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

September 8, 2022 updated by: Amgen

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)

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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All participants received romiplostim for 3 years, unless withdrawn from the study early.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one visit for End of Study (EOS) procedures 4 weeks after romiplostim discontinuation, or, for participants who were withdrawn from the study due to the presence of collagen fibrosis, or had a change to grade 3 reticulin, at 12 weeks after discontinuation of romiplostim.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

Enrollment (Actual)

169

Phase

  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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, intravenous immunoglobulin [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 pegylated recombinant human megakaryocyte growth and development factor (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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Romiplostim

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.
Biological: romiplostim
Romiplostim administered by subcutaneous injection
Other Names:
  • Nplate®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
At Years 1, 2 or 3 after initial exposure of romiplostim

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
12 weeks after romiplostim discontinuation
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).
At Year 1, Year 2, or Year 3 post romiplostim exposure
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.
Baseline, Week 3 and Week 12
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).
12 weeks after romiplostim discontinuation
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.
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.
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.
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.
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.
Every 24 weeks and at the end of study visit (4 weeks or 12 weeks after study drug discontinuation).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Amgen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 11, 2009

Primary Completion (Actual)

January 9, 2014

Study Completion (Actual)

January 14, 2014

Study Registration Dates

First Submitted

May 21, 2009

First Submitted That Met QC Criteria

May 21, 2009

First Posted (Estimate)

May 22, 2009

Study Record Updates

Last Update Posted (Actual)

September 21, 2022

Last Update Submitted That Met QC Criteria

September 8, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20080009

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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