Idiopathic Thrombocytopenic Purpura, Immune Thrombocytopenia, Thrombocytopenia, Thrombocytopenia in Pediatric Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP), Thrombocytopenia in Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP), Thrombocytopenic Purpura
Conditions
Keywords
Immune (Idiopathic) Thrombocytopenic Purpura, Pediatric Immune (Idiopathic) Thrombocytopenic Purpura, Immune Thrombocytopenia
Brief summary
The purpose of this study is to evaluate the efficacy of romiplostim in the treatment of thrombocytopenia in pediatric patients with Immune thrombocytopenia purpura (ITP) as measured by durable platelet response.
Interventions
DRUGRomiplostim
The starting dose of romiplostim is 1 µg/kg administered weekly by subcutaneous injection. Participants will return to the clinic weekly to provide platelet counts and undergo dose titrations under the supervision of the treating physician. Weekly dose increases will continue in increments of 1 µg/kg up to a maximum dose of 10 µg/kg in an attempt to reach a target platelet count of ≥ 50 x 10\^9/L. Dose adjustment will be allowed during the treatment period to maintain a platelet count between ≥ 50 x 10\^9/L and ≤ 200 x 10\^9/L.
DRUGPlacebo
Matching placebo administered by subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of primary ITP according to the American Society of Hematology (ASH) guidelines at least 6 months prior to screening, regardless of splenectomy status * Subject must be refractory to a prior ITP therapy, having relapsed after at least 1 prior ITP therapy, or ineligible for other ITP therapies; prior therapy includes first-line therapies * Age ≥ 1 year and \< 18 years at the time of providing informed consent * The mean of 2 platelet counts taken during the screening period must be ≤ 30 x 10\^9/L with neither count \> 35 x 10\^9/L * A serum creatinine concentration ≤ 1.5 times the laboratory normal range (for each age category) during the screening period * Adequate liver function; serum bilirubin ≤ 1.5 times the laboratory normal range during the screening period; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 times the laboratory normal range during the screening period * Hemoglobin \> 10.0 g/dL during the screening period * Subject and/or subject's legally acceptable representative has provided informed consent prior to any study-specific procedure; subject has provided assent, where required
Exclusion criteria
* Known history of a bone marrow stem cell disorder; any abnormal bone marrow findings other than those typical of ITP must be approved by Amgen before a subject may be enrolled in the study * Known active or prior malignancy except adequately treated basal cell carcinoma * Known history of congenital thrombocytopenia * Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) * Known history of H. pylori by urea breath test or stool antigen test within 6 months of enrollment or successfully treated with no evidence of infection * Known history of systemic lupus erythematosus, evans syndrome, or autoimmune neutropenia * Known history of antiphospholipid antibody syndrome or positive for lupus anticoagulant * Known history of disseminated intravascular coagulation, hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura * Previous history of venous thromboembolism or thrombotic events * Previous use of romiplostim, pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), Eltrombopag, recombinant human thrombopoietin (rHuTPO) or any platelet producing agent * Rituximab (for any indication) or 6-mercaptopurine (6-MP) within 14 weeks before the screening visit, or anticipated use during the time of the proposed study * Splenectomy within 4 weeks of the screening visit * All hematopoietic growth factors including interleukin-11 (IL-11) (oprelvekin) within 4 weeks before the screening visit * Alkylating agents within 8 weeks before the screening visit or anticipated use during the time of the proposed study * Vaccinations known to decrease platelet counts within 8 weeks before the screening visit * Known hypersensitivity to any recombinant E coli-derived product (eg, Infergen, Neupogen, Somatropin, and Actimmune) * Other criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Durable Platelet Response | Week 18 to week 25 | A participant with durable platelet response was defined as achieving at least 6 weekly platelet counts of ≥ 50 x 10\^9/L during the last 8 weeks of treatment (platelet counts obtained from week 18 to week 25). If a platelet count from a participant was not available (missing) in a certain week, that week was imputed as non-response for that participant. Platelet counts were not deemed as a positive response for 4 weeks after the administration of rescue medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Received Rescue Medication During the Treatment Period | 24 weeks | Rescue medication is any medication (other than excluded medications) that is intended to increase platelet counts or prevent bleeding. |
| Percentage of Participants With an Overall Platelet Response | Week 2 to week 25 | Overall platelet response is defined as either a durable platelet response or transient platelet response. Durable platelet response was defined as weekly platelet count ≥ 50 x 10\^9/L for 6 or more times during week 18 to week 25 measurements. Participants may not have had a weekly response within 4 weeks after receiving any rescue medication. Transient platelet response was defined as weekly platelet count ≥ 50 x 10\^9/L for 4 or more times during week 2 to week 25 measurements but without durable platelet response. Participants may not have had a weekly response within 4 weeks after receiving any rescue medications. |
| Number of Weeks With Platelet Response | Week 2 to week 25 | Number of weeks with platelet counts ≥ 50 x 10\^9/L during week 2 to week 25 measurements. Participants may not have had a weekly response within 4 weeks after receiving any rescue medications. |
| Total Number of Composite Bleeding Episodes | Week 2 to week 25 | A composite bleeding episode was defined as clinically significant bleeding events or the use of a rescue medication to prevent a clinical significant bleeding event during weeks 2 through 25 of the treatment period. A clinically significant bleeding event was defined as a Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grade ≥ 2 bleeding event. |
| Number of Participants With Adverse Events | From the first dose of study drug until 4 weeks after last dose; 28 weeks. | A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: * fatal, * life threatening (places the subject at immediate risk of death), * requires in-patient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * congenital anomaly/birth defect, and/or * other significant medical hazard. Adverse events were graded for severity according to the CTCAE version 3.0 grading scale, where Grade 3 = moderate, Grade 4 = life-threatening and Grade 5 = fatal. Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to study drug. This relationship was determined by a yes or no response to the question: Is there a reasonable possibility that the event may have been caused by study drug? |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
This study was conducted at 27 centers in the United States, Canada, and Australia. Participants were enrolled from 24 January 2012 to 03 September 2014.
Pre-assignment details
Participants who met eligibility criteria were enrolled and stratified by the following 3 age categories: ≥ 1 to \< 6 years; 6 to \< 12 years; and 12 to \< 18 years.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received weekly subcutaneous placebo for 24 weeks. | 20 |
| Romiplostim Participants received once weekly subcutaneous romiplostim for 24 weeks at a starting dose of 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. | 42 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligibility Determined | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Romiplostim |
|---|---|---|---|
| Age, Continuous | 9.6 years STANDARD_DEVIATION 4.3 | 9.4 years STANDARD_DEVIATION 4.7 | 9.7 years STANDARD_DEVIATION 4.1 |
| Age, Customized ≥ 12 - < 18 years | 23 participants | 7 participants | 16 participants |
| Age, Customized ≥ 1 - < 6 years | 12 participants | 4 participants | 8 participants |
| Age, Customized ≥ 6 - < 12 years | 27 participants | 9 participants | 18 participants |
| Platelets | 18.3 10^9/L STANDARD_DEVIATION 13.9 | 19.9 10^9/L STANDARD_DEVIATION 19.3 | 17.5 10^9/L STANDARD_DEVIATION 10.7 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 5 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 8 participants | 2 participants | 6 participants |
| Race/Ethnicity, Customized Multiple | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 6 participants | 1 participants | 5 participants |
| Race/Ethnicity, Customized White | 41 participants | 15 participants | 26 participants |
| Sex: Female, Male Female | 35 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Male | 27 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 19 | 41 / 42 |
| serious Total, serious adverse events | 1 / 19 | 10 / 42 |
Outcome results
Primary
Percentage of Participants With a Durable Platelet Response
A participant with durable platelet response was defined as achieving at least 6 weekly platelet counts of ≥ 50 x 10\^9/L during the last 8 weeks of treatment (platelet counts obtained from week 18 to week 25). If a platelet count from a participant was not available (missing) in a certain week, that week was imputed as non-response for that participant. Platelet counts were not deemed as a positive response for 4 weeks after the administration of rescue medication.
Time frame: Week 18 to week 25
Population: Efficacy analysis set (all randomized participants)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Durable Platelet Response | 10.0 percentage of participants |
| Romiplostim | Percentage of Participants With a Durable Platelet Response | 52.4 percentage of participants |
Comparison: The incidence of durable platelet response was compared by the Cochran-Mantel-Haenszel test stratified by the baseline age group. The Mantel-Haenszel common odds ratio (romiplostim vs placebo) was estimated along with its 95% confidence interval.p-value: 0.001895% CI: [1.896, 43.199]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: * fatal, * life threatening (places the subject at immediate risk of death), * requires in-patient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * congenital anomaly/birth defect, and/or * other significant medical hazard. Adverse events were graded for severity according to the CTCAE version 3.0 grading scale, where Grade 3 = moderate, Grade 4 = life-threatening and Grade 5 = fatal. Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to study drug. This relationship was determined by a yes or no response to the question: Is there a reasonable possibility that the event may have been caused by study drug?
Time frame: From the first dose of study drug until 4 weeks after last dose; 28 weeks.
Population: Safety analysis set (all participants who received at least one dose of study drug)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events | Any adverse event (AE) | 19 participants |
| Placebo | Number of Participants With Adverse Events | Serious adverse events (SAE) | 1 participants |
| Placebo | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 0 participants |
| Placebo | Number of Participants With Adverse Events | AE leading to discontinuation from study | 0 participants |
| Placebo | Number of Participants With Adverse Events | Grade 3 AE | 3 participants |
| Placebo | Number of Participants With Adverse Events | Grade 4 AE | 1 participants |
| Placebo | Number of Participants With Adverse Events | Grade 5 AE | 0 participants |
| Placebo | Number of Participants With Adverse Events | Treatment-related adverse events (TRAE) | 5 participants |
| Placebo | Number of Participants With Adverse Events | Treatment-related serious adverse events | 0 participants |
| Placebo | Number of Participants With Adverse Events | TRAE leading to discontinuation of study drug | 0 participants |
| Placebo | Number of Participants With Adverse Events | TRAE leading to discontinuation from study | 0 participants |
| Placebo | Number of Participants With Adverse Events | TRAE Grade 3 | 0 participants |
| Placebo | Number of Participants With Adverse Events | TRAE Grade 4 | 0 participants |
| Placebo | Number of Participants With Adverse Events | TRAE Grade 5 | 0 participants |
| Romiplostim | Number of Participants With Adverse Events | TRAE leading to discontinuation from study | 0 participants |
| Romiplostim | Number of Participants With Adverse Events | Any adverse event (AE) | 41 participants |
| Romiplostim | Number of Participants With Adverse Events | Treatment-related adverse events (TRAE) | 11 participants |
| Romiplostim | Number of Participants With Adverse Events | Serious adverse events (SAE) | 10 participants |
| Romiplostim | Number of Participants With Adverse Events | TRAE Grade 4 | 0 participants |
| Romiplostim | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 0 participants |
| Romiplostim | Number of Participants With Adverse Events | Treatment-related serious adverse events | 1 participants |
| Romiplostim | Number of Participants With Adverse Events | AE leading to discontinuation from study | 0 participants |
| Romiplostim | Number of Participants With Adverse Events | TRAE Grade 3 | 1 participants |
| Romiplostim | Number of Participants With Adverse Events | Grade 3 AE | 6 participants |
| Romiplostim | Number of Participants With Adverse Events | TRAE leading to discontinuation of study drug | 0 participants |
| Romiplostim | Number of Participants With Adverse Events | Grade 4 AE | 2 participants |
| Romiplostim | Number of Participants With Adverse Events | TRAE Grade 5 | 0 participants |
| Romiplostim | Number of Participants With Adverse Events | Grade 5 AE | 0 participants |
Secondary
Number of Weeks With Platelet Response
Number of weeks with platelet counts ≥ 50 x 10\^9/L during week 2 to week 25 measurements. Participants may not have had a weekly response within 4 weeks after receiving any rescue medications.
Time frame: Week 2 to week 25
Population: Efficacy analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Number of Weeks With Platelet Response | 1.0 weeks |
| Romiplostim | Number of Weeks With Platelet Response | 12.0 weeks |
p-value: 0.0004ANOVA
Secondary
Percentage of Participants Who Received Rescue Medication During the Treatment Period
Rescue medication is any medication (other than excluded medications) that is intended to increase platelet counts or prevent bleeding.
Time frame: 24 weeks
Population: Efficacy analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Received Rescue Medication During the Treatment Period | 45.0 percentage of participants |
| Romiplostim | Percentage of Participants Who Received Rescue Medication During the Treatment Period | 40.5 percentage of participants |
p-value: 0.710395% CI: [0.277, 2.391]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an Overall Platelet Response
Overall platelet response is defined as either a durable platelet response or transient platelet response. Durable platelet response was defined as weekly platelet count ≥ 50 x 10\^9/L for 6 or more times during week 18 to week 25 measurements. Participants may not have had a weekly response within 4 weeks after receiving any rescue medication. Transient platelet response was defined as weekly platelet count ≥ 50 x 10\^9/L for 4 or more times during week 2 to week 25 measurements but without durable platelet response. Participants may not have had a weekly response within 4 weeks after receiving any rescue medications.
Time frame: Week 2 to week 25
Population: Efficacy analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With an Overall Platelet Response | 20.0 percentage of participants |
| Romiplostim | Percentage of Participants With an Overall Platelet Response | 71.4 percentage of participants |
Comparison: The incidence of overall platelet response was compared by the Cochran-Mantel-Haenszel test stratified by the baseline age group. The Mantel-Haenszel common odds ratio (romiplostim vs placebo) was estimated along with its 95% confidence interval.p-value: 0.000295% CI: [2.535, 32.265]Cochran-Mantel-Haenszel
Secondary
Total Number of Composite Bleeding Episodes
A composite bleeding episode was defined as clinically significant bleeding events or the use of a rescue medication to prevent a clinical significant bleeding event during weeks 2 through 25 of the treatment period. A clinically significant bleeding event was defined as a Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grade ≥ 2 bleeding event.
Time frame: Week 2 to week 25
Population: Efficacy analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Number of Composite Bleeding Episodes | 4.0 bleeding episodes | Standard Deviation 6.9 |
| Romiplostim | Total Number of Composite Bleeding Episodes | 1.9 bleeding episodes | Standard Deviation 4.2 |