A Phase 4 interventional study of romiplostim in Thrombocytopenia and Idiopathic Thrombocytopenic Purpura, sponsored by Amgen. Completed. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-09-21.
Sponsored by Amgen · Phase 4, Interventional, and Treatment
The purpose of this study is to evaluate changes in bone marrow morphology (structure) after long-term exposure to romiplostim.
Participants diagnosed with ITP according to the American Society of Hematology (ASH) Guidelines were sequentially enrolled into the following groups:
All participants received romiplostim for 3 years, unless withdrawn from the study early.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one visit for End of Study (EOS) procedures 4 weeks after romiplostim discontinuation, or, for participants who were withdrawn from the study due to the presence of collagen fibrosis, or had a change to grade 3 reticulin, at 12 weeks after discontinuation of romiplostim.
697 studies on the registry are indexed under Thrombocytopenia; 153 are open to participants now.
This study's enrollment of 169 is above the median of 55 across 472 interventional studies indexed under Thrombocytopenia.
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Exclusion Criteria:
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
Also known as: Nplate®
Percentage of Participants With Collagen Fibrosis
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
Number of Participants With Collagen Fibrosis 12 Weeks After Romiplostim Discontinuation in Participants Who Developed Collagen Fibrosis at Years 1, 2, or 3
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
Percentage of Participants Who Developed an Increased Modified Bauermeister Grade
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
Percentage of Participants With Clinically Relevant Changes in Total Cardiac Output Corrected (QTc) Intervals
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
Number of Participants With Improvement of Reticulin to a Grade of ≤ 2 for Participants Who Developed Grade 3 Reticulin
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
Percentage of Participants With CTCAE Grade ≥ 2 Shift in Anemia or Neutropenia
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.
Number of Participants With Adverse Events (AEs)
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.
Number of Participants Who Developed Antibodies or Neutralizing Antibodies to Romiplostim or to Endogenous Thrombopoietin
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).
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.
| Milestone | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|
| Started | 50 | 50 | 69 |
| Completed | 23 | 33 | 47 |
| Not completed | 27 | 17 | 22 |
| Withdrew: Ineligibility determined | 0 | 0 | 1 |
| Withdrew: Noncompliance | 0 | 0 | 1 |
| Withdrew: Adverse event | 3 | 1 | 2 |
| Withdrew: Withdrawal by subject | 8 | 9 | 6 |
| Withdrew: Requirement for alternative therapy | 1 | 2 | 3 |
| Withdrew: Physician decision | 2 | 0 | 3 |
| Withdrew: Death | 4 | 2 | 1 |
| Withdrew: Protocol-specified criteria | 5 | 2 | 3 |
| Withdrew: Pregnancy | 0 | 1 | 1 |
| Withdrew: Lost to follow-up | 1 | 0 | 0 |
| Withdrew: Other | 3 | 0 | 1 |
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.
| percentage of participants | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|
| Percentage of Participants With Collagen Fibrosis | 0.0 (0.0 to 10.0) | 0.0 (0.0 to 9.0) | 3.4 (0.4 to 11.9) |
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.
| participants | Cohort 1 | Cohort 2 | Cohort 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 |
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 | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|
| Percentage of Participants Who Developed an Increased Modified Bauermeister Grade | 0.0 (0.0 to 10.3) | 5.1 (0.6 to 17.3) | 12.1 (5.0 to 23.3) |
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.
| percentage of participants | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|
| Percentage of Participants With Clinically Relevant Changes in Total Cardiac Output Corrected (QTc) Intervals | 0.0 (0.0 to 7.1) | 0.0 (0.0 to 7.1) | 0.0 (0.0 to 5.2) |
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).
| participants | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|
| Number of Participants With Improvement of Reticulin to a Grade of ≤ 2 for Participants Who Developed Grade 3 Reticulin | — | — | 3 |
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.
| percentage of participants | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|
| CTCAE grade ≥2 shift in anemia | 6.0 (1.3 to 16.5) | 4.0 (0.5 to 13.7) | 8.7 (3.3 to 18.0) |
| CTCAE grade ≥2 shift in neutropenia | 8.0 (2.2 to 19.2) | 6.0 (1.3 to 16.5) | 13.0 (6.1 to 23.3) |
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.
| participants | Cohort 1 | Cohort 2 | Cohort 3 |
|---|---|---|---|
| All adverse events | 46 | 45 | 67 |
| Grade ≥ 2 | 39 | 39 | 59 |
| Grade ≥ 3 | 25 | 21 | 38 |
| Grade ≥ 4 | 13 | 8 | 16 |
| Serious adverse events | 16 | 12 | 28 |
| Leading to discontinuation of study drug | 6 | 5 | 4 |
| Leading to discontinuation from study | 6 | 2 | 3 |
| Fatal adverse events | 4 | 2 | 1 |
| Treatment-related adverse events | 14 | 22 | 24 |
| Treatment-related grade ≥ 2 | 8 | 14 | 10 |
| Treatment-related grade ≥ 3 | 2 | 7 | 3 |
| Treatment-related grade ≥ 4 | 0 | 1 | 0 |
| Treatment-related serious adverse events | 1 | 2 | 3 |
| Treatment-related -> discontinuation of study drug | 1 | 1 | 2 |
| Treatment-related -> discontinuation from study | 1 | 0 | 2 |
| Treatment-related fatal adverse events | 0 | 0 | 0 |
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.
| participants | Romiplostim |
|---|---|
| Antibodies to romiplostim | 7 |
| Persistent antibodies to romiplostim | 4 |
| Transient antibodies to romiplostim | 3 |
| Antibodies to TMP | 4 |
| Persistent antibodies to TMP | 1 |
| Transient antibodies to TMP | 3 |
| Antibodies to TPO | 6 |
| Persistent antibodies to TPO | 2 |
| Transient antibodies to TPO | 4 |
| Neutralizing antibodies to romiplostim | 1 |
| Neutralizing antibodies to TPO | 0 |
Collected over 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.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cohort 1 | — | 16/50 (32%) | 45/50 (90%) |
| Cohort 2 | — | 12/50 (24%) | 43/50 (86%) |
| Cohort 3 | — | 28/69 (40.6%) | 66/69 (95.7%) |
| Overall | — | 56/169 (33.1%) | 154/169 (91.1%) |
| Event | Cohort 1 | Cohort 2 | Cohort 3 | Overall |
|---|---|---|---|---|
| ThrombocytopeniaBlood and lymphatic system disorders | 2/50 | 0/50 | 4/69 | 6/169 |
| Urinary Tract InfectionInfections and infestations | 2/50 | 1/50 | 0/69 | 3/169 |
| Cerebrovascular AccidentNervous system disorders | 2/50 | 0/50 | 0/69 | 2/169 |
| Pulmonary EmbolismRespiratory, thoracic and mediastinal disorders | 0/50 | 2/50 | 0/69 | 2/169 |
| AnaemiaBlood and lymphatic system disorders | 1/50 | 0/50 | 2/69 | 3/169 |
| Idiopathic Thrombocytopenic PurpuraBlood and lymphatic system disorders | 0/50 | 1/50 | 2/69 | 3/169 |
| Atrial FibrillationCardiac disorders | 0/50 | 0/50 | 2/69 | 2/169 |
| CholecystitisHepatobiliary disorders | 0/50 | 0/50 | 2/69 | 2/169 |
| PneumoniaInfections and infestations | 0/50 | 0/50 | 2/69 | 2/169 |
| OsteoarthritisMusculoskeletal and connective tissue disorders | 0/50 | 0/50 | 2/69 | 2/169 |
| Event | Cohort 1 | Cohort 2 | Cohort 3 | Overall |
|---|---|---|---|---|
| NasopharyngitisInfections and infestations | 6/50 | 21/50 | 14/69 | 41/169 |
| HeadacheNervous system disorders | 12/50 | 14/50 | 25/69 | 51/169 |
| ContusionInjury, poisoning and procedural complications | 6/50 | 9/50 | 19/69 | 34/169 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 8/50 | 10/50 | 19/69 | 37/169 |
| DiarrhoeaGastrointestinal disorders | 7/50 | 7/50 | 18/69 | 32/169 |
| EpistaxisRespiratory, thoracic and mediastinal disorders | 9/50 | 10/50 | 18/69 | 37/169 |
| Upper Respiratory Tract InfectionInfections and infestations | 11/50 | 7/50 | 13/69 | 31/169 |
| PetechiaeSkin and subcutaneous tissue disorders | 9/50 | 11/50 | 14/69 | 34/169 |
| Gingival BleedingGastrointestinal disorders | 3/50 | 5/50 | 13/69 | 21/169 |
| CoughRespiratory, thoracic and mediastinal disorders | 4/50 | 7/50 | 13/69 | 24/169 |
| Age, Continuous(years) | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Mean | 55.5 ± 17.1 | 48.6 ± 16.5 | 46.6 ± 16.3 | 49.8 ± 16.9 |
| Sex: Female, Male(Participants) | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Female | 27 | 38 | 49 | 114 |
| Male | 23 | 12 | 20 | 55 |
| Race/Ethnicity, Customized(participants) | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| White or Caucasian | 48 | 47 | 59 | 154 |
| Black or African American | 0 | 0 | 1 | 1 |
| Hispanic or Latino | 1 | 3 | 7 | 11 |
| Asian | 1 | 0 | 1 | 2 |
| Other | 0 | 0 | 1 | 1 |
| Time Since ITP Diagnosis(years) | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Mean | 9.94 ± 10.29 | 10.50 ± 11.87 | 5.36 ± 6.41 | 8.24 ± 9.72 |
| Number of Prior ITP Therapies(participants) | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| 0 | 0 | 0 | 0 | 0 |
| 1 | 16 | 16 | 29 | 61 |
| 2 | 11 | 15 | 20 | 46 |
| 3 | 8 | 9 | 10 | 27 |
| ≥ 4 | 15 | 10 | 10 | 35 |
| Had Splenectomy(participants) | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| No | 28 | 35 | 46 | 109 |
| Yes | 22 | 15 | 23 | 60 |
| Any Prior History of Bone Marrow Abnormalities(participants) | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| No | 48 | 47 | 64 | 159 |
| Yes | 2 | 3 | 5 | 10 |
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