Immunomodulation With Romiplostim in Young Adults With ITP

Study Overview
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Brief Summary
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The study aims to investigate immunomodulatory effects of thrombopoietin-receptor Agonist (TPO-RA) in patients with primary ITP, who failed first-line therapy or who became intolerant to it. It is hypothesized that the early phase of this autoimmune disease may exhibit a stronger immunomodulatory potential in response to a stimulus, such as romiplostim. Such a process may subsequently be capable to induce regulatory mechanisms or tolerance. Romiplostim (a thrombopoietin-receptor agonist, TPO-RA) will be administered subcutaneously once weekly over 22 weeks with a starting dose of 1mcg/kg body weight. The dose will be adjusted based on platelet counts as described in the summary of Product Characteristics (SmPC).

Official Title
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Thrombopoietin-receptor Agonist-immunomodulation in Young Adult Primary Immune Thrombocytopenia (ITP): A Multi-center Open Label Trial With Romiplostim

Conditions
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Immune Thrombocytopenia

Intervention / Treatment
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* Drug: romiplostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent as documented by signature (see informed consent form) Primary ITP according to the definition of Rodeghiero et al. (52) and a platelet count of <30x109/l Age range: 18-45 years Previously treated patients, with failure or intolerance to first-line therapy, or relapse after first-line therapy, i.e. corticosteroids, intravenous immunoglobulin (IVIG), or anti-D immunoglobulins Exclusion Criteria: Adults older than 45 and children younger than 18 years Platelet count higher than 30x109/l at time of screening Suspicion of secondary ITP Positive family history for ITP Presence or history of autoimmune disease as judged by the investigator Hepatosplenomegaly Presence or history of relevant hepatic disease as judged by the investigator Presence or history of thromboembolic disease as judged by the investigator Patients with splenectomy Women who are pregnant or breast feeding Intention to become pregnant during the course of the study Lack of safe double contraception (see 7.1) Any vaccination 2 weeks prior start of the study Drugs with a known impact on the immune system or on platelet function must be recorded and an exclusion of the study should be discussed with the study center Known or suspected non-compliance, drug or alcohol abuse Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia of the study subject Participation in another study with investigational drug within the 30 days preceding and during the present study Previous enrolment into the current study Previous treatment with romiplostim or eltrombopag Hypersensitivity to the active substance or to any of the excipients or to E. coli derived proteins Enrolment of the investigator, his/her family members, employees and other dependent persons

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Romiplostim<br>Romiplostim (a thrombopoietin-receptor agonist, TPO-RA) will be administered subcutaneously once weekly over 22 weeks with a starting dose of 1mcg/kg body weight. The dose will be adjusted based on platelet counts as described in the summary of Product Characteristics (SmPC). Followup examination at week 52. | Drug: romiplostim<br> <br> * Other names: Nplate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Interleukin (IL)-4 concentrations (pg/ml) from baseline to week 22 | The primary aim of the study is to demonstrate an immunomodulatory effect of the study drug. Investigators expect a shift in the Th1/Th2 balance towards Th2. The primary outcome is to compare the pre- and post-treatment IL-4 concentrations (pg/ml) of all included patients (Th2 profile). Assessment of change in pre- and post-treatment IL-4 concentrations (pg/ml). | baseline and 22 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in immunomodulation as assessed by immune cell characteristics between baseline and week 22 | Immunologic parameters will be investigated between baseline and week 22 of the study: immune cell characteristics fluorescence-activated cell sorting (FACS): B cells: cluster of Differentiation Antigen (CD)3- cluster of Differentiation Antigen (CD)19+ Memory B lymphocytes CD19+cluster of Differentiation Antigen (CD)10-cluster of Differentiation Antigen (CD)27+cluster of Differentiation Antigen (CD)38- Plasma cells: CD19+ CD10- cluster of Differentiation Antigen (CD)20- CD27++ cluster of Differentiation Antigen (CD)38++ Tcells and subpopulations: CD3+/ CD3+ CD4+/ CD3+ cluster of Differentiation Antigen (CD)8+ natural killer (NK) cells CD3- cluster of Differentiation Antigen (CD)16+ cluster of Differentiation (CD)56+ Monocytes CD56- cluster of Differentiation Antigen (CD)14 (low) CD16+ cluster of Differentiation Antigen (CD)33 Tregs CD4+ cluster of Differentiation Antigen (CD)25 superhigh FoxP3+ | baseline and 22 weeks | 
| Change in immunomodulation as assessed by immune cell characteristics between baseline and week 10 | Immunologic parameters will be investigated between baseline and week 10 of the study: immune cell characteristics FACS: B cells: CD3- CD19+ Memory B lymphocytes CD19+CD10-CD27+CD38- Plasma cells: CD19+ CD10- CD20- CD27++ CD38++ Tcells and subpopulations: CD3+/ CD3+ CD4+/ CD3+ CD8+ NK cells CD3- CD16+ CD56+ Monocytes CD56- CD14 (low) CD16+ CD33 Tregs CD4+ CD25 superhigh FoxP3+ | baseline and 10 weeks | 
| Change in immunomodulation as assessed by messenger ribonucleic acid (mRNA) of cytokines between baseline and week 22 | mRNA of cytokines will be investigated between baseline and week 22 mRNA essays (real-time quantitative PCR): cytokine mRNA (interleucin (IL)2, interleucin (IL)4, interleucin (IL)6, interleucin (IL)10, IL17, interleucin (IL)35, IFNgamma, TNFalpha, transforming growth factor (TGF)-β) | baseline and 22 weeks | 
| Change in immunomodulation as assessed by mRNA of immune cells between baseline and week 22 | mRNA of immune cells will be investigated between baseline and week 22 mRNA essays (real-time quantitative PCR): mRNA Th1 (T-bet), Th2 (GATA-3), Th17 (RORγt), Tregs (Foxp3) | baseline and 22 weeks | 
| Change in immunomodulation as assessed by mRNA of cytokines between baseline and week 10 | mRNA of cytokines will be investigated between baseline and week 10 mRNA essays (real-time quantitative PCR): cytokine mRNA (IL2, IL4, IL6, IL10, IL17, IL35, IFNgamma, TNFalpha, TGF-β) | baseline and 10 weeks | 
| Change in immunomodulation as assessed by mRNA of immune cells between baseline and week 10 | mRNA of immune cells will be investigated between baseline and week 10 mRNA essays (real-time quantitative PCR): mRNA Th1 (T-bet), Th2 (GATA-3), Th17 (RORγt), Tregs (Foxp3) | baseline and 10 weeks | 
| Change in immunomodulation as assessed by cytokine concentrations between baseline and week 22 | cytokine concentration will be investigated between baseline and week 22 ELISA Cytokines: IL2, IL4, IL6, IL10, IL17, IL35, IFNgamma, TNFalpha, TGF- β | baseline and 22 weeks | 
| Change in immunomodulation as assessed by cytokine concentrations between baseline and week 10 | cytokine concentration will be investigated between baseline and week 10 ELISA Cytokines: IL2, IL4, IL6, IL10, IL17, IL35, IFNgamma, TNFalpha, TGF- β | baseline and 10 weeks | 
| Clinical response between baseline and week 52: number of severe bleeding | Clinical characterization of response to romiplostim therapy will be assessed additionally : measurement of severe bleeding (score Bolton-Maggs) | baseline and 52 weeks | 
| Clinical response between baseline and week 52: number of days in hospital | Clinical characterization of response to romiplostim therapy will be assessed additionally : need of inpatient daycare | baseline and 52 weeks | 
| Clinical response between baseline and week 52: platelet more than >100G/l | Clinical characterization of response to romiplostim therapy will be assessed additionally : assessment of platelet response to romiplostim, according to the definitions of Rodeghiero et al. (49). | baseline and 52 weeks | 
| Change in immunomodulation as assessed by immune cell characteristics between baseline and week 52 | Immunologic parameters will be investigated between baseline and week 52 of the study: immune cell characteristics FACS: B cells: CD3- CD19+ Memory B lymphocytes CD19+CD10-CD27+CD38- Plasma cells: CD19+ CD10- CD20- CD27++ CD38++ Tcells and subpopulations: CD3+/ CD3+ CD4+/ CD3+ CD8+ NK cells CD3- CD16+ CD56+ Monocytes CD56- CD14 (low) CD16+ CD33 Tregs CD4+ CD25 superhigh FoxP3+ | baseline and 52 weeks | 
| Change in immunomodulation as assessed by mRNA of immune cells between baseline and week 52 | mRNA of immune cells will be investigated between baseline and week 52 mRNA essays (real-time quantitative PCR): mRNA Th1 (T-bet), Th2 (GATA-3), Th17 (RORγt), Tregs (Foxp3) | baseline and 52 weeks | 
| Change of immunomodulation as assessed by mRNA of cytokines between baseline and week 52 | mRNA of cytokines will be investigated between baseline and week 52 mRNA essays (real-time quantitative PCR): cytokine mRNA (IL2, IL4, IL6, IL10, IL17, IL35, IFNgamma, TNFalpha, TGF-β) | baseline and 52 weeks | 
| Change in immunomodulation as assessed by cytokine concentrations between baseline and week 52 | cytokine concentration will be investigated between baseline and week 52 ELISA Cytokines: IL2, IL4, IL6, IL10, IL17, IL35, IFNgamma, TNFalpha, TGF- β | baseline and 52 weeks | 
| Clinical response between baseline and week 52: frequency of use of rescue treatment |  | baseline and week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunomodulation