary categorization of Tc 99m tilmanocept activity in a given DAS28 joint. The purpose of the visual assessments is to obtain dichotomized classifications of tracer uptake (herein referenced as 'localization') on planar images. Per subject localization rate is the number of subjects with at least one localized DAS28 joint per number of subjects in the analysis population.

Time frame: For Groups 1-9, 60 ± 15 min or 180 ± 15 minute post injection planar and SPECT/CT images are used

Tc 99m Tilmanocept Joint Localization Rate in Rheumatoid Arthritis Identified Joints

Per joint (clinically RA-identified) joint localization rate of Tc 99m tilmanocept is defined as the number of localized joints per number of joints from subjects in the analysis population Groups 1-9 using SPECT imaging.

Time frame: Whole-body planar scan at 60 ± 15 and 180 ± 15 minutes post Tc 99m tilmanocept administration with a duration of approximately 25 to 30 minutes at each timepoint.

Concordance

Concordance is defined as the relationship or the presence of Tc99m localization in anatomical areas of active RA defined by clinical symptomology (defined as joint swelling (SJC) and/or tenderness (TJC) during the screening DAS28 evaluation).

Time frame: Qualitative (i.e., visual) assessments of planar images were acquired at the 60 ± 15-minute and 180 ± 15-minute timepoints in Groups 1-9.

Localization Intensity

Localization intensity is defined as the presence of Tc99m in each DAS28 joint and is output in tilmanocept uptake value (TUV) units, as computed using the following equation: 〖TUV〗=ROI/BRAIN×100 where ROI = decay-corrected avg voxel intensity of the joint ROI and BRAIN =decay-corrected avg voxel intensity of the brain RR

Data from ClinicalTrials.gov

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Subjects enrolled in Groups 10-11 will receive a whole body planar SPECT scan performed 15 minutes post-injection for dosimetry.

Whole body planar SPECT imaging (60 Minutes post-injection)PROCEDURE

Subjects enrolled in Groups 10-11 will receive a whole body planar SPECT scan performed 60 minutes post-injection for dosimetry.

Whole body planar SPECT imaging (180 Minutes post-injection)PROCEDURE

Subjects enrolled in Groups 10-11 will receive a whole body planar SPECT scan performed 180 minutes post-injection for dosimetry.

Whole body planar SPECT imaging (18-20 Hours post-injection)PROCEDURE

Subjects enrolled in Groups 10-11 will receive a whole body planar SPECT scan performed 18-20 Hours post-injection for dosimetry.

Blood Collection for PK Testing (15 Mins Before Injection)PROCEDURE

Blood will be collected for subjects enrolled in Groups 10-11 for the purpose of PK analysis within 15 minutes prior to administration of Tc 99m tilmanocept

Blood Collection for PK Testing (after injection)PROCEDURE

Blood will be collected for subjects enrolled in Groups 10-11 for the purpose of PK analysis immediately following administration of Tc 99m tilmanocept (00:00)

Blood Collection for PK Testing (15 minutes post injection)PROCEDURE

Blood will be collected for subjects enrolled in Groups 10-11 for the purpose of PK analysis at 15 ± 5 minutes post injection of Tc 99m tilmanocept

Blood Collection for PK Testing (60 minutes post injection)PROCEDURE

Blood will be collected for subjects enrolled in Groups 10-11 for the purpose of PK analysis at 60 ± 15 minutes post injection of Tc 99m tilmanocept

Blood Collection for PK Testing (180 minutes post injection)PROCEDURE

Blood will be collected for subjects enrolled in Groups 10-11 for the purpose of PK analysis at 180 ± 15 minutes post injection of Tc 99m tilmanocept

Blood Collection for PK Testing (18-20 hours post injection)PROCEDURE

Blood will be collected for subjects enrolled in Groups 10-11 for the purpose of PK analysis at 18-20 hours post injection of Tc 99m tilmanocept

Planar Image with both Hands in Field of ViewPROCEDURE

Subjects in Groups 1-9 and Groups 10 and 11 will receive planar imaging with both hands in the field of view at 60 and 180 minutes post-injection.

Time frame: Post-injection imaging at 60±15 and 180±15 min

Per Subject Localization Rate of Tc 99m Tilmanocept in Areas Other Than RA

Per subject localization rate of Tc 99m tilmanocept in areas other than RA is defined as the number of subjects with at least one localized DAS28 joint per number of subjects in the analysis population.

Time frame: Imaging taken 60 ± 15 min and 180 ± 15 min post-injection

Maximum Observed Concentration (Cmax)

Maximum observed concentration (Cmax) will be calculated, whenever possible, using Tc 99m tilmanocept total radioactivity in whole blood and urine.

Time frame: 15 minutes prior to administration. Immediately after administration. 15 ± 5 minutes post administration • 60 ± 15 minutes post administration • 180 ± 15 minutes post administration • 18 to 20 hours post administration

Time to Cmax (Tmax)

Time to Cmax (tmax) will be calculated, whenever possible, using Tc 99m tilmanocept total radioactivity in whole blood and urine.

Time frame: Radioactivity was quantitated at each time point -15 mins prior to administration• Immediately after administration •15 ± 5 minutes post administration • 60 ± 15 minutes post administration • 180 ± 15 minutes post administration • 18 to 20 hours post admi

Area Under the Concentration-time Curve (AUC) From Hour 0 to the Last Measureable Concentration (AUC0-t)

Area under the concentration-time curve (AUC) from Hour 0 to the last measureable concentration (18 to 20 hours) (AUC0-t) will be calculated, whenever possible, using Tc 99m tilmanocept total radioactivity in whole blood and urine.

Time frame: Hour 0 to hour 18-20, with time points immediately post injection, 0.25 hr, 1 hr, 3 hr and 18-20 hr after injection

AUC Extrapolated to Infinity

AUC extrapolated to infinity will be calculated, whenever possible, using Tc 99m tilmanocept total radioactivity in whole blood and urine.

Time frame: 15 mins prior to administration • Immediately after administration • 15 ± 5 minutes post administration • 60 ± 15 minutes post administration • 180 ± 15 minutes post administration • 18 to 20 hours post administration

Apparent Terminal Elimination Rate Constant (Z)

Apparent terminal elimination rate constant (Z) will be calculated, whenever possible, using Tc 99m tilmanocept total radioactivity in whole blood and urine.

Apparent Terminal Elimination Half-life (t1/2)

Apparent terminal elimination half-life (t1/2) will be calculated, whenever possible, using Tc 99m tilmanocept total radioactivity in whole blood and urine.

Radiation Dosimetry of Tc 99m Tilmanocept

Mean total radiation dose per organ (mSv/MBq) in HC females, HC males, females with active RA, and males with active RA. Results were obtained at the subject level from Hybrid Dosimetry™ Version 2.8.3 and OLINDA/EXM® Version 2.1RC93 in accordance with NAV3-21 Protocol Amendment 6. The Hybrid Dosimetry™ function provides an efficient way to generate kinetic data for selected organs via regions of interest (ROI) drawing. From this data, residence times are calculated and transferred to OLINDA/EXM®, which generates absorbed dose tables using the MIRD methodology.

Time frame: Planar images were taken 15 ± 5 minutes, 60 ± 5 minutes, 180 ± 5 minutes, 18 to 20 hours after Tc 99m tilmanocept administration and processed in accordance with the NAV3-21 protocol endpoints using established dosimetry software.