Rheumatoid Arthritis
Conditions
Keywords
tilmanocept, RA imaging, synovial biopsy
Brief summary
This study is a comparison of quantitative Tc 99m tilmanocept imaging with IHC analysis of CD206 expression in synovial tissue of RA subjects.
Detailed description
This is a Manocept Platform phase 2b, open-label, multi-center, multinational, non-randomized, single-dose study designed to assess the relationship between quantitative Tc 99m tilmanocept planar imaging and synovial histopathology in subjects clinically diagnosed with RA.
Interventions
Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface.
Sponsors
Navidea Biopharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The subject has provided written informed consent with HIPAA (Health Information Portability and Accountability Act) or equivalent authorization before the initiation of any study-related procedures. 2. Women and men of childbearing potential must use adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) for the duration of the study. 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 RA as determined by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria (score of ≥ 6/10 at or before screening). 5. The subject has a 28-joint disease activity score (DAS28) of ≥ 3.2 (includes the C-reactive protein \[CRP\] 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 biologic disease-modifying antirheumatic drug (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 (nonsteroidal anti-inflammatory drug) or oral corticosteroids, the dose has been at a stable dose for ≥ 28 days prior to imaging. The corticosteroid dose should be ≤ 10 mg/day of prednisone or an equivalent steroid dose. 9. The subject has a hand or wrist joint with a minimum ultrasound gray-scale synovitis score of 2 (range 0 to 3).
Exclusion criteria
1. The subject is pregnant or lactating. 2. The subject size or weight is not compatible with imaging per the investigator. 3. The subject has had or is currently receiving radiation therapy or chemotherapy. 4. The subject has renal insufficiency as demonstrated by a glomerular filtration rate of \< 60 mL/min. 5. 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. 6. 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. 7. The subject has a known allergy to or has had an adverse reaction to dextran exposure. 8. The subject has received an investigational product within 30 days prior to the Tc 99m tilmanocept administration (Day 0). 9. The subject has received intra-articular corticosteroids ≤ 8 weeks prior to imaging (Day 0). 10. The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior to the administration of Tc 99m tilmanocept (Day 0). 11. The subject has an intolerance to anesthetic and antiseptic agents indicated for the synovial biopsy procedure. 12. The subject is currently receiving anticoagulants (oral anti-platelet agents are permitted) or has a condition that is contraindicated with ultrasound-guided synovial biopsy e.g., needle phobia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Joint-specific Tilmanocept Uptake and CD206 Expression | Through study completion, up to 45 days | The correlation between joint-specific tilmanocept uptake value (TUVjoint) and the number and area fraction of CD206 expression as determined by IHC assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Joint-specific Tilmanocept Uptake and CD68 and CD163 Expression | Through study completion, up to 45 days | The correlation between TUVjoint and the number and area fraction of CD68 and CD163 determined by IHC assessments. |
| Classification of Synovial Anatomic Pathotype by IHC Assessment | Through study completion, up to 45 days | Classification of synovial anatomic pathology into * Lympho-myeloid * Diffuse myeloid * Pauci-immune fibroid types as a function of CD68, CD163, CD206, CD3, CD20, CD55, and TE7 expression determined by IHC assessments using a polytomous logistic regression model. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Objective: Correlation Between CD206, CD68, and CD163 Expression | Through study completion, up to 45 days | * Determine the relationship between TUVjoint and mRNA expression profiles of CD68, CD163, and CD206 as determined by RNA sequencing (RNA-seq). * Determine the relationship between TUVjoint and the number, size, and intensity of CD68, CD163, and CD206 as determined by (optional) flow cytometry. * Evaluate synovial expression of CD3, CD20, CD55, and TE-7 and CD206 in synovial tissue biopsy specimens. * Assessment of the relationship between TUVglobal and synovial anatomic pathology. |
| Safety Evaluation - AEs | Through study completion, up to 45 days | Evaluate safety through the examination of adverse event (AE) incidence. |
| Safety Evaluation - Laboratory Tests, ECGs, and Vital Signs | Through study completion, up to 45 days | Evaluate safety through physical examination findings, and changes over time in laboratory tests, electrocardiograms (ECGs), and vital signs. |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RA Subjects on Stable Therapy RA subjects who are on stable treatment will receive a single dose of 150 mcg tilmanocept radiolabeled with 10 mCi Tc 99m.
Tc 99m tilmanocept: Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | RA Subjects on Stable Therapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 59.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United Kingdom | 7 participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 12 / 20 |
| serious Total, serious adverse events | 1 / 20 |
Outcome results
Primary
Correlation Between Joint-specific Tilmanocept Uptake and CD206 Expression
The correlation between joint-specific tilmanocept uptake value (TUVjoint) and the number and area fraction of CD206 expression as determined by IHC assessment.
Time frame: Through study completion, up to 45 days
Population: Data not collected.
Secondary
Classification of Synovial Anatomic Pathotype by IHC Assessment
Classification of synovial anatomic pathology into * Lympho-myeloid * Diffuse myeloid * Pauci-immune fibroid types as a function of CD68, CD163, CD206, CD3, CD20, CD55, and TE7 expression determined by IHC assessments using a polytomous logistic regression model.
Time frame: Through study completion, up to 45 days
Population: All enrolled subjects injected with Tc99m technetium
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RA Subjects on Stable Therapy | Classification of Synovial Anatomic Pathotype by IHC Assessment | Pauci-immune/Fibroid | 8 Participants |
| RA Subjects on Stable Therapy | Classification of Synovial Anatomic Pathotype by IHC Assessment | Diffuse/Myeloid | 8 Participants |
| RA Subjects on Stable Therapy | Classification of Synovial Anatomic Pathotype by IHC Assessment | Lympho-Myeloid | 4 Participants |
Secondary
Correlation Between Joint-specific Tilmanocept Uptake and CD68 and CD163 Expression
The correlation between TUVjoint and the number and area fraction of CD68 and CD163 determined by IHC assessments.
Time frame: Through study completion, up to 45 days
Population: Data not collected.
Other Pre-specified
Exploratory Objective: Correlation Between CD206, CD68, and CD163 Expression
* Determine the relationship between TUVjoint and mRNA expression profiles of CD68, CD163, and CD206 as determined by RNA sequencing (RNA-seq). * Determine the relationship between TUVjoint and the number, size, and intensity of CD68, CD163, and CD206 as determined by (optional) flow cytometry. * Evaluate synovial expression of CD3, CD20, CD55, and TE-7 and CD206 in synovial tissue biopsy specimens. * Assessment of the relationship between TUVglobal and synovial anatomic pathology.
Time frame: Through study completion, up to 45 days
Population: Data not collected.
Other Pre-specified
Safety Evaluation - AEs
Evaluate safety through the examination of adverse event (AE) incidence.
Time frame: Through study completion, up to 45 days
Population: All enrolled subjects injected with Tc99m technetium.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RA Subjects on Stable Therapy | Safety Evaluation - AEs | Serious Adverse Events | 1 Adverse Events |
| RA Subjects on Stable Therapy | Safety Evaluation - AEs | Adverse Events | 25 Adverse Events |
Other Pre-specified
Safety Evaluation - Laboratory Tests, ECGs, and Vital Signs
Evaluate safety through physical examination findings, and changes over time in laboratory tests, electrocardiograms (ECGs), and vital signs.
Time frame: Through study completion, up to 45 days
Population: All enrolled subjects injected with Tc99m technetium.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RA Subjects on Stable Therapy | Safety Evaluation - Laboratory Tests, ECGs, and Vital Signs | Clinically Significant Laboratory Tests | 0 Incidents |
| RA Subjects on Stable Therapy | Safety Evaluation - Laboratory Tests, ECGs, and Vital Signs | Clinically Significant ECG Readings | 0 Incidents |
| RA Subjects on Stable Therapy | Safety Evaluation - Laboratory Tests, ECGs, and Vital Signs | Clinically Significant Vital Signs | 0 Incidents |