Study of a New Medication for Childhood Chronic Immune Thrombocytopenia (ITP), a Blood Disorder of Low Platelet Counts That Can Lead to Bruising Easily, Bleeding Gums, and/or Bleeding Inside the Body.

Phase 3CompletedNCT01520909

GlaxoSmithKline92 enrolled

Overview

The purpose of this study is to investigate the efficacy, safety and tolerability of eltrombopag in children with previously treated chronic immune thrombocytopenia who are between 1 and 17 years of age. This is a 2 part study. In part 1, patients will be randomized to receive either eltrombopag or placebo for 13 weeks. All patients who complete part 1 will enter part 2. In part 2, all patients will receive 24 weeks of eltrombopag.

This is a two part, double-blind, randomized, placebo-controlled and open-label Phase III study to investigate the efficacy, safety and tolerability of eltrombopag in pediatric patients with previously treated chronic ITP. In Part 1, patients will be randomized to receive eltrombopag or placebo in a 13-week double-blind, placebo-controlled treatment period. After completing Part 1, patients will begin Part 2, in which they will receive eltrombopag in an open-label manner during a 24-week treatment period.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Idiopathic Thrombocytopenic Purpura

Interventions

Eligibility

Sex: ALLMin age: 1 YearMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Written informed consent must be obtained from the patient's guardian and accompanying informed assent from the patient (for children over 6 years old) * Patients must be between 1 year and \<18 years of age at Day 1 * Patients will have a confirmed diagnosis of chronic ITP for at least 1 year, at screening, according to the guidelines published in the International Working Group Report * A peripheral blood smear or bone marrow examination will support the diagnosis of ITP with no evidence of other causes of thrombocytopenia. * Patients must be refractory or have relapsed after at least one prior ITP therapy, or patients must be unable, for a medical reason, to continue other ITP treatments. * Patients must have a Day 1 (or within 48 hours prior) platelet count \<30 Gi/L. * Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 2 weeks prior to Day 1, or these therapies must have been completed at least 1 week prior to Day 1 and have been clearly ineffective. * Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to Day 1. * Patients treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to Day 1. * Patients must have a complete blood count (CBC) not suggestive of another hematological disorder. * Patients must have the following laboratory results: * prothrombin time international normalized ratio (INR) and activated partial thromboplastin time (aPTT) within 80 to 120% of the normal range. * clinical chemistries that do NOT exceed the upper limit of normal reference range by more than 20% for the following: creatinine, ALT, AST, total bilirubin, and alkaline phosphatase. * total albumin that is not below the lower limit of normal by more than 10%. * Female patients of child-bearing potential (after menarche) must: * have a negative pregnancy test within 24 hours of first dose of study treatment, * agree and be able to provide a blood or urine specimen for pregnancy testing during the study, * agree to use effective contraception during the study and for 28 days following the last dose of study treatment, and not be lactating. * Male patients with a female partner of childbearing potential must agree to use effective contraception from 2 weeks prior to administration of the first dose of study treatment until 3 months after the last dose of study treatment. * In France, a patient will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. Exclusion Criteria: * Patients with any clinically relevant abnormality, other than ITP, identified on the screening examination or any other medical condition or circumstance, which in the opinion of the investigator makes the patient unsuitable for participation in the study or suggests another primary diagnosis (e.g. Thrombocytopenia is secondary to another disease). * Patients with concurrent or past malignant disease, including myeloproliferative disorder. * Patients expected not to be suitable for continuation of their current therapy for at least 13 additional weeks. * Patients with a history of platelet agglutination abnormality that prevents reliable measurement of platelet counts. * Patients with a diagnosis of secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, anti-phospholipid antibody syndrome, chronic hepatitis B infection, hepatitis c virus infection, or any evidence of active hepatitis at the time of subject screening. * Patients with Evans syndrome (autoimmune thrombocytopenia and autoimmune hemolysis). * Patients with known inherited thrombocytopenia (e.g. MYH9 disorders). * Patients treated with any medication that affects platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDS) or anti-coagulants for \>3 consecutive days within 2 weeks of Day 1. * Patients who have received treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding Day 1. * Patients who have previously received eltrombopag or any other thrombopoietin receptor agonist. * Any patient considered to be a child in care, defined as one who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. This can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The definition of a child in care does not include a child who is adopted or who has an appointed legal guardian. * Patients who have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipients that contraindicates their participation. * Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with the patient's safety or compliance to the study procedures.

Outcomes

Primary Outcomes

Number of Participants Achieving a Platelet Count >=50 Giga Cells Per Liter (Gi/L) for at Least 6 Out of 8 Weeks, Between Weeks 5 and 12 of Part 1

Participants who achieved a platelet count \>=50 Gi/L for at least 6 out of 8 weeks, between Weeks 5 and 12 of Part 1, were reported.

Time frame: From Week 5 up to Week 12 of Part 1

Secondary Outcomes

Percentage of Responders

Percentage of participants who responded (defined as platelet count \>= 50 Gi/L in absence of rescue) at least once up to week 12 of Part 1 (Odds of achieving a platelet count \>=50 Gi/L during the first 12 weeks of Part 1)

Time frame: From Week 1 up to Week 12 of Part 1

Number of Participants Achieving a Platelet Count >=50 Gi/L at Any Time During the First 12 Weeks of Part 1

Participants who achieved a platelet count \>=50 Gi/L at any time during the first 12 weeks of Part 1 were reported.

Time frame: From Baseline up to Week 12 of Part 1

Number of Participants Achieving a Platelet Count >=50 Gi/L at Any Time During the First 6 Weeks of Part 1

Participants who achieved a platelet count \>=50 Gi/L at any time during the first 6 weeks of Part 1 were reported.

Time frame: From Baseline up to Week 6 of Part 1

Weighted Mean Platelet Count

The weighted mean platelet count is defined as "the area under the platelet-time curve divided by the duration of the study (12 weeks)". Weighted mean platelet counts from baseline to week 12 of the randomized period was compared between placebo and eltrombopag using an analysis of covariance model (ANCOVA) adjusting for baseline platelet count and age cohort. For each subject the area between two adjacent visits with platelet counts was calculated. The area was calculated for all pairs of adjacent visits starting at Day 1 of randomized period and then the total sum of all the areas was divided by the total duration of time during the randomized period. For each subject, this method calculates an 'average' platelet count and it allows the possibility that subjects may have had different number of assessments during different times relative to baseline.

Time frame: Baseline and Week 12 of Part 1

Maximum Duration for Which a Participant Continuously Maintained a Platelet Count of >=50 Gi/L During the First 12 Weeks of Part 1

The maximum duration for which a participant continuously maintained a platelet count \>=50 Gi/L was calculated and summarized for the first 12 weeks of Part 1. Participants with non-weekly assessments were assumed to have maintained a positive response for each week between two assessments that had positive responses. If a participant achieved a positive response at an assessment and then achieved a negative response at the next assessment, then it was assumed that the participant had achieved a positive response for one day.

Time frame: From Baseline up to Week 12 of Part 1

Number of Participants Who Required a Protocol-defined Rescue Treatment During Part 1

Rescue treatment is defined as either a new immune (idiopathic) thrombocytopenic purpura (ITP) medication, an increase in the dose of a concomitant ITP medication from Baseline, a platelet transfusion, or a splenectomy.

Time frame: From Baseline up to Week 12 of Part 1

Number of Participants With Any Bleeding and Significant Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale During Part 1

The WHO Bleeding Scale is a measure of bleeding severity with the following grades: Grade 0=no bleeding; Grade 1=petechiae; Grade 2=mild blood loss; Grade 3=gross bleeding; Grade 4=debilitating blood loss. The WHO grades were dichotomized into the following categories: no bleeding=Grade 0; any bleeding=Grades 1 to 4; no clinically significant bleeding=Grades 0 to 1; clinically significant bleeding=Grades 2 to 4. Baseline was defined as the Day 1 assessment or the latest possible screening assessment.

Time frame: From Baseline through Follow-up of Part 1

Number of Participants Who Achieved a Platelet Count >=50 Gi/L at Any Time During Part 2

Participants who achieved a platelet count \>=50 Gi/L at any time during Part 2 (up to Week 24) were reported.

Time frame: From Baseline up to Week 24 of Part 2

Number of Weeks in Which Participants Achieved a Platelet Count >=50 Gi/L, Between Weeks 4 and 24 of Part 2

Platelet response was analyzed after Week 4 for the eltrombopag-only period to allow participants who had been randomized to placebo in the Randomized Period time to escalate to their optimal dose of eltrombopag. Participants with non-weekly assessments were assumed to have maintained a positive response for each week between two assessments that had positive responses. If the participant achieved a positive response at an assessment and then achieved a negative response at the next assessment, then it was assumed that the participant had achieved a positive response for one day.

Time frame: From Week 4 up to Week 24 of Part 2

Maximum Duration for Which a Participant Continuously Maintained a Platelet Count of >=50 Gi/L During Part 2

The maximum duration for which a participant continuously maintained a platelet count of \>=50 Gi/L was calculated and summarized for the 24 weeks of eltrombopag dosing (Part 2). Participants with non-weekly assessments were assumed to have maintained a positive response for each week between two assessments that had positive responses. If the participant achieved a positive response at an assessment and then achieved a negative response at the next assessment, then it was assumed that the participant had achieved a positive response for one day.

Time frame: From Baseline up to Week 24 of Part 2

Number of Participants Who Reduced or Discontinued Baseline Concomitant ITP Medications During Part 2 Without Requiring Subsequent Rescue Therapy

Participants who discontinued or had a sustained reduction of a baseline immune (idiopathic) thrombocytopenic purpura (ITP) medication during the 24 weeks of Part 2 (Open-Label Period) and without requiring subsequent rescue therapy. For participants randomized to placebo in Part 1, Baseline is defined as Week 13 of Part 1. For participants randomized to eltrombopag in Part 1, Baseline is defined as Day 1 of Part 1. A sustained reduction was defined as a reduction for 4 weeks or more.

Time frame: From Baseline up to Week 24 of Part 2

Number of Participants Who Required a Protocol-defined Rescue Treatment During Part 2

Rescue treatment was defined as either a new immune (idiopathic) thrombocytopenic purpura (ITP) medication, an increase in the dose of a concomitant ITP medication from Baseline, a platelet transfusion, or a splenectomy.

Time frame: From Baseline up to Week 24 of Part 2

Number of Participants With Any Bleeding and Significant Bleeding as Assessed Using the WHO Bleeding Scale During Part 2

The WHO Bleeding Scale is a measure of bleeding severity with the following grades: Grade 0 = no bleeding, Grade 1 = petechiae, Grade 2 = mild blood loss, Grade 3 = gross bleeding and Grade 4 = debilitating blood loss. The WHO Grades were dichotomized into the following categories: no bleeding = Grade 0; any bleeding = Grade 1 to 4; no clinically significant bleeding = Grade 0 to 1; clinically significant bleeding = Grade 2 to 4.

Time frame: From Baseline of Part 2 through Follow-up

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) During Part 1

An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect. Medical or scientific judgment should be exercised in other situations.

Time frame: From Day 1 of Treatment up to Week 13 of Part 1+ 1 day

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) During Part 2

An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death, is life threatening; requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect. Medical or scientific judgment should be exercised in other situations.

Time frame: From Day 1 of Part 2 up to Week 24 of Part 2 + 1 day

Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters at Any Time Post-Baseline During Part 1

Clinical chemistry parameters were summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: Grade 0 (G0), none; Grade 1 (G1), mild; Grade 2 (G2), moderate; Grade 3 (G3), severe; Grade 4 (G4), life-threatening or disabling. Clinical chemistry parameters included: aspartate amino transferase (AST), alkaline phosphatase (ALP), total bilirubin, albumin, alanine amino transferase (ALT), prothrombin international normalized ratio (PT INR), activated partial thromboplastin time (APTT), and creatinine. The Baseline value is defined as the value taken at Day 1 or, if missing, the latest non-missing Screening value. For serum creatinine, due to the variations in creatinine, the average of the Screening and the Day 1 values will be used as Baseline. The maximum post-Baseline toxicity grade includes any scheduled or unscheduled post-Baseline assessment during Part 1.

Time frame: From Baseline up to Week 13 of Part 1

Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters at Any Time Post-Baseline During Part 2

Clinical chemistry parameters were summarized according to the NCI CTCAE, version 4.0: G0, none; G1, mild; G2, moderate; G3, severe; G4, life-threatening or disabling. Clinical chemistry parameters included: AST, ALP, total bilirubin, albumin, ALT, and creatinine. For participants randomized to Placebo in Part 1, the BL value for Part 2 is defined as the value taken at Week 13 of Part 1. For serum creatinine, the value taken at Week 13 of Part 1 will be used as BL. For participants randomized to Eltrombopag in Part 1, the BL value is defined as the value taken on Day 1 or, if missing, the latest non-missing Screening value. For serum creatinine, due to the variations in creatinine, the average of the Screening and the Day 1 values will be used as BL. For participants who do not have both a Screening and Day 1 value, the Screening or Day 1 value will be used as BL. The maximum post-BL toxicity grade includes any scheduled or unscheduled post-BL assessment.

Time frame: From Baseline (BL) of Part 2 through Follow-up

Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Hematology Parameters at Any Time Post-Baseline During Part 1

Hematology parameters were summarized according to the NCI CTCAE, version 4.0: G0, none; G1, mild; G2, moderate; G3, severe; G4, life-threatening or disabling. Hematology parameters included: leukocytes, neutrophils, hemoglobin (increased), hemoglobin (anemia), lymphocytes (increased), and lymphocytes (decreased). The Baseline value is defined as the value taken at Day 1 or, if missing, the latest non-missing Screening value. The maximum post-Baseline toxicity grade includes any scheduled or unscheduled post-Baseline assessment during Part 1.

Time frame: From Baseline up to Week 13 of Part 1

Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Hematology Parameters at Any Time Post-Baseline During Part 2

Hematology parameters were summarized according to the NCI CTCAE, version 4.0: G0, none, G1, mild; G2, moderate; G3, severe; G4, life-threatening or disabling. Hematology parameters included: leukocytes, neutrophils, hemoglobin (increased), hemoglobin (anemia), lymphocytes (increased), and lymphocytes (decreased). For participants randomized to Placebo in Part 1, the BL value for Part 2 is defined as the value taken at Week 13 of Part 1. For participants randomized to Eltrombopag in Part 1, the BL value is defined as the value taken on Day 1 or, if missing, the latest non-missing Screening value. For participants who do not have both a Screening and Day 1 value, the Screening or Day 1 value will be used as BL. The maximum post-BL toxicity grade includes any scheduled or unscheduled post-BL assessment.

Time frame: From Baseline up to Week 24 of Part 2 and Follow-up Weeks 1 to 4 (up to Study Week 41)

Number of Participants With Vital Sign Data Falling Outside the Reference Ranges (RR) at the Indicated Visit During Part 1

Vital sign measurements were taken before any blood draws and included systolic blood pressure(SBP), diastolic blood pressure(DBP), and heart rate(HR). The number of participants are reported with vital sign data falling outside the standard reference ranges RR as reference range high(RRH) and reference range low(RRL). The Baseline(BL) value is defined as the value taken at Day 1 or if missing, the latest non-missing SCR value. RR for Blood Pressure (mmHg) are read as: Lower Limit of Normal, Normal Range, Upper Limit of Normal. For Ages 1 to 5 years (yrs) ranges are SBP \<85, 85 to 115, \>115; DBP \<45, 45 to70, \>70. Ages 6 to 11 yrs: SBP \<85, 85 to 120, \>120;, DBP \<50, 50 to 75, \>75. Ages 12 to 17 yrs: SBP \<95, 95 to 135, \>135; DBP \<55, 55 to 85, \>85. RR for HR(bpm) are ages 1 to \< 3 yrs: \<90, 90 to 140, \>140; ages 3 to \< 5 yrs: \<75, 75 to 130, \>130, ages 5 to \< 8yrs: \<65, 65 to 115, \>115; ages 8 to \< 12yrs: \<55, 55 to 110, \>110; and ages 12 to 18 yrs: \<55, 55 to 110, \>110.

Time frame: From Screening (SCR) up to Week 13 of Part 1

Number of Participants With Vital Sign Data Falling Outside the Reference Ranges (RR) at the Indicated Visit During Part 2

Vital sign measurements were taken before any blood draw and included systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate(HR). The number of participants are reported with vital sign data falling outside the standard RR as reference range high(RRH) and reference range low(RRL) from SCR up to Week 24 of Part 2 and from Follow-up Week 1 to Week 4. RR for Blood Pressure(mmHg) are read as: Lower Limit of Normal, Normal Range, Upper Limit of Normal. For Ages 1 to 5 years (yrs) ranges are SBP \<85, 85 to 115, \>115; DBP \<45, 45 to70, \>70. Ages 6 to 11 yrs: SBP \<85, 85 to 120, \>120; DBP \<50, 50 to 75, \>75. Ages 12 to 17 yrs: SBP \<95, 95 to 135, \>135; DBP \<55, 55 to 85, \>85. RR for HR (bpm) are ages 1 to \< 3 yrs: \<90, 90 to 140, \>140; ages 3 to \< 5 yrs: \<75, 75 to 130, \>130, ages 5 to \< 8yrs: \<65, 65 to 115, \>115; ages 8 to \< 12yrs: \<55, 55 to 110, \>110; and ages 12 to 18 yrs: \<55, 55 to 110, \>110.

Time frame: From Week 1 up to Week 24 of Part 2 and Follow-up Week 1 to Week 4 (up to Week 41)

Number of Participants With a Change in Visual Acuity Since Baseline at Week 12 of Part 1

The visual acuity assessment was performed by an ophthalmologist or an optometrist under the guidance of an ophthalmologist. Visual acuity is defined as acuteness or clearness of vision. Change in visual acuity results are presented as No (no change from Baseline), Not Clinically Significant (NCS), Improvement, and Worsening since Baseline. The Baseline value was obtained at the Screening Visit.

Time frame: Baseline and Week 12 of Part 1

Number of Participants With a Change in Visual Acuity Since Baseline at Week 24 of Part 2

The visual acuity assessment was performed by an ophthalmologist or an optometrist under the guidance of an ophthalmologist. Visual acuity is defined as acuteness or clearness of vision. Change in visual acuity results are presented as No Change, NCS, Improvement, and Worsening since Baseline. The Baseline value was obtained at the Screening Visit.

Time frame: Baseline and Week 24 of Part 2

Number of Participants With a Change in Visual Acuity Since Baseline at Follow-Up Week 24

The visual acuity assessment was performed by an ophthalmologist or an optometrist under the guidance of an ophthalmologist. Visual acuity is defined as acuteness or clearness of vision. Change in visual acuity results are presented as No Change, NCS, Improvement, and Worsening since Baseline. The Baseline value was obtained at the Screening Visit.

Time frame: Baseline and Follow-Up Week 24 (Study Week 61)

Number of Participants With Worsening Visual Acuity Due to Cataracts at Week 12 of Part 1

The visual acuity assessment was performed by an ophthalmologist or an optometrist under the guidance of an ophthalmologist. Visual acuity is defined as acuteness or clearness of vision. The number of participants with worsening visual acuity due to cataracts at Week 12 of Part 1 are presented. Change due to cataracts is categorized as "Yes" or "No."

Time frame: Baseline and Week 12 of Part 1

Number of Participants With Worsening Visual Acuity Due to Cataracts at Week 24 of Part 2

The visual acuity assessment was performed by an ophthalmologist or an optometrist under the guidance of an ophthalmologist. Visual acuity is defined as acuteness or clearness of vision. The number of participants with worsening visual acuity due to cataracts at Week 24 of Part 2 are presented. Change due to cataracts is categorized as "Yes" or "No.

Time frame: Baseline and Week 24 of Part 2

Number of Participants With Worsening Visual Acuity Due to Cataracts at Follow-Up Week 24

The visual acuity assessment was performed by an ophthalmologist or an optometrist under the guidance of an ophthalmologist. Visual acuity is defined as acuteness or clearness of vision. The number of participants with worsening visual acuity due to cataracts at Follow-up Week 24 are presented. Change due to cataracts is categorized as "Yes" or "No."

Time frame: Baseline and Follow-Up Week 24 (Week 61)

Pharmacokinetic (PK) Assessments for Eltrombopag for AUC (0-t)

Single PK samples were collected at each visit during Part 1 Weeks 2, 4, 6, 8, 10, 12 and at each weekly or monthly visit during Part 2 Weeks 1-12 (Study Weeks 13-37). The concentration data were pooled across visits to identify population PK and variability parameter estimates and covariate effects. AUC(0-t) is defined as the area under the concentration-time curve over the dosing interval. The AUC(0-t) for a 50mg dose was estimated for each cohort. From the final model, a single value of each PK parameter was estimated for each subject, and geometric mean (95% CI) values are presented for each cohort for a 50mg dose.