Rheumatoid Arthritis
Conditions
Keywords
RA, Tilmanocept
Brief summary
This study will confirm the ability of Tc 99m tilmanocept imaging to predict clinical response in individuals with RA who are beginning anti-TNFα therapy.
Detailed description
This is a prospective, open-label, multicenter study designed to evaluate the early predictive capacity of Tc 99m tilmanocept planar imaging for downstream clinical response(s) in individuals with moderate to severe RA who are candidates for change in anti-TNFα therapy. Temporal (Baseline to 5 week) differences in quantitative imaging will be correlated with longitudinal (Baseline to 12- and 24-week) assessments of clinical RA outcomes to evaluate the clinical utility of Tc 99m tilmanocept for the expedited evaluation of antirheumatic treatment efficacy when compared with longitudinal assessments in clinical practice.
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) authorization before the initiation of any study-related procedures. 2. The subject is at least 18 years of age and was ≥ 18 years of age at the time of RA diagnosis. 3. The subject is a candidate for initiation of, or change to, a new anti-TNFα bDMARD therapy. 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). 5. The subject has moderate to severe RA as determined by 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. Subjects receiving bDMARD or janus kinase (JAK) inhibitor therapy must have been at a stable dose \> 60 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 stable for \> 28 days prior to the first imaging visit (Day 0). The corticosteroid dose must be ≤ 10 mg/day of prednisone or an equivalent steroid dose.
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 is currently receiving radiation therapy or chemotherapy or has received radiation or chemotherapy within the past 5 years. 4. The subject has an active malignancy or a history of malignancy within the past 5 years. 5. The subject has had a finger, hand, and/or wrist amputation or hand or wrist joint arthroplasty. 6. The subject has renal insufficiency as demonstrated by a glomerular filtration rate of \< 60 mL/min. 7. The subject has hepatic insufficiency as demonstrated by ALT (alanine aminotransferase \[SGPT\]) or AST (aspartate aminotransferase \[SGOT\]) greater than 2 times the upper limit of normal. 8. 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. 9. The subject has a history of hypersensitivity reactions to TNF-inhibitors. 10. The subject has a known allergy to or has had an adverse reaction to dextran exposure. 11. The subject has received an investigational product within 30 days prior to the Tc 99m tilmanocept administration at the first imaging visit (Day 0). 12. The subject has received intra-articular corticosteroid injections ≤ 8 weeks prior to the first imaging visit (Day 0). 13. The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior to the administration of Tc 99m tilmanocept at the first imaging visit (Day 0). 14. The subject has heart failure \[New York Heart Association (NYHA) Class III-IV\], a demyelinating disorder, or a chronic/latent infection \[e.g., +Purified Protein Derivative (PPD) test, Human Immunodeficiency Virus (HIV), Hepatitis B\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Specificity of Tilmanocept Uptake Value (TUV) | Up to 213 days | Specificity of the change in TUVglobal with bucketing from baseline to 5 weeks after a change in anti-TNFα therapy (ΔTUVglobal\[5w\] with bucketing) with respect to ACR50 at week 24 after the change in therapy. |
| Sensitivity of Tilmanocept Uptake Value (TUV) | Up to 213 days | Sensitivity of the change in TUVglobal with bucketing from baseline to 5 weeks after change in anti-TNFα therapy (ΔTUVglobal\[5w\] with bucketing) with respect to ACR50 at week 24 after the change in therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NPV, and PPV, and OA of ΔTUVglobal[5w] With Bucketing With Respect to ACR50 at Weeks 12 and 24 | up to 213 days | Concordance of ΔTUVglobal\[5w\] (with bucketing) and clinical criteria, including ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance between ΔTUVglobal\[5w\] and the clinical criteria will be evaluated using NPV, PPV and overall accuracy. |
| Negative Predictive Value (NPV) of TUV Baseline at Week 12 | up to 213 days | Negative predictive value (NPV) of TUVglobal obtained at baseline (TUVglobal\[b\]) with respect to ACR50 at week 12 |
| Concordance of TUV Baseline and Change in Clinical Disease Activity Index (CDAI), 28-joint Count Disease Activity Score (DAS28), and American College of Rheumatology (ACR) Response Criteria | Up to 213 days | TUVglobal\[b\] 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, by the CFB of DAS28 to 12 +/- 1 weeks and 24 +/- 1 weeks and by the CFB in each of the ACR Response Criteria components at 12 +/- 1 weeks and at 24 +/- 1 weeks. |
| Concordance of TUV Baseline to Week 5 and Change in Clinical Disease Activity Index (CDAI) | Up to 213 days | ΔTUVglobal\[5w\] and response to new anti-TNFα bDMARD therapy defined by the CFB of CDAI to 12 +/- 1 weeks and 24 +/- 1 weeks. |
| Concordance of TUV Baseline to Week 5 and Clinical Disease Activity Index (CDAI),28-joint Count Disease Activity Score (DAS28), and American College of Rheumatology (ACR) Response Criteria | Up to 213 days | Concordance of ΔTUVglobal\[5w\] (without bucketing) and clinical criteria, including ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance between ΔTUVglobal\[5w\] and the clinical criteria will be evaluated using NPV, PPV, sensitivity, specificity, and overall accuracy. |
| Negative Predictive Value (NPV) of TUV Baseline at Week 24 | Up to 213 days | NPV of TUV global obtained at baseline (TUVglobal\[b\]) with respect to ACR50 at week 24 after change in anti-TNFα therapy |
| Correlation of TUV Baseline to Week 5 and ACR Response Criteria Components | Up to 213 days | Correlation of ΔTUVglobal\[5w\] and response to new anti-TNFα bDMARD therapy from baseline to 24 +/- 1 weeks defined by the changes from baseline in each of the ACR Response Criteria components, including: * Tender joint count (TJC) * Swollen joint count (SJC) * Patient assessment of global disease activity * Rheumatologist assessment of global disease activity * Patient assessment of pain * Patient assessment of physical function * Acute-phase reactant value |
| Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs | Up to 213 days | Incidence of AEs related to Tc 99m tilmanocept. |
| Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in Clinical Laboratory Tests | Up to 213 days | Number of participants with changes over time in clinical laboratory tests (hematology, serum chemistry, urinalysis, and RA panel). |
| Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in ECG Parameters | Up to 213 days | Number of participants with changes over time in ECG parameters (PRS Interval, QRS Duration, QT Interval, and QTc Interval). |
| Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in Vital Signs | Up to 213 days | Number of participants with changes over time in vital signs (blood pressure, heart rate, respiratory rate, and temperature). |
| Concordance of TUV Baseline to Week 12 and Clinical Disease Activity Index (CDAI),28-joint Count Disease Activity Score (DAS28), and American College of Rheumatology (ACR) Response Criteria | Up to 213 days | Concordance of ΔTUVglobal\[12w\] and change in clinical criteria, including ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance between ΔTUVglobal\[12w\] and the clinical criteria will be evaluated using NPV, PPV, sensitivity, specificity, and overall accuracy. |
| Sensitivity and Specificity of ΔTUVglobal[5w] With Bucketing With Respect to ACR50 at Week 12 | Up to 213 days | Concordance of ΔTUVglobal\[5w\] with bucketing and ACR50 at week 12, evaluated using sensitivity and specificity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Candidates for Initiation of Anti-TNFα bDMARD Therapy All subjects will be candidates for initiation of, or change to, a new anti-TNFα bDMARD for RA treatment.
TC99m-tilmanocept: Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface. | 169 |
| Total | 169 |
Baseline characteristics
| Characteristic | Candidates for Initiation of Anti-TNFα bDMARD Therapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 41 Participants |
| Age, Categorical Between 18 and 65 years | 128 Participants |
| Age, Continuous | 59.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 65 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 104 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 17 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 | 0 Participants |
| Race (NIH/OMB) White | 146 Participants |
| Region of Enrollment United States | 169 participants |
| Sex: Female, Male Female | 141 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 169 |
| other Total, other adverse events | 0 / 169 |
| serious Total, serious adverse events | 5 / 169 |
Outcome results
Primary
Sensitivity of Tilmanocept Uptake Value (TUV)
Sensitivity of the change in TUVglobal with bucketing from baseline to 5 weeks after change in anti-TNFα therapy (ΔTUVglobal\[5w\] with bucketing) with respect to ACR50 at week 24 after the change in therapy.
Time frame: Up to 213 days
Population: Data not collected.
Primary
Specificity of Tilmanocept Uptake Value (TUV)
Specificity of the change in TUVglobal with bucketing from baseline to 5 weeks after a change in anti-TNFα therapy (ΔTUVglobal\[5w\] with bucketing) with respect to ACR50 at week 24 after the change in therapy.
Time frame: Up to 213 days
Population: Data not collected.
Secondary
Concordance of TUV Baseline and Change in Clinical Disease Activity Index (CDAI), 28-joint Count Disease Activity Score (DAS28), and American College of Rheumatology (ACR) Response Criteria
TUVglobal\[b\] 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, by the CFB of DAS28 to 12 +/- 1 weeks and 24 +/- 1 weeks and by the CFB in each of the ACR Response Criteria components at 12 +/- 1 weeks and at 24 +/- 1 weeks.
Time frame: Up to 213 days
Population: Data not collected.
Secondary
Concordance of TUV Baseline to Week 12 and Clinical Disease Activity Index (CDAI),28-joint Count Disease Activity Score (DAS28), and American College of Rheumatology (ACR) Response Criteria
Concordance of ΔTUVglobal\[12w\] and change in clinical criteria, including ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance between ΔTUVglobal\[12w\] and the clinical criteria will be evaluated using NPV, PPV, sensitivity, specificity, and overall accuracy.
Time frame: Up to 213 days
Population: Data not collected.
Secondary
Concordance of TUV Baseline to Week 5 and Change in Clinical Disease Activity Index (CDAI)
ΔTUVglobal\[5w\] and response to new anti-TNFα bDMARD therapy defined by the CFB of CDAI to 12 +/- 1 weeks and 24 +/- 1 weeks.
Time frame: Up to 213 days
Population: Data not collected.
Secondary
Concordance of TUV Baseline to Week 5 and Clinical Disease Activity Index (CDAI),28-joint Count Disease Activity Score (DAS28), and American College of Rheumatology (ACR) Response Criteria
Concordance of ΔTUVglobal\[5w\] (without bucketing) and clinical criteria, including ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance between ΔTUVglobal\[5w\] and the clinical criteria will be evaluated using NPV, PPV, sensitivity, specificity, and overall accuracy.
Time frame: Up to 213 days
Population: Data not collected.
Secondary
Correlation of TUV Baseline to Week 5 and ACR Response Criteria Components
Correlation of ΔTUVglobal\[5w\] and response to new anti-TNFα bDMARD therapy from baseline to 24 +/- 1 weeks defined by the changes from baseline in each of the ACR Response Criteria components, including: * Tender joint count (TJC) * Swollen joint count (SJC) * Patient assessment of global disease activity * Rheumatologist assessment of global disease activity * Patient assessment of pain * Patient assessment of physical function * Acute-phase reactant value
Time frame: Up to 213 days
Population: Data not collected.
Secondary
Negative Predictive Value (NPV) of TUV Baseline at Week 12
Negative predictive value (NPV) of TUVglobal obtained at baseline (TUVglobal\[b\]) with respect to ACR50 at week 12
Time frame: up to 213 days
Population: Data not collected.
Secondary
Negative Predictive Value (NPV) of TUV Baseline at Week 24
NPV of TUV global obtained at baseline (TUVglobal\[b\]) with respect to ACR50 at week 24 after change in anti-TNFα therapy
Time frame: Up to 213 days
Population: Data not collected.
Secondary
NPV, and PPV, and OA of ΔTUVglobal[5w] With Bucketing With Respect to ACR50 at Weeks 12 and 24
Concordance of ΔTUVglobal\[5w\] (with bucketing) and clinical criteria, including ACR Response Criteria, CDAI, DAS28, and HAQ-DI©. Concordance between ΔTUVglobal\[5w\] and the clinical criteria will be evaluated using NPV, PPV and overall accuracy.
Time frame: up to 213 days
Population: Data not collected.
Secondary
Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs
Incidence of AEs related to Tc 99m tilmanocept.
Time frame: Up to 213 days
Population: All subjects injected with Tc 99m tilmanocept were evaluated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs | Adverse Events Severity - Mild | 47 Adverse Events |
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs | Adverse Events Severity - Moderate | 84 Adverse Events |
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs | Adverse Events Severity - Severe | 1 Adverse Events |
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs | Adverse Events Relatedness - Possibly Related | 1 Adverse Events |
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs | Adverse Events Relatedness - Probably Not Related | 1 Adverse Events |
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by AEs | Adverse Events Relatedness - Definitely Not Related | 130 Adverse Events |
Secondary
Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in Clinical Laboratory Tests
Number of participants with changes over time in clinical laboratory tests (hematology, serum chemistry, urinalysis, and RA panel).
Time frame: Up to 213 days
Population: All subjects injected with Tc 99m tilmanocept were evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in Clinical Laboratory Tests | 2 Participants |
Secondary
Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in ECG Parameters
Number of participants with changes over time in ECG parameters (PRS Interval, QRS Duration, QT Interval, and QTc Interval).
Time frame: Up to 213 days
Population: All subjects injected with Tc 99m tilmanocept were evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in ECG Parameters | 2 participants |
Secondary
Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in Vital Signs
Number of participants with changes over time in vital signs (blood pressure, heart rate, respiratory rate, and temperature).
Time frame: Up to 213 days
Population: All subjects injected with Tc 99m tilmanocept were evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Candidates for Initiation of Anti-TNFα bDMARD Therapy | Safety of IV-administered Tilmanocept Radiolabled With Tc 99m Assessed by Number of Participants With Changes Over Time in Vital Signs | 9 participants |
Secondary
Sensitivity and Specificity of ΔTUVglobal[5w] With Bucketing With Respect to ACR50 at Week 12
Concordance of ΔTUVglobal\[5w\] with bucketing and ACR50 at week 12, evaluated using sensitivity and specificity.
Time frame: Up to 213 days
Population: Data not collected.