E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Cold Agglutinin Disease (CAD) |
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E.1.1.1 | Medical condition in easily understood language |
Patients with Primary Cold Agglutinin Disease (CAD) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of multiple intravenous doses of 100 mg/kg ANX005 in participants with CAD |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence and severity of treatment-emergent adverse events (AEs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continuous evaluation for the duration of the subject's participation in the study |
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E.5.2 | Secondary 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 Haptoglobin Absolute reticulocyte count - Change from baseline in FACIT-Fatigue scores over time - Proportion of participants achieving FACIT-Fatigue score ≥40 over time |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continuous evaluation for the duration of the subject's participation in the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |