Idiopathic Thrombocytopenic Purpura, Thrombocytopenia, Thrombocytopenia in Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP), Thrombocytopenic Purpura
Conditions
Keywords
splenectomy, platelet, AMG 531, thrombopoietin, blood disorder, bleeding disorder, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura, immune (idiopathic) thrombocytopenic purpura, TPO, thrombopoietic protein
Brief summary
This is a phase 3b, multi-center, randomized, Standard of Care (SOC)-controlled, open-label, 52-week treatment study to compare romiplostim to medical SOC for Idiopathic Thrombocytopenia Purpura (ITP), with a 6-month Safety Follow-up. Patients randomized to romiplostim must complete the taper or discontinuation of medical SOC for ITP as soon as medically feasible after the initiation of romiplostim. After the completion or discontinuation of the study treatment period, any participant who does not transfer in to another romiplostim study will complete a 6-month Safety Follow-up period.
Interventions
DRUGMedical Standard of Care for ITP
BIOLOGICALRomiplostim
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is ≥ 18 years of age * Subject has a diagnosis of Idiopathic Thrombocytopenia Purpura (ITP) according to the American Society of Hematology (ASH) guidelines * If subject is \> 60 years of age, subject has a written bone marrow biopsy report confirming the diagnosis of ITP * Subject has received at least 1 prior therapy for ITP * Subject has a platelet count \< 50,000 or their platelet count falls to \< 50,000 during or after a clinically-indicated taper or discontinuation of current ITP therapy * Before any study-specific procedure, the appropriate written informed consent must be obtained
Exclusion criteria
* Subject has had a splenectomy for any reason * Subject has an active malignancy * Subject has a history of cancer, other than basal cell carcinoma or cervical carcinoma in situ, with treatment or active disease within 5 years * Subject has a known history of bone marrow stem cell disorder * Subject has participated in any study evaluating polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), recombinant human thrombopoietin (rHuTPO), AMG 531, or a thrombopoietic protein * Subject is receiving other investigational agents or procedures * Subject is currently enrolled in, or has completed within the last 30 days, another investigational device or drug study * Subject is pregnant or breast feeding * Subject is not using adequate contraceptive precautions * Subject has known sensitivity to any recombinant E. coli-derived product * 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 * Subject has any kind of disorder that compromises the ability of the subject to comply with study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Splenectomy During 52-Week Treatment Period | 52 weeks | Occurrence of a splenectomy. Participants who discontinued study during the treatment period prior to reporting a splenectomy were considered as having had a splenectomy. |
| Number of Participants With Treatment Failure During 52-Week Treatment Period | 52 weeks | Treatment failure was defined by platelet counts ≤ 20 x 10\^9/L for 4 consecutive weeks at the highest recommended dose and schedule, a major bleeding event, or change in therapy due to an intolerable side effect or bleeding symptom. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in ITP-PAQ Physical Health Domain of Symptoms | Baseline and 52 weeks | Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of symptoms. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates. |
| Change in ITP-PAQ Physical Health Domain of Fatigue | Baseline and 52 weeks | Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of fatigue. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates. |
| Time to Splenectomy | 52 weeks | Time to splenectomy in days calculated from date of randomization to date of splenectomy, or censored at date of end of treatment visit if no splenectomy was done during treatment period. |
| Change in ITP-PAQ Physical Health Domain of Activity | Baseline and 52 weeks | Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of activity. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates. |
| Change in ITP-PAQ Physical Health Domain of Bother | Baseline and 52 weeks | Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of bother. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates. |
| Percentage of Participants With Platelet Response | Weeks 1-8, and Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 | Platelet response was defined as platelet counts \> 50 x 10\^9/L, measured at each study visit (excluding those within 8 weeks of prior rescue medication use) up to the time of splenectomy or the end of initial treatment period, whichever occurred first. |
Participant flow
Recruitment details
First Subject Enrolled: 20-Dec-2006 Last Subject Enrolled: 01-Nov-2007
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Medical standard of care treatments were selected and prescribed by the investigator according to standard institutional practices or therapeutic guidelines and administered for up to 52 weeks. | 77 |
| Romiplostim Romiplostim administered by subcutaneous injection once weekly at a starting dose of 3 μg/kg, adjusted to a maximum dose of 10 μg/kg to maintain a platelet count between 50 and 200 x 10\^9/L for up to 52 weeks. | 157 |
| Total | 234 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Safety Follow Up Period | Adverse Event | 1 | 3 |
| Safety Follow Up Period | Death | 3 | 0 |
| Safety Follow Up Period | Ineligibility determined | 1 | 1 |
| Safety Follow Up Period | Noncompliance | 1 | 0 |
| Safety Follow Up Period | Other | 1 | 4 |
| Safety Follow Up Period | Requirement for alternative therapy | 0 | 1 |
| Safety Follow Up Period | Withdrawal by Subject | 2 | 3 |
| Treatment Period | Adverse Event | 2 | 3 |
| Treatment Period | Death | 2 | 1 |
| Treatment Period | Ineligibility determined | 1 | 1 |
| Treatment Period | Lost to Follow-up | 1 | 1 |
| Treatment Period | Noncompliance | 1 | 1 |
| Treatment Period | Other | 2 | 2 |
| Treatment Period | Protocol Violation | 1 | 0 |
| Treatment Period | Requirement for alternative therapy | 1 | 0 |
| Treatment Period | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Standard of Care | Romiplostim | Total |
|---|---|---|---|
| Age, Continuous | 54.7 Years STANDARD_DEVIATION 19.3 | 54.8 Years STANDARD_DEVIATION 18.8 | 54.7 Years STANDARD_DEVIATION 18.9 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian (Chinese, Bangladeshi, Indian, Pakistani) | 1 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 6 Participants | 6 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 9 Participants | 14 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White or Caucasian | 69 Participants | 137 Participants | 206 Participants |
| Sex: Female, Male Female | 46 Participants | 85 Participants | 131 Participants |
| Sex: Female, Male Male | 31 Participants | 72 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 73 | 136 / 156 |
| serious Total, serious adverse events | 28 / 73 | 36 / 156 |
Outcome results
Primary
Number of Participants With Splenectomy During 52-Week Treatment Period
Occurrence of a splenectomy. Participants who discontinued study during the treatment period prior to reporting a splenectomy were considered as having had a splenectomy.
Time frame: 52 weeks
Population: The Full Analysis set includes all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care | Number of Participants With Splenectomy During 52-Week Treatment Period | Had splenectomy | 28 Participants |
| Standard of Care | Number of Participants With Splenectomy During 52-Week Treatment Period | Did not have splenectomy | 49 Participants |
| Romiplostim | Number of Participants With Splenectomy During 52-Week Treatment Period | Had splenectomy | 14 Participants |
| Romiplostim | Number of Participants With Splenectomy During 52-Week Treatment Period | Did not have splenectomy | 143 Participants |
p-value: <0.000195% CI: [0.084, 0.352]Cochran-Mantel-Haenszel
Primary
Number of Participants With Treatment Failure During 52-Week Treatment Period
Treatment failure was defined by platelet counts ≤ 20 x 10\^9/L for 4 consecutive weeks at the highest recommended dose and schedule, a major bleeding event, or change in therapy due to an intolerable side effect or bleeding symptom.
Time frame: 52 weeks
Population: Full analysis set. Participants who discontinued study during treatment period prior to experiencing treatment failure were considered as having had treatment failure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care | Number of Participants With Treatment Failure During 52-Week Treatment Period | Had treatment failure | 23 Participants |
| Standard of Care | Number of Participants With Treatment Failure During 52-Week Treatment Period | Did not have treatment failure | 54 Participants |
| Romiplostim | Number of Participants With Treatment Failure During 52-Week Treatment Period | Had treatment failure | 18 Participants |
| Romiplostim | Number of Participants With Treatment Failure During 52-Week Treatment Period | Did not have treatment failure | 139 Participants |
p-value: 0.000595% CI: [0.154, 0.611]Cochran-Mantel-Haenszel
Secondary
Change in ITP-PAQ Physical Health Domain of Activity
Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of activity. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates.
Time frame: Baseline and 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Change in ITP-PAQ Physical Health Domain of Activity | 8.2 Units on a scale | Standard Error 3.7 |
| Romiplostim | Change in ITP-PAQ Physical Health Domain of Activity | 17.1 Units on a scale | Standard Error 3.5 |
p-value: 0.0246Mixed Models Analysis
Secondary
Change in ITP-PAQ Physical Health Domain of Bother
Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of bother. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates.
Time frame: Baseline and 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Change in ITP-PAQ Physical Health Domain of Bother | 13.0 Units on a scale | Standard Error 2.7 |
| Romiplostim | Change in ITP-PAQ Physical Health Domain of Bother | 16.8 Units on a scale | Standard Error 2.5 |
p-value: 0.0076Mixed Models Analysis
Secondary
Change in ITP-PAQ Physical Health Domain of Fatigue
Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of fatigue. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates.
Time frame: Baseline and 52 weeks
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Change in ITP-PAQ Physical Health Domain of Fatigue | 9.5 Units on a scale | Standard Error 3.2 |
| Romiplostim | Change in ITP-PAQ Physical Health Domain of Fatigue | 11.2 Units on a scale | Standard Error 3.1 |
p-value: 0.3434Mixed Models Analysis
Secondary
Change in ITP-PAQ Physical Health Domain of Symptoms
Change from Baseline in the Immune Thrombocytopenic Purpura (ITP) Patient Assessment Questionnaire (PAQ) physical health domain of symptoms. This domain has a range of 0 to 100, with higher scores indicating a better health-related quality of life. Model included fixed effects of baseline assessment, geographic region, treatment group, assessment week, splenectomy status and treatment group-by-assessment week interaction. Treatment group and splenectomy status are time-varying covariates.
Time frame: Baseline and 52 weeks
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Change in ITP-PAQ Physical Health Domain of Symptoms | 12.5 Units on a scale | Standard Error 2.1 |
| Romiplostim | Change in ITP-PAQ Physical Health Domain of Symptoms | 16.0 Units on a scale | Standard Error 1.9 |
p-value: 0.0133Mixed Models Analysis
Secondary
Percentage of Participants With Platelet Response
Platelet response was defined as platelet counts \> 50 x 10\^9/L, measured at each study visit (excluding those within 8 weeks of prior rescue medication use) up to the time of splenectomy or the end of initial treatment period, whichever occurred first.
Time frame: Weeks 1-8, and Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52
Population: Full analysis set. N indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care | Percentage of Participants With Platelet Response | Week 6 [N=66, 151] | 30.3 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 20 [N=58, 139] | 36.2 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 4 [N=170, 152] | 30.0 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 24 [N=58, 138] | 31.0 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 7 [N=66, 151] | 30.3 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 28 [N=57, 137] | 40.4 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 3 [N=70, 152] | 34.3 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 32 [N=55, 135] | 34.5 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 8 [N=65, 151] | 29.2 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 36 [N=54, 135] | 33.3 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 5 [N=68, 152] | 32.4 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 40 [N=52, 134] | 38.5 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 12 [N=62, 149] | 25.8 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 44 [N=51, 131] | 51.0 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 2 [N=71, 153] | 28.2 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 48 [N=48, 130] | 41.7 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 16 [N=61, 147] | 34.4 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 52 [N=38, 122] | 50.0 percentage of participants |
| Standard of Care | Percentage of Participants With Platelet Response | Week 1 [N=75, 154] | 6.7 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 52 [N=38, 122] | 90.2 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 1 [N=75, 154] | 3.9 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 2 [N=71, 153] | 75.8 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 3 [N=70, 152] | 73.0 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 4 [N=170, 152] | 73.7 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 5 [N=68, 152] | 71.1 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 6 [N=66, 151] | 74.2 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 7 [N=66, 151] | 75.5 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 8 [N=65, 151] | 68.2 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 12 [N=62, 149] | 79.2 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 16 [N=61, 147] | 82.3 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 20 [N=58, 139] | 83.5 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 24 [N=58, 138] | 92.0 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 28 [N=57, 137] | 88.3 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 32 [N=55, 135] | 87.4 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 36 [N=54, 135] | 89.6 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 40 [N=52, 134] | 88.8 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 44 [N=51, 131] | 86.3 percentage of participants |
| Romiplostim | Percentage of Participants With Platelet Response | Week 48 [N=48, 130] | 88.5 percentage of participants |
Secondary
Time to Splenectomy
Time to splenectomy in days calculated from date of randomization to date of splenectomy, or censored at date of end of treatment visit if no splenectomy was done during treatment period.
Time frame: 52 weeks
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care | Time to Splenectomy | NA days |
| Romiplostim | Time to Splenectomy | NA days |