E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autoimmune-haemolytic Anemia Antiphospholipid Syndrome Immune-mediated Thrombocytopenia |
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E.1.1.1 | Medical condition in easily understood language |
antibodies directed against - red blood cells - phospholipids or phospholipid-binding proteins - platelets
with consecutive anemia, thrombocytopenia or risk to experience thromboembolic events |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003825 |
E.1.2 | Term | Autoimmune hemolytic anemia |
E.1.2 | System Organ Class | 100000154058 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023095 |
E.1.2 | Term | ITP |
E.1.2 | System Organ Class | 100000157088 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002817 |
E.1.2 | Term | Antiphospholipid syndrome |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Autoimmune haemolytic anaemia, antiphospholipid syndrome: To investigate whether 5mg/m2, 20mg or 50mg rituximab suffice to suppress CD20+ cells over a defined period of time
Immune-mediated thrombocytopenia: to investigate whether repetitive infusions of 50mg rituximab over 2 years (8 every 3 months) reduce the relapse rate of rituximab treated patients, which according to published data is 38%. |
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E.2.2 | Secondary objectives of the trial |
To investigate the Pharmacokinetics of very low doses of Rituximab To investigate the immunogenicity of very low doses of Rituximab To calculate the drug cost reduction of our treatment regimen To investigate the safety of very low doses of Rituximab To investigate the effects of very low doses of Rituximab on hemolysis specific parameters and hemoglobin To investigate CD20+ cell counts in patients with immune-mediated thrombocytopenia To investigate platelet counts and response to rituximab treatment in patients with immune-mediated thrombocytopenia To investigate platelet function after infusion of rituximab To investigate antibody levels directed against platelets (immune-mediated thrombocytopenia) To investigate Cardiolipin-, beta2-glycoprotein-I-, antiphospholipid- antibody levels and lupus anticoagulant in patients with anitphospholipid syndrome To investigate coagulation specific biomarkers in those patients with antiphospholipid syndrome |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Signed informed consent obtained before any trial related activities • Ability to understand the nature and the purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the trial • Men or women aged ≥18 years of age with a diagnosis of autoimmune-mediated haemolytic anemia, antiphospholipid syndrome or immune-mediated thrombocytopenia • In female subjects either childbearing potential terminated by surgery or one year post- menopausal, or a negative urine pregnancy test during screening and the willingness not to become pregnant during the entire study period by practicing reliable methods of contraception • Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant • Normal laboratory values unless the investigator considers an abnormality to be clinically irrelevant
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E.4 | Principal exclusion criteria |
• Previous treatment with rituximab, obinutuzumab, ofatumumab or ocrelizumab within 12 months • Clinically relevant infection (<1 week) • Intravenous immunoglobulins, unless cyclic thrombocytopenia occures • Relevant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, hematological, endocrine, inflammatory or neurological diseases, that may interfere with the aim of the study • Ascertained or presumed hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or major allergic reactions in general, which the investigator considers may compromise the safety of the participants • Use of medication during 2 weeks before the start of the study, which the investigator considers may affect the validity of the study • Drug abuse, alcohol (>1 drinks/day, defined according to USDA Dietary Guidelines) • Pregnancy (positive pregnancy test at screening or during study phase), lactation or unreliable contraception in female subjects with child-bearing potential |
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E.5 End points |
E.5.1 | Primary end point(s) |
Antiphospholipid Syndrome and Autoimmune haemolytic anaemia: CD19/20+ cell counts Immune-mediated Thrombocytopenia: Relapse rate |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Antiphospholipid Syndrome, Autoimmune-haemolytic anaemia: baseline, End of each infusion, +2h after infusion potentially +24h and +7d after first infusion before 2nd infusion before 3rd infusion during end-of-study visit
Immune-mediated Thrombocytopenia: End of study visit (2 years) |
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E.5.2 | Secondary end point(s) |
- plasma concentrations of rituximab - Immunogenicity (neutralizing anti-drug antibodies, human antichimeric antibodies) - Safety (Laboratory data and adverse events) - Platelet counts and reticulated platelets - hemoglobin levels, hemolysis specific parameters -antibody levels (antiphospholipid-specific antibodies, anti-platelet antibodies) - platelet function - coagulation specific tests in patients with immune-mediated thrombocytopenia - immune-mediated thrombocytopenia: response: permanent suppression of CD20+ cell counts, platelet counts, complete response (defined as platelets above 100 G/L), complete sustained response (permanent platelet count >100 G/L), partial response (platelets 50-100 G/L) for patients with initial platelet counts <50 G/L, as stable patients will also be included a 50% increase in platelet counts from baseline platelet count will be considered as response, overall response (includes the before mentioned responses), patients with platelets <30 G/L are defined as non-responders; response at 1, 3, 6 months, time to complete response, relapse will be defined as >50% reduction in platelet counts or platelet counts <30G/L after initial response or need for further treatment, relapse-free survival, treatment free survival (need for further treatment, usually at <30 G/L) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PK at each visit to the ward (baseline, end of each infusion and 1 and 2h thereafter, control visits) - AE, Safety, (baseline, end of each infusion and 1 and 2h thereafter, control visits) - Immunogenicity: Baseline of each study day -hemoglobin levels: Trial day 1 each time-point, and baseline of all other trial days, all control visits - hemolysis specific data: baseline of each study day and all control visits - antibody levels: at each visit - platelet function: during first two infusions - coagulation specific biomarkers: every visit - response at 1, 3, 6 months -CD20+ cells: each visit
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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 | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
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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We plan to include 8-12 patients with anti-phospholipid syndrome and 8-12 patients with autoimmune hemolytic anaemia in this pilot trial.
We plan to include a minimum of 24 patients with immune-mediated thrombocytopenia |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |