Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
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|ClinicalTrials.gov Identifier: NCT00907478|
Recruitment Status : Completed
First Posted : May 22, 2009
Results First Posted : January 1, 2015
Last Update Posted : February 9, 2017
|Condition or disease||Intervention/treatment||Phase|
|Thrombocytopenia Idiopathic Thrombocytopenic Purpura||Biological: romiplostim||Phase 4|
Participants diagnosed with ITP according to the American Society of Hematology (ASH) Guidelines were sequentially enrolled into the following groups:
- Bone marrow biopsy at Baseline and Year 1
- Bone marrow biopsy at Baseline and Year 2
- Bone marrow biopsy at Baseline and Year 3.
All participants received romiplostim for 3 years, unless withdrawn from the study early. Participants returned for one visit for End of Study (EOS) procedures 4 weeks after romiplostim discontinuation, or, for participants who were withdrawn from the study due to the presence of collagen fibrosis, or had a change to grade 3 reticulin, at 12 weeks after discontinuation of romiplostim.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||169 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Prospective, Phase IV, Open-Label, Multi-Center Study Evaluating Changes in Bone Marrow Morphology in Adult Subjects Receiving Romiplostim for the Treatment of Thrombocytopenia Associated With Immune (Idiopathic) Thrombocytopenia Purpura (ITP)|
|Study Start Date :||August 2009|
|Primary Completion Date :||January 2014|
|Study Completion Date :||January 2014|
Participants received romiplostim administered weekly by subcutaneous injection for up to 3 years.
The starting dose of romiplostim was 1 μg/kg; weekly dose increases continued in increments of 1 μg/kg/week to a maximum dose of 10 μg/kg in an attempt to reach a target platelet count of ≥ 50 x 10^9/L.
Romiplostim administered by subcutaneous injection
Other Name: Nplate®
- Percentage of Participants With Collagen Fibrosis [ Time Frame: At Years 1, 2 or 3 after initial exposure of romiplostim ]The percentage of participants who developed collagen fibrosis as evidenced by trichrome staining. Bone marrow biopsy samples were assessed using the modified Bauermeister grading scale by a central laboratory.
- Number of Participants With Collagen Fibrosis 12 Weeks After Romiplostim Discontinuation in Participants Who Developed Collagen Fibrosis at Years 1, 2, or 3 [ Time Frame: 12 weeks after romiplostim discontinuation ]The number of participants with collagen fibrosis as evidenced by trichrome staining 12 weeks after romiplostim discontinuation in participants who developed collagen fibrosis at Years 1, 2, or 3 after initial exposure of romiplostim, assessed by the central laboratory using the modified Bauermeister grading scale.
- Percentage of Participants Who Developed an Increased Modified Bauermeister Grade [ Time Frame: At Year 1, Year 2, or Year 3 post romiplostim exposure ]Increased modified Bauermeister grade refers to an increase by ≥ 2 severity grades or an increase to grade 4 (ie, grade 0 to 2-4, grade 1 to 3-4, grade 2 to 4, or grade 3 to 4 over baseline). The modified Bauermeister scale provides a means of assessing the development of increased reticulin and collagen in bone marrow according to the following: 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 Clinically Relevant Changes in Total Cardiac Output Corrected (QTc) Intervals [ Time Frame: Baseline, Week 3 and Week 12 ]A clinically relevant change in QTc (Fridericia) interval is defined as an absolute QTc interval >500 ms or a QTc Interval increase from Baseline >60 ms post romiplostim exposure. 12-lead electrocardiograms (ECG) were performed in triplicate at Baseline, Week 3 and Week 12; the average of of the 3 values at each assessment was used.
- Number of Participants With Improvement of Reticulin to a Grade of ≤ 2 for Participants Who Developed Grade 3 Reticulin [ Time Frame: 12 weeks after romiplostim discontinuation ]The number of participants who had any improvement of reticulin to a grade of ≤ 2 for participants who developed grade 3 reticulin after initial exposure to romiplostim as measured by the modified Bauermeister grading scale. The modified Bauermeister scale provides a means of assessing the development of increased reticulin and collagen in bone marrow according to the following: 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 CTCAE Grade ≥ 2 Shift in Anemia or Neutropenia [ Time Frame: From the first dose of study drug until 4 weeks after treatment discontinuation or 12 weeks after treatment discontinuation for patients who developed collagen fibrosis or a change to grade 3 reticulin; the overall median treatment duration was 154 weeks. ]Anemia was identified by laboratory values with hemoglobin < the lower limit of normal (LLN) or the Medical Dictionary for Regulatory Activities (MedDRA) terms prespecified by the sponsor. Neutropenia was identified by laboratory values with absolute neutrophil count <1.8x10^9/L or the MedDRA terms pre-specified by the sponsor. Severity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, based on the following: Grade 1: Mild AE; Grade 2: Moderate AE; Grade 3: Severe AE; Grade 4: Life-threatening or disabling AE; Grade 5: Death related to AE.
- Number of Participants With Adverse Events (AEs) [ Time Frame: From the first dose of study drug until 4 weeks after treatment discontinuation or 12 weeks after treatment discontinuation for patients who developed collagen fibrosis or a change to grade 3 reticulin; the overall median treatment duration was 154 weeks. ]An AE was defined as any untoward medical occurrence in a participant that did not necessarily have a causal relationship with this treatment, or any such occurrence or worsening of a pre-existing medical condition from the first dose of investigational product through the last study visit. A serious adverse event is defined as an AE that is fatal or life threatening, requires or prolongs hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or other significant medical hazard. The relationship of each AE to the study drug was assessed by the investigator. The severity of each AE was graded using using CTCAE 3.0; For any AEs not listed in CTCAE, the Amgen Standard Severity Scoring System was used: 1: Mild- Aware of sign or symptom, but easily tolerated; 2 Moderate- Discomfort enough to cause interference with usual activity; 3: Severe- Incapacitating with inability to work or do usual activity; 4: Life-threatening; 5: Fatal.
- Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin [ Time Frame: Every 24 weeks and at the end of study visit (4 weeks or 12 weeks after study drug discontinuation). ]
Two validated assays were used to test for antibodies to romiplostim, the thrombopoietin-mimetic peptide component of romiplostim (TMP) and to endogenous thrombopoietin (TPO). The first was an immunoassay to confirm the presence of antibodies. The second was a cell-based bioassay to detect neutralizing or inhibitory effects in vitro. If a sample was positive in both assays, a participant was defined as positive for neutralizing antibodies.
Persistent antibodies were those positive at the last timepoint tested and transient are defined as positive post-dose but negative at the last time point tested.
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00907478