Long-term Study of Romiplostim in Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)

Phase 3

Completed

Conditions: Immune Thrombocytopenia

Interventions: Drug: Romiplostim

Registration Number: NCT02279173

Lead Sponsor: Amgen

Brief Summary: This is a phase 3b single arm, open label, multicenter study describing the percentage of time pediatric participants with ITP have a platelet response while receiving romiplostim, defined as a platelet count ≥ 50 x 10\^9/L in the absence of ITP rescue medications for the past 4 weeks.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 203

Inclusion Criteria

Diagnosis of primary ITP according to The American Society of Hematology (ASH) Guidelines at least 6 months before screening, regardless of splenectomy status
Age ≥ 1 year and < 18 years of age
Refractory to prior ITP therapy, relapsed after at prior ITP therapy, or be ineligible for other therapies. Examples of prior therapy include: corticosteroids, intravenous Immunoglobulin (IVIG), anti-D immunoglobulin, platelet transfusions.
Platelet count ≤ 30 x10^9/L or is experiencing uncontrolled bleeding
Has provided informed consent before any study-specific procedure;
Adequate hematologic, renal, and liver function during screening:
- Hemoglobin > 10.0 g/dL
- Serum creatinine ≤ 1.5 x the upper limit of normal (ULN)
- Total serum bilirubin ≤ 1.5 x the ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x the ULN
For the EU, Switzerland and Turkey protocol supplement, subject must agree to a scheduled bone marrow biopsy and aspirate at Year 1 or Year 2 following romiplostim treatment and any unscheduled biopsies if clinically indicated
For the EU, Switzerland and Turkey protocol supplement, a reticulin grade of 0, 1, 2, or 3 according to the modified Bauermeister grading scale, as assessed by central laboratory from a bone marrow biopsy performed within 1 year prior to planned first dose of romiplostim or consent to a pre-treatment bone marrow biopsy and aspirate prior to planned first dose of romiplostim

Exclusion Criteria

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)
Prior bone marrow transplant or peripheral blood progenitor cell transplant
Active or prior malignancy except non-melanoma skin cancers within the last 5 years
History of myelodysplastic syndrome
History of bleeding diathesis
History of congenital thrombocytopenia
History of Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV)
History of systemic lupus erythematosus, Evans syndrome, or autoimmune neutropenia
History of antiphospholipid antibody syndrome or known positive for lupus anticoagulant
History of disseminated intravascular coagulation, hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura
History of venous thromboembolism or thrombotic events
Previous use of romiplostim or previous use of eltrombopag within 4 weeks of enrollment
Previous use of pegylated recombinant human megakaryocyte growth and development factor (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 investigational study
Will have investigational procedures while enrolled on study
Female subject of child bearing potential (defined as having first menses) 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®)
Has previously enrolled into this study
Will not be available for protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge
Any kind of disorder that, may compromise the subject to give written informed consent and/or to comply with all required study procedures

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Romiplostim	Romiplostim	Participants received romiplostim administered weekly by subcutaneous injection for up to 3 years. The starting dose was 1 µg/kg titrated in 1 µg/kg increments up to a maximum of 10 µg/kg to reach a target platelet count ≥ 50 x 10⁹/L.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Developed Collagen After Exposure to Romiplostim	Year 1 (Cohort 1) and year 2 (Cohort 2)	The percentage of participants who developed collagen as evidenced by trichrome staining, defined as a Grade 4 on the modified Bauermeister grading scale: Grade 0: No reticulin fibers demonstrable Grade 1: Occasional fine individual fibers and foci of a fine fiber network Grade 2: Fine fiber network throughout most of the section; no coarse fibers Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining) Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining)
Percentage of Participants With Increased Modified Bauermeister Grade	Baseline, year 1 (Cohort 1) and year 2 (Cohort 2)	The percentage of participants with an increased modified Bauermeister grade defined as an increase by ≥ 2 severity grades or an increase to grade 4 (i.e., grade 0 to 2-4, grade 1 to 3-4, grade 2 to 4, or grade 3 to 4 over baseline). The modified Bauermeister grading scale: Grade 0: No reticulin fibers demonstrable Grade 1: Occasional fine individual fibers and foci of a fine fiber network Grade 2: Fine fiber network throughout most of the section; no coarse fibers Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining) Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining) Participants without an evaluable baseline result were assumed to have a baseline modified Bauermeister score of 0.
Percentage of Time With a Platelet Response During the First 6 Months of Treatment	Week 2 to Month 6, platelet response was assessed every week.	Platelet response was defined as a platelet count of ≥ 50 x 10⁹/L with no rescue medication use for ITP in the past 4 weeks. Monthly platelet response was calculated based on the median platelet count during each month. For each participant, the percentage of time with platelet response during the first 6 months was calculated as the number of months a platelet response was observed divided by the total number of months response was assessed.
Percentage of Participants Who Developed Bone Marrow Abnormalities	Year 1 (Cohort 1) and year 2 (Cohort 2)	The percentage of participants with bone marrow abnormalities (eg, myelodysplastic syndrome, monosomy 7) based on analysis of bone marrow biopsy and aspirate samples using cytogenetics and fluorescence in situ hybridization.

Secondary Outcome Measures

Name	Time	Method
Percentage of Time With a Platelet Response During the Overall Treatment Period	From week 2 to the end of the treatment period, 36 months	Platelet response was defined as a platelet count of ≥ 50 x 10⁹/L with no rescue medication use in the past 4 weeks. Monthly platelet response was calculated based on the median platelet count during each month. For each participant, the percentage of time with platelet response was calculated as the number of months a platelet response was observed divided by the total number of months response was assessed.
Percentage of Time With an Increase in Platelet Count ≥ 20 x 10⁹ Cells/L Above Baseline	Baseline and from week 2 to month 36	The percentage of time with an increase in platelet count ≥ 20 x 10⁹ cells/L above baseline from week 2 until the end of the treatment period without rescue medication use within the past 4 weeks. For each participant, the percentage of time with an increase in platelet count ≥ 20 x10⁹ cells/L above baseline was calculated as the number of months the median platelet count was ≥ 20 x10⁹ cells/L above baseline divided by the total number of months assessed.
Number of Participants Reporting Use of Rescue Medications for ITP During the Treatment Period	From first dose of romiplostim to the end of the treatment period, 36 months	Rescue medication is defined as any medication or transfusion, other than romiplostim and excluded medications, that is administered after enrollment to the participant with the intent of raising platelet counts or to prevent bleeding and includes concomitant medications for ITP in which the dose and/or schedule was increased. Permitted rescue medications included the following: * corticosteroids * platelet transfusions * Intravenous immunoglobulin (IVIG) * azathioprine * anti-D immunoglobulin * danazol
Number of Participants Who Developed Anti-Romiplostim or Anti-Thrombopoietin Neutralizing Antibodies	Week 12, week 52 and every 24 weeks thereafter up to month 36	Blood samples were first tested for the presence of binding antibodies to romiplostim or the peptide portion of romiplostim, and to endogenous thrombopoietin (eTPO). Samples testing positive for binding antibodies were then tested for neutralizing antibodies by assessing their ability to neutralize romiplostim and/or eTPO in a cell-based bioassay. Participants who developed neutralizing antibodies are those who had a postbaseline positive result with a negative or no result at baseline. Transient is defined as a negative result at the participant's last time point tested within the study period.
Number of Participants With Adverse Events	SAEs were collected from Screening through end-of-study follow-up (up to 38 months). Nonserious AEs were collected from first to last dose of study drug during the treatment period (up to 36 months).	An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant, which does not necessarily have a causal relationship with study treatment. A serious adverse event (SAE) was defined as an AE that met at least 1 of the following criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event Adverse events were graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grading scale, where Grade 1 = mild AE; Grade 2 = moderate AE; Grade 3 = severe AE; Grade 4 = life-threatening or disabling; Grade 5 = death related to AE.
Percentage of Participants Who Developed Increased Reticulin	Baseline, year 1 (Cohort 1) and year 2 (Cohort 2)	The percentage of participants with increased reticulin as evidenced by silver staining and defined as any increase from baseline in the modified Bauermeister grade: Grade 0: No reticulin fibers demonstrable Grade 1: Occasional fine individual fibers and foci of a fine fiber network Grade 2: Fine fiber network throughout most of the section; no coarse fibers Grade 3: Diffuse fiber network with scattered thick coarse fibers but no mature collagen (negative to trichrome staining) Grade 4: Diffuse, often course fiber network with areas of collagenization (positive trichrome staining) Participants without an evaluable baseline result were assumed to have a baseline modified Bauermeister score of 0.