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    Summary
    EudraCT Number:2018-003418-41
    Sponsor's Protocol Code Number:NAV3-32
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-11-22
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2018-003418-41
    A.3Full title of the trial
    A Comparison of Tc 99m Tilmanocept Quantitative Imaging with Immunohistochemical (IHC) Analysis of CD206 Expression in Synovial Tissue from Subjects Clinically Diagnosed with Rheumatoid Arthritis (RA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A comparison of a radioactive imaging method with an existing immunological (involving cells from the Immune System) based method that involves staining of tissues from a patient with a known rheumatoid arthritic joint.
    A.4.1Sponsor's protocol code numberNAV3-32
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04078191
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNavidea Biopharmaceuticals Ltd
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNavidea Biopharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNavidea Biopharmaceuticals
    B.5.2Functional name of contact pointClinical NAV3-32 Trial Team
    B.5.3 Address:
    B.5.3.1Street Address4995 Bradenton Ave Suite 240
    B.5.3.2Town/ cityDublin, OH
    B.5.3.3Post code43017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+441844261155
    B.5.5Fax number+441635581584
    B.5.6E-mailclinicalnav332@navidea.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Lymphoseek
    D.2.1.1.2Name of the Marketing Authorisation holderNavidea Biopharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nametechnetium Tc 99m tilmanocept
    D.3.4Pharmaceutical form Kit for radiopharmaceutical preparation
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot applicable
    D.3.9.1CAS number 1185986-76-8
    D.3.9.3Other descriptive nameTILMANOCEPT
    D.3.9.4EV Substance CodeSUB119775
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product Yes
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid arthritis
    E.1.1.1Medical condition in easily understood language
    Inflammation in the lining of joints caused by the immune system
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assessment of the relationship between joint-specific tilmanocept uptake value (TUVjoint) and synovial anatomic pathology.

    IHC assessment of macrophage expression of the CD206 receptor.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    -Assessments of CD68 and CD163 receptor expression levels through IHC microscopy.
    -Classification of synovial anatomic pathology as Lympho-myeloid, Diffuse myeloid, Pauci-immune fibroid.

    Exploratory objectives:
    -To determine the relationship between TUVjoint and mRNA expression profiles of CD68, CD163, and CD206 as determined by RNA sequencing (RNA-seq).
    -To determine the relationship between TUVjoint and the number, size, and intensity of CD68, CD163, and CD206 as determined by (optional) flow cytometry.
    -To evaluate synovial expression of CD3, CD20, CD55, and TE-7 and CD206 in synovial tissue biopsy specimens.

    - Assessment of the relationship between global tilmanocept uptake value (TUVglobal) and synovial anatomic pathology

    Safety objectives:
    Evaluate safety through the examination of adverse event (AE) incidence, physical examination findings, and changes over time in laboratory tests, electrocardiograms (ECGs), and vital signs.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 > 60 days prior to the imaging visit (Day 0). bDMARD therapy should not be administered less than 4 days prior to the imaging visit.
    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).
    E.4Principal 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 had a finger, hand, and/or wrist amputation or hand or wrist joint arthroplasty.
    5. The subject has renal insufficiency as demonstrated by a glomerular filtration rate of < 60 mL/min.
    6. 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.
    7. 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.
    8. The subject has a known allergy to or has had an adverse reaction to dextran exposure.
    9. The subject has received an investigational product within 30 days prior to the Tc 99m tilmanocept administration (Day 0).
    10. The subject has received injectable (e.g., intra-articular, intramuscular, etc.) corticosteroids ≤ 8 weeks prior to imaging (Day 0).
    11. The subject has received any radiopharmaceutical within 7 days or 10 half-lives prior to the administration of Tc 99m tilmanocept (Day 0).
    12. The subject has an intolerance to anesthetic and antiseptic agents indicated for the synovial biopsy procedure.
    13. 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.
    E.5 End points
    E.5.1Primary end point(s)
    The correlation between joint-specific tilmanocept uptake value (TUVjoint) and the number and area fraction of CD206 expression as determined by IHC assessment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At interim analysis and end of study.
    E.5.2Secondary end point(s)
    Secondary end points:
    The correlation between TUVjoint and the number and area fraction of CD68 and CD163 determined by IHC assessments.
    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.
    The correlation between the expression of CD68, CD163, and CD206.

    Exploratory end points:
    - The correlation of the expression of CD3, CD20, CD55, and TE7 with CD206 as measured through IHC.
    - The correlation of TUVjoint with the expression of CD206, CD163, and CD68 as measured through RNA-seq.
    - The number and size of CD206, CD163, and CD68 expressing macrophages as measured through (optional) flow cytometry and their correlation with TUVjoint.
    - The correlation between TUVglobal and synovial anatomic pathology as determined by IHC assessments.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At interim analysis and end of study.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Study comparing the correlation between radiopharmaceutical localization and immunohistochemical results. Confirming mechanism of action for the intended indication.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Compn of radiopharmaceutical localisation with IHC analysis of CD206 expression in synovial tissue
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    European Union
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 24
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Normal treatment of that condition.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-18
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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