Trial Outcomes & Findings for Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP) (NCT NCT00907478)

Last Updated: 2022-09-21

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

169 participants

Primary outcome timeframe

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

Results posted on

2022-09-21

Participant Flow

Eligible patients were adults diagnosed with immune (idiopathic) thrombocytopenic purpura (ITP) with a platelet count \< 50 x 10\^9/L. The first patient enrolled 11 August 2009 and the last patient was enrolled 11 November 2010. Participants were enrolled at 60 study centers in Australia, Europe, and North America.

204 patients were screened, 35 were considered screen failures. Participants were enrolled sequentially into the following cohorts: • Bone marrow biopsy at Baseline and Year 1 • Bone marrow biopsy at Baseline and Year 2 • Bone marrow biopsy at Baseline and Year 3.

Participant milestones

Participant milestones
Measure	Cohort 1 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Overall Study STARTED	50	50	69
Overall Study COMPLETED	23	33	47
Overall Study NOT COMPLETED	27	17	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Overall Study Ineligibility determined	0	0	1
Overall Study Noncompliance	0	0	1
Overall Study Adverse Event	3	1	2
Overall Study Withdrawal by Subject	8	9	6
Overall Study Requirement for alternative therapy	1	2	3
Overall Study Physician Decision	2	0	3
Overall Study Death	4	2	1
Overall Study Protocol-specified criteria	5	2	3
Overall Study Pregnancy	0	1	1
Overall Study Lost to Follow-up	1	0	0
Overall Study Other	3	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=69 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.	Total n=169 Participants Total of all reporting groups
Age, Continuous	55.5 years STANDARD_DEVIATION 17.1 • n=113 Participants	48.6 years STANDARD_DEVIATION 16.5 • n=163 Participants	46.6 years STANDARD_DEVIATION 16.3 • n=160 Participants	49.8 years STANDARD_DEVIATION 16.9 • n=483 Participants
Sex: Female, Male Female	27 Participants n=113 Participants	38 Participants n=163 Participants	49 Participants n=160 Participants	114 Participants n=483 Participants
Sex: Female, Male Male	23 Participants n=113 Participants	12 Participants n=163 Participants	20 Participants n=160 Participants	55 Participants n=483 Participants
Race/Ethnicity, Customized White or Caucasian	48 participants n=113 Participants	47 participants n=163 Participants	59 participants n=160 Participants	154 participants n=483 Participants
Race/Ethnicity, Customized Black or African American	0 participants n=113 Participants	0 participants n=163 Participants	1 participants n=160 Participants	1 participants n=483 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 participants n=113 Participants	3 participants n=163 Participants	7 participants n=160 Participants	11 participants n=483 Participants
Race/Ethnicity, Customized Asian	1 participants n=113 Participants	0 participants n=163 Participants	1 participants n=160 Participants	2 participants n=483 Participants
Race/Ethnicity, Customized Other	0 participants n=113 Participants	0 participants n=163 Participants	1 participants n=160 Participants	1 participants n=483 Participants
Time Since ITP Diagnosis	9.94 years STANDARD_DEVIATION 10.29 • n=113 Participants	10.50 years STANDARD_DEVIATION 11.87 • n=163 Participants	5.36 years STANDARD_DEVIATION 6.41 • n=160 Participants	8.24 years STANDARD_DEVIATION 9.72 • n=483 Participants
Number of Prior ITP Therapies 0	0 participants n=113 Participants	0 participants n=163 Participants	0 participants n=160 Participants	0 participants n=483 Participants
Number of Prior ITP Therapies 1	16 participants n=113 Participants	16 participants n=163 Participants	29 participants n=160 Participants	61 participants n=483 Participants
Number of Prior ITP Therapies 2	11 participants n=113 Participants	15 participants n=163 Participants	20 participants n=160 Participants	46 participants n=483 Participants
Number of Prior ITP Therapies 3	8 participants n=113 Participants	9 participants n=163 Participants	10 participants n=160 Participants	27 participants n=483 Participants
Number of Prior ITP Therapies ≥ 4	15 participants n=113 Participants	10 participants n=163 Participants	10 participants n=160 Participants	35 participants n=483 Participants
Had Splenectomy No	28 participants n=113 Participants	35 participants n=163 Participants	46 participants n=160 Participants	109 participants n=483 Participants
Had Splenectomy Yes	22 participants n=113 Participants	15 participants n=163 Participants	23 participants n=160 Participants	60 participants n=483 Participants
Any Prior History of Bone Marrow Abnormalities No	48 participants n=113 Participants	47 participants n=163 Participants	64 participants n=160 Participants	159 participants n=483 Participants
Any Prior History of Bone Marrow Abnormalities Yes	2 participants n=113 Participants	3 participants n=163 Participants	5 participants n=160 Participants	10 participants n=483 Participants

PRIMARY outcome

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

Population: Participants who had evaluable trichrome stain results

Outcome measures

Outcome measures
Measure	Cohort 1 n=35 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 n=39 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=58 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Percentage of Participants With Collagen Fibrosis	0.0 percentage of participants Interval 0.0 to 10.0	0.0 percentage of participants Interval 0.0 to 9.0	3.4 percentage of participants Interval 0.4 to 11.9

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Cohort 1 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=1 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Number of Participants With Collagen Fibrosis 12 Weeks After Romiplostim Discontinuation in Participants Who Developed Collagen Fibrosis at Years 1, 2, or 3	—	—	0 participants

SECONDARY outcome

Timeframe: At Year 1, Year 2, or Year 3 post romiplostim exposure

Population: Participants who had evaluable reticulin silver stain results

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).

Outcome measures

Outcome measures
Measure	Cohort 1 n=34 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 n=39 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=58 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Percentage of Participants Who Developed an Increased Modified Bauermeister Grade	0.0 percentage of participants Interval 0.0 to 10.3	5.1 percentage of participants Interval 0.6 to 17.3	12.1 percentage of participants Interval 5.0 to 23.3

SECONDARY outcome

Timeframe: Baseline, Week 3 and Week 12

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

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.

Outcome measures

Outcome measures
Measure	Cohort 1 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=69 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Percentage of Participants With Clinically Relevant Changes in Total Cardiac Output Corrected (QTc) Intervals	0.0 percentage of participants Interval 0.0 to 7.1	0.0 percentage of participants Interval 0.0 to 7.1	0.0 percentage of participants Interval 0.0 to 5.2

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Cohort 1 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=3 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Number of Participants With Improvement of Reticulin to a Grade of ≤ 2 for Participants Who Developed Grade 3 Reticulin	—	—	3 participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Cohort 1 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=69 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Percentage of Participants With CTCAE Grade ≥ 2 Shift in Anemia or Neutropenia CTCAE grade ≥2 shift in anemia	6.0 percentage of participants Interval 1.3 to 16.5	4.0 percentage of participants Interval 0.5 to 13.7	8.7 percentage of participants Interval 3.3 to 18.0
Percentage of Participants With CTCAE Grade ≥ 2 Shift in Anemia or Neutropenia CTCAE grade ≥2 shift in neutropenia	8.0 percentage of participants Interval 2.2 to 19.2	6.0 percentage of participants Interval 1.3 to 16.5	13.0 percentage of participants Interval 6.1 to 23.3

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Cohort 1 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 n=50 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 n=69 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Number of Participants With Adverse Events (AEs) Treatment-related grade ≥ 3	2 participants	7 participants	3 participants
Number of Participants With Adverse Events (AEs) Treatment-related grade ≥ 4	0 participants	1 participants	0 participants
Number of Participants With Adverse Events (AEs) Treatment-related serious adverse events	1 participants	2 participants	3 participants
Number of Participants With Adverse Events (AEs) All adverse events	46 participants	45 participants	67 participants
Number of Participants With Adverse Events (AEs) Grade ≥ 2	39 participants	39 participants	59 participants
Number of Participants With Adverse Events (AEs) Grade ≥ 3	25 participants	21 participants	38 participants
Number of Participants With Adverse Events (AEs) Grade ≥ 4	13 participants	8 participants	16 participants
Number of Participants With Adverse Events (AEs) Serious adverse events	16 participants	12 participants	28 participants
Number of Participants With Adverse Events (AEs) Leading to discontinuation of study drug	6 participants	5 participants	4 participants
Number of Participants With Adverse Events (AEs) Leading to discontinuation from study	6 participants	2 participants	3 participants
Number of Participants With Adverse Events (AEs) Fatal adverse events	4 participants	2 participants	1 participants
Number of Participants With Adverse Events (AEs) Treatment-related adverse events	14 participants	22 participants	24 participants
Number of Participants With Adverse Events (AEs) Treatment-related grade ≥ 2	8 participants	14 participants	10 participants
Number of Participants With Adverse Events (AEs) Treatment-related -> discontinuation of study drug	1 participants	1 participants	2 participants
Number of Participants With Adverse Events (AEs) Treatment-related -> discontinuation from study	1 participants	0 participants	2 participants
Number of Participants With Adverse Events (AEs) Treatment-related fatal adverse events	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort 1 n=169 Participants Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 1.	Cohort 2 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 2.	Cohort 3 Participants received once weekly romiplostim for 3 years and had a bone marrow biopsy at Baseline and Year 3.
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Transient antibodies to TMP	3 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Antibodies to TPO	6 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Persistent antibodies to TPO	2 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Antibodies to romiplostim	7 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Persistent antibodies to romiplostim	4 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Transient antibodies to romiplostim	3 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Antibodies to TMP	4 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Persistent antibodies to TMP	1 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Transient antibodies to TPO	4 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Neutralizing antibodies to romiplostim	1 participants	—	—
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin Neutralizing antibodies to TPO	0 participants	—	—

Adverse Events

Cohort 1

Serious events: 16 serious events

Other events: 45 other events

Deaths: 0 deaths

Cohort 2

Serious events: 12 serious events

Other events: 43 other events

Deaths: 0 deaths

Cohort 3

Serious events: 28 serious events

Other events: 66 other events

Deaths: 0 deaths

Overall

Serious events: 56 serious events

Other events: 154 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER