A Prospective, Study Evaluating Changes in Bone Marrow Morphology in Adult Subjects Receiving Romiplostim for the Treatment of Thrombocytopenia Associated With Immune (Idiopathic) Thrombocytopenia Purpura (ITP)

• The incidence of clinically relevant changes in QT/QTc intervals, as defined as an absolute QTc interval > 500 ms or a QTc interval increase from baseline ≥ 60 ms post romiplostim exposure [ Time Frame: from Week 3 through End of Study (maximum total time is approximately 3 years + 3 months) ] [ Designated as safety issue: Yes ]
• The incidence of any improvement of reticulin to a grade of ≤ 2 for subjects who developed grade 3 reticulin after initial exposure to romiplostim as measured by the modified Bauermeister grading scale [ Time Frame: At Year 1, Year 2, or Year 3 post romiplostim exposure ] [ Designated as safety issue: Yes ]
• The incidence of CTCAE grade ≥ 2 shift in anemia or neutropenia post romiplostim exposure [ Time Frame: from Screening through End of Study (maximum total time estimated to be approximately 3 years + 3 months) ] [ Designated as safety issue: Yes ]
• The incidence and severity of all adverse events including clinically significant changes in laboratory values [ Time Frame: from Screening through End of Study (maximum total time estimated to be approximately 3 years + 3 months) ] [ Designated as safety issue: Yes ]
• To investigate any changes between each sampling of four cytokines (TGF- β1, PDGF, OPG and bFGF), and any correlation of these changes with bone marrow biopsies, clinical and laboratory findings [ Time Frame: At Week 12 and at Year 1, Year 2, or Year 3 of romiplostim exposure ] [ Designated as safety issue: Yes ]
• The incidence of neutralizing antibody formation to romiplostim or cross-reacting antibodies to endogenous thrombopoietin [ Time Frame: from Screening through End of Study (maximum total time estimated to be approximately 3 years + 3 months) ] [ Designated as safety issue: Yes ]
• The incidence of collagen fibrosis as evidenced by trichrome staining in subjects who developed collagen fibrosis at Yrs 1, 2, or 3 after initial exposure of romiplostim using modified Bauermeister grading scale [ Time Frame: 12 wks after romiplostim discontinuation ] [ Designated as safety issue: Yes ]
• The incidence of bone marrow reticulin increases by ≥ 2 severity grades or increase to grade 4 over baseline as evidenced by reticulin silver staining using the modified Bauermeister grading scale [ Time Frame: At Year 1, Year 2, or Year 3 post romiplostim exposure ] [ Designated as safety issue: Yes ]

• The incidence of collagen fibrosis as evidenced by trichrome staining in subjects who developed collagen fibrosis at Yrs 1, 2, or 3 after initial exposure of romiplostim using modified Bauermeister grading scale [ Time Frame: 12 wks after romiplostim discontinuation ] [ Designated as safety issue: Yes ]
• The incidence of clinically relevant changes in QT/QTc intervals, as defined as an absolute QTc interval > 500 ms or a QTc interval increase from baseline ≥ 60 ms post romiplostim exposure [ Time Frame: Duration of the study ] [ Designated as safety issue: Yes ]
• The incidence and severity of all adverse events including clinically significant changes in laboratory values [ Time Frame: Duration of the study ] [ Designated as safety issue: Yes ]
• The incidence of neutralizing antibody formation to romiplostim or cross-reacting antibodies to endogenous thrombopoietin [ Time Frame: Duration of the study ] [ Designated as safety issue: Yes ]
• The incidence of CTCAE grade ≥ 2 shift in anemia or neutropenia post romiplostim exposure [ Time Frame: Duration of the study ] [ Designated as safety issue: Yes ]
• The incidence of bone marrow reticulin increases by ≥ 2 severity grades or increase to grade 4 over baseline as evidenced by reticulin silver staining using the modified Bauermeister grading scale [ Time Frame: At Year 1, Year 2, or Year 3 post romiplostim exposure ] [ Designated as safety issue: Yes ]
• The incidence of any improvement of reticulin to a grade of ≤ 2 for subjects who developed grade 3 reticulin after initial exposure to romiplostim as measured by the modified Bauermeister grading scale [ Time Frame: Duration of the study ] [ Designated as safety issue: Yes ]
• To investigate any changes between each sampling of four cytokines (TGF- β1, PDGF, OPG and bFGF), and any correlation of these changes with bone marrow biopsies, clinical and laboratory findings [ Time Frame: At Week 12 and at Year 1, Year 2, or Year 3 of romiplostim exposure ] [ Designated as safety issue: Yes ]

This is a prospective, phase IV, multi-center, open label, study evaluating the changes in bone marrow reticulin and collagen in adult subjects receiving romiplostim for the treatment of thrombocytopenia associated with ITP.

The purpose of this study is to evaluate changes in bone marrow morphology (structure) after long-term exposure to romiplostim.

Subjects, diagnosed with ITP according to the ASH Guidelines, will be 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 subjects will receive romiplostim for 3 years, unless withdrawn from the study early. All subjects will return for 1 visit post treatment for End of Study (EOS) procedures.

• Thrombocytopenia
• Idiopathic Thrombocytopenic Purpura

• Experimental: Year 2
  Bone Marrow Biopsy at baseline and Year 2
  Intervention: Biological: romiplostim
• Experimental: Year 3
  Bone Marrow Biopsy at baseline and Year 3
  Intervention: Biological: romiplostim
• Experimental: Year 1
  Bone Marrow Biopsy at baseline and Year 1
  Intervention: Biological: romiplostim

Inclusion Criteria:

• Diagnosis of ITP according to American Society of Hematology (ASH) guidelines
• Subject must have had a bone marrow biopsy within one year prior to planned first dose of romiplostim (with available bone marrow tissue block or unstained histological slides to send to a central laboratory for interpretation) or must consent to a pre-treatment bone marrow biopsy within 3 weeks prior to planned first dose of romiplostim. Central laboratory interpretation is required prior to first dose of romiplostim
• Subject must agree to a scheduled bone marrow biopsy at Year 1, Year 2, or Year 3 following romiplostim treatment and any unscheduled biopsies if clinically indicated
• Subject ≥18 years of age
• Baseline bone marrow reticulin grade of 0, 1, 2, or 3 according to the modified Bauermeister grading scheme as assessed by central laboratory interpretation
• Platelet count < 50 x 10^9/L
• Must have received at least 1 prior ITP therapy (examples of ITP therapy include corticosteroids, IVIG, splenectomy)
• Subject (or legally-acceptable representative) is willing and able to provide written informed consent

Exclusion Criteria:

• Baseline bone marrow biopsy positive for collagen fibrosis
• Any known history of or currently active bone marrow stem cell disorder, hematological malignancy, myeloproliferative disorder, myelodysplastic syndrome
• Any current active malignancy
• Any prior exposure to cytostatic chemotherapy or radiotherapy for malignancy
• Subject has undergone pacemaker placement, cardiac ablation of arrhythmia, and/or any current treatment with Vaughan Williams Class IA - IC and Class III agents (Vaughan Williams, 1970)
• Subject has participated in any study evaluating PEG-rHuMGDF, recombinant human thrombopoietin (rHuTPO), or thrombopoietin receptor agonists (ie romiplostim or eltrombopag)
• Subject has a known hypersensitivity to any recombinant E coli-derived product
• Subject is currently enrolled in or has not yet completed (at least 4 weeks since ending) other investigational device or drug trial(s) or subject is receiving other investigational agent(s)
• Other investigational procedures are excluded
• Subject of child-bearing potential is evidently pregnant (eg positive pregnancy test) or is breast feeding
• Subject is not using adequate contraceptive precautions
• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and does not have a legally acceptable representative and/or is unable to comply with study procedures