E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Immune Thrombocytopenia (ITP) in Paediatric Subjects |
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E.1.1.1 | Medical condition in easily understood language |
Bleeding Disorder - ITP is a condition that may cause easy bruising or bleeding due to an
abnormally low number of platelets in the blood. |
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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 | 10043558 |
E.1.2 | Term | Thrombocytopenia purpura |
E.1.2 | System Organ Class | 100000004851 |
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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 |
The primary objective is to describe the percentage of time that pediatric subjects with immune thrombocytopenia (ITP) have a platelet response in the first 6 months from the start of treatment with romiplostim.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To describe the percentage of time that pediatric subjects with ITP have a platelet response over the study duration
• To describe the percentage of time that pediatric subjects with ITP have an increase in platelet count ≥ 20 x 10 (to the ) 9/L above baseline over the study duration
• To describe the use of rescue ITP medications
• To describe the incidence of antibody formation
• To describe the safety of romiplostim as a long-term treatment in pediatric thrombocytopenic subjects with ITP
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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 |
A supplement to the protocol for European Union (EU) Switzerland, and Turkey. These changes are being made to fulfill the binding elements of the European Medicines Agency Pediatric Investigation Plan (PIP) and include the addition of mandatory bone marrow biopsies and aspirates for evaluation of collagen, reticulin and cytogenetics at baseline and after Year 1 and Year 2 (in separate cohorts) to assess the long term safety of romiplostim in pediatric patients with immune thrombocytopenia
purpura (ITP).
Title: A Single Arm, Open-label, Long-term Efficacy and Safety Study of Romiplostim in Thrombocytopenic Pediatric Subjects With Immune Thrombocytopenia (ITP)
Date: 15 July 2014 (Version 2)
A subset of at least 60 subjects will be enrolled sequentially into the following cohorts:
• Bone marrow biopsy and aspirate at baseline and Year 1
• Bone marrow biopsy and aspirate at baseline and Year 2
All subjects in these 2 cohorts will receive romiplostim for 3 years, unless withdrawn from the study early. They will complete an End of Treatment (EOT) visit at the conclusion of their treatment period and will then return an End of Study (EOS) visit.
Primary Objective: same as main study with addition of:
To evaluate incidence of changes in bone marrow findings at Year 1 and Year 2 after initial exposure to romiplostim
Secondary objectives: same as main study with addition of:
• To evaluate the incidence of increased reticulin as evidenced by silver staining at Year 1 or Year 2, after exposure to romiplostim |
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E.3 | Principal inclusion criteria |
• Diagnosis of primary ITP according to The American Society of Hematology (ASH) Guidelines (Neunert et al, 2011) at least 6 months before screening, regardless of splenectomy status
• Age ≥ 1 year and < 18 years at the time of providing informed consent
• Subject must be refractory to a prior ITP therapy, having relapsed after at least 1 prior ITP therapy, or be ineligible for other ITP therapies
• Examples of prior therapy include but are not limited to: corticosteroids, IVIG, anti-D immunoglobulin, and platelet transfusions. Subjects who have failed a splenectomy are eligible for study participation
• Subject has a documented platelet count ≤ 30 x10 (to the)9/L or is experiencing bleeding that is uncontrolled with conventional therapies
• Subject’s legally acceptable representative (or subject, if applicable) has provided informed consent before any study-specific procedure; and subject has proved assent, where required by the IRB/IEC
• Adequate hematologic, renal, and liver function during the screening period:
- Hemoglobin > 10.0 g/dL
- Serum creatinine ≤ 1.5 times the upper limit of normal
- Total serum bilirubin ≤ 1.5 times the upper limit of normal
- AST and ALT ≤ 3.0 times the upper limit of normal
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E.4 | Principal exclusion criteria |
Exclusion Criteria
• Known history of a bone marrow stem cell disorder (Any abnormal bone marrow findings other than those typical of ITP must be approved by Amgen before a subject may be enrolled in the study)
• Prior bone marrow transplant or peripheral blood progenitor cell transplant
• Known active or prior malignancy except non-melanoma skin cancers within the last 5 years
• Known history of myelodysplastic syndrome
• Known history of bleeding diathesis
• Known history of congenital thrombocytopenia
• Known history of hepatitis B, hepatitis C or human immunodeficiency virus
• Known history of systemic lupus erythematosus, Evans syndrome, or autoimmune neutropenia
• Known history of antiphospholipid antibody syndrome or known positive for lupus anticoagulant
• Known history of disseminated intravascular coagulation, hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura
• History of venous thromboembolism or thrombotic events
• Previous use of romiplostim. Previous use of eltrombopag within 4 weeks of enrollment.
• Previous use of PEG-rHuMGDF, recombinant human thrombopoietin (rHuTPO) or any other platelet producing agent
• Rituximab (for any indication) or 6-mercaptopurine within 8 weeks of enrollment, or anticipated use at any time during the study
• Splenectomy within 4 weeks of the screening visit
• Alkylating agents within 8 weeks before the screening visit or anticipated use during the time of the proposed study
• Vaccinations known to decrease platelet counts within 8 weeks before the screening visit
• Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
• Subject will have investigational procedures performed while enrolled in this clinical study
• Female subject of child bearing potential (defined as having first menses) is not willing to use, in combination with her partner highly effective methods of birth control during treatment and for 1 month after the end of treatment
• Subject is pregnant or breast feeding, or might become pregnant within 1 month after the end of treatment
• Subject has known hypersensitivity to any recombinant Escherichia coli derived product (eg, Infergen, Neupogen, somatropin, and Actimmune®)
• Subject has previously enrolled into this study
• Subject will not be available for protocol-required study visits or procedures, to the best of the subject’s and investigator’s knowledge
• Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures
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E.5 End points |
E.5.1 | Primary end point(s) |
The percentage of time with a platelet count of ≥ 50 x 10 (to the) 9/L starting from week 2 in the first 6 months of the treatment period without rescue medication use within the past 4 weeks
In addition, for protocol supplement:
• Evaluation of bone marrow changes after Year 1 and Year 2 for the following:
- Incidence of collagen as evidenced by trichrome staining (using the modified Bauermeister grading scale) after romiplostim exposure
- Incidence of bone marrow reticulin increases in severity ≥ 2 grades (ie, grade 0 to 2-4, 1 to 3-4, 2 to 4), compared to baseline, or an increase to grade 3 or grade 4 as
evidenced by reticulin silver staining using the modified Bauermeister grading scale after romiplostim exposure
- Incidence of bone marrow abnormalities (eg, myelodysplastic syndrome, monosomy 7) as evidenced by cytogenetics and fluorescence in situ hybridization |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The percentage of time with a platelet count of ≥ 50 x 10 (to the) 9/L starting from week 2 until the end of the treatment period without rescue medication use within the past 4 weeks
• The percentage of time with an increase in platelet count ≥ 20 x 10 (to the) 9/L above baseline starting from week 2 until the end of the treatment period without rescue medication use in the past 4 weeks.
• Subject incidence of rescue ITP medications used
• The incidence of anti-romiplostim neutralizing antibodies and cross reactive antibodies to TPO at any time during the study
• The incidence of adverse events, including clinically significant changes in laboratory values
In addition, for protocol supplement:
• The incidence of increased reticulin as evidenced by silver staining at Year 1 or Year 2, after exposure to romiplostim |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | 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) | 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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
Australia |
Belgium |
Brazil |
Canada |
Czech Republic |
France |
Hungary |
Israel |
Mexico |
Peru |
Poland |
Russian Federation |
South Africa |
Spain |
Switzerland |
Turkey |
United Kingdom |
United States |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |