E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
An autoimmune disease charcaterized by low platelet count and increased risk of bleeding |
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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 | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021245 |
E.1.2 | Term | Idiopathic thrombocytopenic purpura |
E.1.2 | System Organ Class | 100000004851 |
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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 determine if maintenance therapy with low-dose rituximab is superior to placebo in prolonging responses among ITP patients who achieved an initial response with rituximab. |
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E.2.2 | Secondary objectives of the trial |
1. To explore if the initial overall response rate, at week 24, can be improved by at least 10% by adding dexamethasone to rituximab (induction phase). 2. To assess the safety of study treatment, especially infectious episodes (induction & maintenance phases). 3. To assess bleeding complications during the study (induction & maintenance phases). 4. To assess the use of rescue medications and other platelet-elevating therapies during the study (induction & maintenance phases). 5. To determine rate of sustained Complete Response (CR) (induction & maintenance phases). 6. To determine the duration of overall response and CR (induction & maintenance phases). 7. To assess health-related quality of life and fatigue (induction & maintenance phases). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. To determine levels of CD19+ cells following induction and during maintenance phases, in order to investigate an eventual association between CD19+ cells and response or relapse. 2. Ancillary (spin-off) studies to the proposed trial (Ancillary studies will be only performed in certain centers in Norway), with the following objectives (more details are provided in Appendix III; procedures are provided in a separate protocol): a. To study the effect of rituximab on antiplatelet antibodies and to investigate an eventual association between antiplatelet antibodies and response. b. To study the effect of rituximab on gene expression profiling and miRNA expression in ITP. c. To study the effect of rituximab on megakaryocyte differentiation and apoptosis. d. To study the effect of rituximab on B, memory B and T-cells in the peripheral blood and in bone marrow in responding, non-responding and relapsing patients. e. To study the association between response to rituximab and human microbiota. 3. To retrospectively assess the rate of minor response and no response at week 24 where minor response is define as increase in platelet count to between 30 and 50 X109/L and to estimate the time to retreatment in this group. 4. To determine the number of patients in the entire cohort who contracted Covid-19 infection. 5. To retrospectively collect information on the number of patients who have received anti-Covid 19 vaccine, including: number, type and date of vaccine, and anti-spike and anti-nucleocapsid antibody titer or any information of the response to vaccine.
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E.3 | Principal inclusion criteria |
First randomization (Induction phase) 1. Male or female aged ≥18 years. 2. Diagnosis of primary ITP of less than one year duration and having a platelet count of ≤ 30 x109/L measured within 4 weeks prior to inclusion with failure to achieve response or relapse after one cycle of dexamethasone (40 mg daily for 4 days) or after 3 to 4 weeks under any other steroid (prednisone or prednisolone). Platelet count between 31 to 50 x109/L is accepted if higher platelet count is required due to concomitant antiplatelet therapy or bleeding. 3. Scheduled intravenous treatment of rituximab. 4.Rituximab infusion will be more than 2 weeks after the first injection of an anti-COVID-19 vaccine. 5. Signed and dated written informed consent. 6. Females of child-bearing potential accepting to follow effective contraceptive methods for at least 18 months following the first administration of rituximab.
Second randomization (maintenance phase) 1. Completion of the induction phase (phase 1) of the study. 2. Sustained response at the end of phase 1. 3. a.Randomization within 4 weeks after the completion of phase 1, i.e. between week 24 and 28 for a patient who can’t be vaccinated or is already vaccinated against COVID-19 or, b. 16 weeks after the completion of phase 1 if needed to allow the patient to receive anti-COVID-19 vaccine (see Section 10.4.5.2. for vaccination recommendations).
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E.4 | Principal exclusion criteria |
First randomization (Induction phase) 1. Previous treatment for ITP with: rituximab, other immune suppressants (including mycophenolate mofetil, azathioprin, cyclosporine), dapsone,danazol,thrombopoietin receptor agonist, chemotherapy or splenectomy. 2.Anti-COVID-19 unvaccinated patient with at least one of the following characteristics: a. ≥65 years old b. Obesity c. Diagnosed Arterial hypertension d. Diagnosed Diabetes mellitus e. Known Kidney disease f. Known Lung disease
3. Pregnancy or lactation. 4. Known active gastro-duodenal ulcer. 5. Secondary ITP: ITP associated with lymphoma, chronic lymphocytic leukemia, autoimmune disorders, common variable immune deficiency, human immunodeficiency virus, hepatitis C or thrombocytopenia associated with myeloid dysplasia. 6. Concomitant autoimmune hemolytic anemia. 7. History of any major cardiovascular event within the 6 months prior to randomization, including but not limited to: myocardial infarction, unstable angina, cerebrovascular accident, or New York Heart Association Class III or IV heart failure. 8. Active hepatitis B virus or patients with positive HBsAG or HBcAB. 9. Patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection. 10. Known allergy and/or sensitivity or contraindication to rituximab or dexamethasone. 11. Patients in a severely immune compromised state 12. Known contraindication to a treatment with any proton-pump inhibitor. 13. Active malignancy or history of malignant disease during the last 2 years except cured skin cancer. 14.Patients with history of poor compliance or history of alcohol/drug abuse or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
Second randomization (maintenance phase) 1. Severe allergic reaction or serum sickness due to rituximab in phase 1 of the study. 2. Pregnancy. 3. Treatment with rescue medication after week 18. 4. Patients refusing to continue in the study (withdrawal of consent). 5. Splenectomy performed for any cause.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint: sustained overall response during maintenance phase [loss of overall response is defined as: (1) two consecutive measurements with platelet counts < 50 x 109/L taken at 1-8-week interval, and/or, (2) use of any ITP-directed therapies, other than study medication, because of bleeding or thrombocytopenia, except for preoperative elevation of platelet count] (this endpoint applies to maintenance phase only).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
First randomization: 24 weeks and 52 weeks for 2. randomization |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: 1. Overall response during induction phase defined as mean platelet count, determined in week 24 (± 2 weeks) after induction therapy, > 50 x 109/L, without use of any other ITP-directed therapies after week 18 following the first randomization (this endpoint applies to induction phase only). 2. Safety assessed by the frequency of > grade II adverse events (this endpoint applies to both phases). 3. Grade of bleeding (this endpoint applies to both phases). 4. Sustained Complete Response (CR) during maintenance phase defined as platelet count > 100 x 109/L maintained during maintenance phase, without the use of any ITP-directed therapies 5.Complete Response (CR) during induction phase, defined as platelet count, determined in week 24 (± 2 weeks), > 100 x 109/L without use of any other ITP-directed therapies after week 18 following the first randomization (induction phase) 6.Administration of rescue medication or any other elevating platelet therapy 1. After week 18 (induction phase) 2. During maintenance phase (maintenance phase). 7. Percentage of patients with more than 80% of platelet counts level > 50 x 109/L during the maintenance phase (this endpoint applies to maintenance phase only). 8. Health-related quality of life (this endpoint applies to both phases). 9. Fatigue using an analogical scale of 0-10 and General Fatigue Questionnaire (this endpoint applies to both phases).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Sustained overall response:24weeks and 52 weeks for 1. and 2.randomization 2.Sustained complete response: 24 weeks and 52 weeks .Rescue medication and remaining endpoints: 18 weeks and 52 weeks |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
mechanisms and biomarkers |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
First Phase : open-label, 2 parallel arms.Second phase doubleblind with 2 paralell arms |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Egypt |
Tunisia |
France |
Denmark |
Norway |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 7 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |