Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)

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.

Time frame: At Years 1, 2 or 3 after initial exposure of romiplostim

Population: Participants who had evaluable trichrome stain results

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.

Time frame: Every 24 weeks and at the end of study visit (4 weeks or 12 weeks after study drug discontinuation).

Population: All participants who received at least one dose of romiplostim.

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.

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.

Population: All participants who received at least one dose of romiplostim

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.

Time frame: 12 weeks after romiplostim discontinuation

Population: Participants with collagen fibrosis at Year 1, 2 or 3 and with available trichome staining results 12 weeks after study drug discontinuation. One participant with collagen fibrosis refused the follow-up bone marrow biopsy.

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).

Time frame: 12 weeks after romiplostim discontinuation

Population: Participants with Grade 3 reticulin at Year 1, 2 or 3 and who had a follow-up bone marrow biopsy 12 weeks after romiplostim discontinuation. Two participants with grade 3 reticulin did not have a bone marrow biopsy performed 12 weeks after romiploastim discontinuation.

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).

Time frame: At Year 1, Year 2, or Year 3 post romiplostim exposure

Population: Participants who had evaluable reticulin silver stain results

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.

Time frame: Baseline, Week 3 and Week 12

Population: All participants who received at least one dose of romiplostim.

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.

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.

Population: All participants who received at least one dose of romiplostim