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 characterized 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 | 10005329 - Blood and lymphatic system disorders |
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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 |
Objectives safety run-in • to assess safety and tolerability of daratumumab in patients with ITP.- Other objectives as main study.
Objectives main part • to determine the efficacy of treatment with daratumumab defined as response at week 12 for safety run-in and cohort 1, and week 16 for cohort 2. • to characterize the safety of daratumumab in patients with ITP.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: -to assess rates of sustained response (sR) at week 24.-to assess the duration of response (DOR) -•To determine the time to treatment failure (TTF) -•To assess bleeding complications during the study. Exploratory objectives: •to characterize immunological effects of daratumumab treatment: -to characterize various subsets of immunocompetent cells in the bone marrow and blood before and during daratumumab therapy and at study week 24 (only peripheral blood). • -to identify a potential biomarker (whether or not changes to antibody levels or levels of immuno-competent cells correlate with response). • to determine HRQoL and level of fatigue before and after treatment with daratumumab and to assess difference in HRQoL and fatigue between patients with or without response, prior to and after daratumumab.• To assess time from first dose of study medication to first platelet count >50x109/L• To assess rates of complete and partial response (CR) to daratumumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female aged ≥18 years. 2. Primary ITP with a platelet count of ≤30 X 109/L measured within 2 weeks prior to inclusion with failure to achieve response or relapse after corticosteroid therapy, and at least one second-line therapy including rituximab (last infusion ≥24 weeks before study inclusion) and/or TPO-RA. The dose of steroids or/and TPO-RAs (romiplostim, eltrombopag and avatrombopag) has not been changed during the last 2 weeks preceding the inclusion. For the safety run-in phase, a platelet count of 15-30 X 109/L will be required. 3. Signed and dated written informed consent. 4. Females of child-bearing potential accepting to follow effective contraceptive methods for at least 24 weeks following the administration of first daratumumab injection. A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control e.g. condom with spermicidal foam/film/gel/cream/ suppository, and all men must also not donate sperm during the study and for 3 month following discontinuation of Daratumumab (for details see appendix VII). |
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E.4 | Principal exclusion criteria |
1. Patients with active bleeding during the last 7 days prior to inclusion. Active bleeding is defined as any clinically overt hemorrhage (including radiologically diagnosed bleeding) with ongoing hemoglobin fall or bleeding requiring immediate intervention. 2. Pregnancy or lactation. 3. Surgery planned within the 3 next months. 4. Secondary ITP: ITP associated with lymphoma, chronic lymphocytic leukemia, drug induced or ITP secondary to autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, common variable immune deficiency, human immunodeficiency virus, or hepatitis C. 5. Concomitant autoimmune hemolytic anemia. 6. Known allergy and/or sensitivity or contraindication to daratumumab. 7. Current active malignancy likely to require chemotherapy or surgical treatment during the study period or within one year after the start of the study treatment. 8. 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. 9. Patient unable to attend all the visits planned for the trial. 10. Positive at screening for hepatitis B virus (HBV) surface and core antibodies unrelated to vaccination: - patients with positive HBV surface antigen (HbsAg) are not eligible - patients who are HbsAg negative and HBV core antigen antibody positive (HBcAg) will be tested for HBV surface antibody (HBsAb) and HBV DNA. If HBsAb titer is >1000 IU/ml, patients may be enrolled. Monthly HBV DNA monitoring will be required while on treatment and for the 6 months after the last dose of the study drug. - patients who are HBcAb positive, HBsAg negative with HBsAb titer <100 IU/ml or negative, are not eligible. 11. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD. 12. Known moderate or severe persistent astma within the past 2 years, uncontrolled asthma of any classification. 13. Patient participating in another clinical trial with an investigational drug. |
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E.5 End points |
E.5.1 | Primary end point(s) |
End points safety run-in Safety and tolerability defined as: 1. Treatment-emergent adverse events/ serious adverse events (TEAEs/SAE) incl. hematological treatment related adverse events. 2. Incidence of platelet counts decrease during the treatment and up to 2 weeks after the treatment. 3. Incidence of abnormal changes from baseline in laboratory values per CTCAE criteria V 5.0 (e.g., hematology, chemistry).
End points main part • response after daratumumab treatment defined as: o • Safety run in and Cohort 1: proportion of patients who achieve platelet count ≥50x109/L in 2 measurements (taken at least 24 hours apart) during week 12 (after first study drug injection), without having received rescue therapy for the last 4 weeks, nor having had dose increment of TPO-RA or corticosteroids during the study period. • Cohort 2: proportion of patients who achieve platelet count ≥50x109/L in 2 measurements (taken at least 24 hours apart) during week 16 after first study drug injection without having received rescue therapy for the last 4 weeks , nor having had dose increment of TPO-RA or corticosteroids during the study period.
• safety assessed by the incidence, severity and relationship of treatment emergent adverse events
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Main part: 12 or 16 weeks |
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E.5.2 | Secondary end point(s) |
Secondary end points: • Sustained response (sR) defined as platelet count ≥ 50x109/L in 2 measurements (taken at least 24 hours apart) measured at study week 24 (+/-2 weeks) without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids. • DOR defined as the duration of sustained platelet count ≥50x109/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids. Duration will not consider the 4 weeks following the last daratumumab injection in the study. . Loss of response is defined as platelet count < 50 x 109/L after achieving response, in 2 consecutive blood samples taken at least 24 hours apart. • TTF defined as the time with platelet count ≥50x109/L from 4 weeks after the last daratumumab injection to the first platelet count <30x109/L of two counts taken in two consecutive measurements at least 24 hours apart, or administration of any platelet elevating therapy after achieving response. Date of first platelet count measurement or administration of platelet elevation therapy will be used for the calculation of TTF.• -Total number of bleeding episodes per patient. A bleeding episode is defined as any bleeding other than cutaneous, i.e. any bleeding episode of WHO grade >1. -Maximum severity on the World Health Organisation (WHO) bleeding scale -Change in Khellaf score measured at the day of first daratumumab administration and at week 24 evaluation. Exploratory end points: • Level of anti-GPIIb/IIIa and Ib antibodies before daratumumab therapy and at study week 24 for all included patients. • Analysis of platelet bound antibodies and functional testing of immunocompetent cells in peripheral blood and bone marrow before, during daratumumab therapy and at study week 24 (only peripheral blood). Platelet bound antibodies will also be tested at study week 8 (safety run-in), week 12 (cohort 1), at study week 16 (cohort 2). • Measurement of HRQoL and fatigue using SF36v1 and MFI-20 questionnaire before daratumumab therapy, at week 8 for safety run-in, at week 12 for cohort 1, at week 16 for cohort 2 and at study week 24 for all patients in the study.-• Time to first platelet count >50x109/L measured from the day of first administration of study medication. • Rates of complete response defined as a proportion of patients with platelet count >100x 109/L determined at week 12 for the safety run-in and cohort 1, week 16 for cohort 2 and week 24 for all patients (requires two measurements taken at least 24 hours apart) without having received rescue therapy after week 8, or having had dose increment of corticosteroids or TPO-RA during the study period.• Rates of partial response defined as a proportion of patients with platelet count >30 x 109/ but <50x 109/L (or at least doubling of the platelet count from baseline, determined at week 12 for the safety run-in and cohort 1, week 16 for cohort 2 and week 24 for all patients (requires two measurements taken at least 24 hours apart) without having received rescue therapy after week 8, or having had dose increment of corticosteroids or TPO-RA during the study period
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
8 weeks (safety run-in), 12 weeks, 16 weeks and 24 weeks or end of 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 | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Cohort 1: 1800mg daratumumab once a week x 8 (8 weeks). Cohort 2: daratumumab 1800mg x 10 (12 weeks) |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 | 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 | 5 |
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 | 5 |