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    EudraCT Number:2020-005854-90
    Sponsor's Protocol Code Number:ANX005-CAD-01
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-01-05
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2020-005854-90
    A.3Full title of the trial
    A Phase 2, Single-Center, Open-Label, Repeat-Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of Intravenous ANX005 in Participants with Primary Cold Agglutinin Disease
    Eine offene, monozentrische Phase-2-Studie mit Mehrfachdosierung zur Bewertung der Sicherheit, Verträglichkeit, Pharmakokinetik, Pharmakodynamik und klinischen Wirkung von intravenösem ANX005 bei Teilnehmern mit primärer Kälteagglutininkrankheit
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Investigation of the influence of ANX005 on the body of patients with primary cold agglutinin disease in terms of safety and tolerability. A Phase 2, single-center, open-label, repeat-dose study.
    Untersuchung des Einflusses von ANX005 auf den Körper von Patienten mit primärer Kälteagglutininkrankheit in Bezug auf Sicherheit und Verträglichkeit. Eine offene, monozentrische Phase-2-Studie mit Mehrfachdosierung.
    A.4.1Sponsor's protocol code numberANX005-CAD-01
    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 SponsorAnnexon, Inc.
    B.1.3.4CountryUnited States
    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 supportAnnexon, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelerion Austria GmbH
    B.5.2Functional name of contact pointClinical Project Manager at CRO
    B.5.3 Address:
    B.5.3.1Street AddressHainburger Strasse 33
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1030
    B.5.4Telephone number+43140338050
    B.5.5Fax number+431403380566
    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 No
    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.3.2Product code ANX005
    D.3.4Pharmaceutical form Solution for injection
    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 INNANX005
    D.3.9.2Current sponsor codeANX005
    D.3.9.3Other descriptive nameRecombinant humanized IgG4 monoclonal antibody
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 No
    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
    Primary Cold Agglutinin Disease (CAD)
    E.1.1.1Medical condition in easily understood language
    Patients with Primary Cold Agglutinin Disease (CAD)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of multiple intravenous doses of 100 mg/kg ANX005 in participants with CAD
    E.2.2Secondary objectives of the trial
    - To evaluate the pharmacokinetics (PK) of ANX005 in participants with CAD
    - To evaluate the effect of ANX005 on classical complement pathway inhibition as measured by complement system related biomarkers in participants with CAD
    - To assess the effect of multiple intravenous doses of ANX005 on the markers of disease activity in participants with CAD
    - To assess the effect of multiple intravenous doses of ANX005 on fatigue
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ≥ 18 years of age on the day of signing informed consent
    2. Body weight < 150 kg
    3. Diagnosis of CAD at least 3 months prior to screening based upon all of the following:
    a. Positive direct antiglobulin test (DAT) ≥ 1+ for C3d
    b. Negative or only weakly positive (1+ or less) direct antiglobulin test for IgG
    c. Cold agglutinin (IgM) titer ≥1:64 at 4°C or lower titer with signs and symptoms consistent with cold agglutinin disease and demonstration of positive IgM autoantibodies
    d. Evidence of active hemolysis defined as presence of any one of the following:
    i. Lactate dehydrogenase (LDH) > upper limit of normal (ULN)
    ii. Indirect bilirubin > ULN
    iii. Haptoglobin < lower limit of normal (LLN)
    4. Evidence of active hemolysis (defined above) at screening
    5. Hgb level ≤ 10.0 g /dL at screening with no alternative explanation for anemia apart from CAD
    6. Vaccinations against encapsulated bacterial organisms (N. meningitidis, H. influenzae and S. pneumoniae) within 5 years prior to screening or participant must be willing to complete vaccinations at least 2 weeks prior to dosing with ANX005. Documentation of vaccinations must be received at the study site in advance of the scheduled screening visit
    7. Females must be of non-childbearing potential
    8. Females with a history of a bilateral tubal occlusion/ligation procedure who do not meet any of the other criteria for non-childbearing potential (postmenopausal or permanently sterile), must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Day 1
    9. Males must agree to use adequate methods of contraception throughout the study and for at least 1 month after the final study visit (at least 2 months after the last administration of study medication)
    10. Able to comply with the requirements of the study and complete the full sequence of protocol-related doses, procedures, and evaluations
    11. Able to understand and provide written informed consent
    E.4Principal exclusion criteria
    Exclusion Criteria:
    1. History of cold agglutinin disease secondary to infection, rheumatologic disease, or active malignancy
    2. History of hemolytic anemia due to another condition besides CAD including, but not limited to, paroxysmal nocturnal hemoglobinuria (PNH), Evan’s syndrome, sickle cell disease, thalassemia, thrombotic thrombocytopenia purpura, hemolytic-uremic syndrome (HUS), red cell membrane disorders (e.g. hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikliocytosis, hereditary stomatocytosis, hereditary exocytosis), pyruvate kinase deficiency, glucose-6-phosphate deficiency, or hemolytic anemia secondary to autoimmunity (e.g. systemic lupus erythematosus, rheumatoid arthritis), infectious cause (e.g. Epstein-Barr Virus, cytomegalovirus, mycoplasma, hepatitis virus, human immunodeficiency virus), malignancy (e.g. lymphoproliferative disorder requiring treatment, lymphoma, leukemia, multiple myeloma), or medications (e.g. anti-neoplastics, non-steroidal anti-inflammatory drugs, antibiotics). Note: Mixed autoimmune hemolytic anemia may potentially be enrolled, but should first be discussed with the medical monitor
    3. History of solid organ, bone marrow, or stem cell transplantation
    4. History of splenectomy within the 3 months prior to screening
    5. Clinically significant ongoing illness or medical condition affecting any major organ system, including chronic infections, or a medical history that would jeopardize the safety of the participant, limit participation in the study, or compromise the interpretation of the data derived from the participant
    6. History of active lymphoma, lymphoproliferative disorder requiring therapy, or any other active malignant disease that has not been adequately treated
    7. Signs and symptoms of, or a diagnosis consistent with, a chronic autoimmune disorder not resulting from primary CAD
    8. History of meningitis or septicemia within the past 2 years
    9. Clinically significant infection that required systemic medical intervention (not including antibiotic prophylaxis; i.e., viral, bacterial, fungal, or mycobacterial) within 1 month prior to screening
    10. Positive serology for human immunodeficiency virus (HIV) 1 or 2 at screening
    11. Evidence of hepatitis C virus (HCV) antibody at screening require reflex testing for HCV RNA. Participant with positive HCV RNA viral load at screening will be excluded. Participants with positive HCV Ab, but negative HCV RNA viral load are eligible but should be monitored throughout the study
    12. Evidence of active or prior hepatitis B virus (HBV) infection. Participants with positive hepatitis B surface antigen (HBsAg) at screening are excluded from the study. Participants with positive HBV core Ab and HBV DNA viral load at screening are excluded from the study
    13. Known genetic deficiencies of the complement cascade system
    14. Active alcohol or substance abuse or any other reason that makes it unlikely that the participant will comply with study procedures
    15. Females who are pregnant (positive serum pregnancy test at screening or positive urine pregnancy test on Day 1) or lactating
    16. Hypersensitivity to any of the excipients in the ANX005 drug product
    17. Hypersensitivity to or previous allergic reaction to the active substance or to any of the excipients in any of the immunizations required for this study
    18. History of previous sensitivities or allergic or anaphylactic reactions to previous IV medication
    19. Platelet count <30 × 109/L
    20. Absolute neutrophil count <1 × 109/L
    21. CAD Therapy Exclusion Criteria:
    a. Received rituximab or other B cell depleting therapy (e.g. ocrezliumab, datatumumab, ofatumumab, obinutuzumab) within 3 months prior to first dose of study medication
    b. Received bortezomid, bendamustine, fludarabine, cyclophosphamide, or chlorambucil within 6 months prior to first dose of study medication
    c. Received eculizumab, C1 esterase inhibitor, or other complement pathway inhibitor within 1 month prior to first dose of study medication
    d. Received IV or subcutaneous (SC) immunoglobulin treatment within 3 months prior to first dose of study medication unless on chronic substitution therapy
    e. Received plasmapheresis or immunoadsorption treatment within 3 months prior to first dose of study medication
    f. If receiving glucocorticoids, the daily dose must not exceed 30 mg prednisone (or equivalent) and must be stable for at least 14 days prior to the first dose of study medication
    g. If receiving immunosuppressants (e.g. azathioprine, mycophenolate mofetil, cyclosporine), must be on a stable dose for at least 6 weeks prior to the first dose of study medication
    22. Treatment with an investigational therapeutic agent within 30 days or five half-lives, whichever is longer, prior to treatment with study medication
    E.5 End points
    E.5.1Primary end point(s)
    Incidence and severity of treatment-emergent adverse events (AEs)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Continuous evaluation for the duration of the subject's participation in the study
    E.5.2Secondary end point(s)
    - Serum ANX005 concentrations over time
    - Change from baseline in levels of classical complement pathway biomarkers (e.g. C1q, C4, CH50, cellular complement deposition)
    - Change from baseline in levels of the following disease activity markers:
    Hemoglobin (Hgb)
    Lactate dehydrogenase (LDH)
    Total and indirect bilirubin
    Absolute reticulocyte count
    - Change from baseline in FACIT-Fatigue scores over time
    - Proportion of participants achieving FACIT-Fatigue score ≥40 over time
    E.5.2.1Timepoint(s) of evaluation of this end point
    Continuous evaluation for the duration of the subject's participation in the 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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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. 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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    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 months7
    E.8.9.1In the Member State concerned days0
    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: 3
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state6
    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)
    To date, there is no approved therapy for cold agglutinin disease, although other medications may be prescribed. Upon completion of participation in this clinical trial, the investigator will discuss with patients other options for treatment of CAD.
    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 Decision2021-02-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-08
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