INTERVENTION: Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 12.5‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Powder for oral suspension INN or Proposed INN: ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Pharmaceutical form CONDITION: Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] To assess the efficacy of eltrombopag, relative to placebo, in achieving platelet counts of = 50 Gi/L, when administered to pediatric subjects with previously treated chronic ITP during the first 12 weeks of Part 1, the randomized treatment period. ; MedDRA version: 14.1 Level: PT Classification code 10021245 Term: Idiopathic thrombocytopenic purpura System Organ Class: 10005329 ‐ Blood and lymphatic system disorders SECONDARY OUTCOME: Secondary end point(s): The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 ; Gi/L for at least 6 out of 8 weeks, between weeks 5‐12 of Part 1. ; Weighted mean platelet change (area under the platelet‐time curve divided by duration), for subjects receiving eltrombopag relative to placebo, from baseline to Week 12 of Part 1. ; The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 Gi/L at any time during the first 6 weeks of Part 1. ; The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 Gi/L at any time during the first 12 weeks of Part 1. ; The proportion of subjects achieving platelet counts = 50 Gi/L at any time during Part 2. ; Maximum period of time with platelet counts continuously = 50 Gi/L for subjects receiving eltrombopag relative to placebo during the first 12 weeks of Part 1. ; The proportion of weeks in which subjects achieve platelet counts = 50 Gi/L, between weeks 4‐24 of Part 2. ; Maximum period of time with platelet counts continuously = 50 Gi/L during Part 2. ; The proportion of subjects who reduced or discontinued baseline concomitant ITP medications during Part 2. PRIMARY OUTCOME: Main Objective: To assess the efficacy of eltrombopag, relative to placebo, in achieving platelet counts of = 50 Gi/L, when administered to pediatric subjects with previously treated chronic ITP during the first 12 weeks of Part 1, the randomized treatment period. Primary end point(s): The odds of achieving platelet counts = 50 Gi/L during the first 12 weeks of Part 1, the randomized treatment period, for subjects receiving eltrombopag relative to placebo. Secondary Objective: • To describe the efficacy of eltrombopag in achieving platelet counts = 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP. • To assess the efficacy of eltrombopag in achieving sustained platelet counts = 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP. • To describe the effect of eltrombopag on reduction and/or interruption of concomitant ITP therapies, when administered for 24 weeks to pediatric subjects with previously treated chronic ITP.; • To describe the effect of eltrombopag on the need for rescue ITP medication when administered to pediatric subjects with previously treated chronic ITP. • To assess the efficacy of eltrombopag in decreasing the incidence and severity of bleeding symptoms when administered in pediatric subjects with previously treated chronic. Please refer to the protocol for The remaining objectives P12 Timepoint(s) of evaluation of this end point: Primary endpoint will be based on platelet counts obtained through the first 12 weeks of Part 1. ; The proportion of subjects receiving eltrombopag, relative to placebo, who required protocol‐defined rescue treatment during Part 1. ; The proportion of subjects who required protocol‐defined rescue treatment during Part 2. ; Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the World Health Organization (WHO) Bleeding Scale for subjects receiving eltrombopag relative to placebo, during Part 1. ; Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the WHO Bleeding Scale during Part 2. ; Safety and tolerability parameters including blood pressure and heart rate, ophthalmic examinations, clinical laboratory assessments and frequency of all adverse events, categorized using Common Terminology Criteria for Adverse Events (CTCAE) v4 toxicity grades. ; PK data collected in this study will be included in a population PK analysis in order to estimate primary model‐based PK parameters such as CL/F, Q/F, Vc/F, Vp/F, and ka and the influence of potential covariates on these parameters. ; Timepoint(s) of evaluation of this end point: Secondary endpoints span up to 13 weeks in Part 1 and up to 24 weeks in Part 2. INCLUSION CRITERIA: 1. Written informed consent must be obtained from the subject’s guardian and accompanying informed assent from the subject (for children over 6 years old). 2. Subjects must be between 1 year and <18 years of age at Day 1. 3. Subjects 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 [Rodeghiero, 2009]. 4. A peripheral blood smear or bone marrow examination will support the diagnosis of ITP with no evidence of other causes of thrombocytopenia. 5. Subjects must be refractory or have relapsed after at least one prior ITP therapy, or subjects must be unable, for a medical reason, to continue other ITP treatments. 6. Subjects must have a Day 1 (or within 48 hours prior) platelet count <30 Gi/L. 7. Previous therapy for ITP with immunoglobulins (IVIg and anti‐D) must have been completed at least 2 weeks prior to Day 1, or these therap
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.
<b>BACKGROUND: </b>The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia.<b>METHODS: </b>PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909.<b>FINDINGS: </b>Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3-140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial.<b>INTERPRETATION: </b>Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events.<b>Funding: </b>GlaxoSmithKline.
Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed
INN:
ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 12.5‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed
INN:
ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed
INN:
ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed
INN:
ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Powder for oral suspension INN or Proposed
INN:
ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Pharmaceutical form
CONDITION:
Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] To assess the efficacy of eltrombopag, relative to placebo, in achieving platelet counts of = 50 Gi/L, when administered to pediatric subjects with previously treated chronic ITP during the first 12 weeks of Part 1, the randomized treatment period. ; MedDRA version: 14.1 Level: PT Classification code 10021245 Term: Idiopathic thrombocytopenic purpura System Organ Class: 10005329 ‐ Blood and lymphatic system disorders
SECONDARY OUTCOME:
Secondary end point(s): The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 ; Gi/L for at least 6 out of 8 weeks, between weeks 5‐12 of Part 1. ; Weighted mean platelet change (area under the platelet‐time curve divided by duration), for subjects receiving eltrombopag relative to placebo, from baseline to Week 12 of Part 1. ; The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 Gi/L at any time during the first 6 weeks of Part 1. ; The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 Gi/L at any time during the first 12 weeks of Part 1. ; The proportion of subjects achieving platelet counts = 50 Gi/L at any time during Part 2. ; Maximum period of time with platelet counts continuously = 50 Gi/L for subjects receiving eltrombopag relative to placebo during the first 12 weeks of Part 1. ; The proportion of weeks in which subjects achieve platelet counts = 50 Gi/L, between weeks 4‐24 of Part 2. ; Maximum period of time with platelet counts continuously = 50 Gi/L during Part 2. ; The proportion of subjects who reduced or discontinued baseline concomitant ITP medications during Part 2.
PRIMARY OUTCOME:
Main Objective: To assess the efficacy of eltrombopag, relative to placebo, in achieving platelet counts of = 50 Gi/L, when administered to pediatric subjects with previously treated chronic ITP during the first 12 weeks of Part 1, the randomized treatment period. Primary end point(s): The odds of achieving platelet counts = 50 Gi/L during the first 12 weeks of Part 1, the randomized treatment period, for subjects receiving eltrombopag relative to placebo. Secondary Objective: • To describe the efficacy of eltrombopag in achieving platelet counts = 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP. • To assess the efficacy of eltrombopag in achieving sustained platelet counts = 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP. • To describe the effect of eltrombopag on reduction and/or interruption of concomitant ITP therapies, when administered for 24 weeks to pediatric subjects with previously treated chronic ITP.; • To describe the effect of eltrombopag on the need for rescue ITP medication when administered to pediatric subjects with previously treated chronic ITP. • To assess the efficacy of eltrombopag in decreasing the incidence and severity of bleeding symptoms when administered in pediatric subjects with previously treated chronic. Please refer to the protocol for The remaining objectives P12 Timepoint(s) of evaluation of this end point: Primary endpoint will be based on platelet counts obtained through the first 12 weeks of Part 1. ; The proportion of subjects receiving eltrombopag, relative to placebo, who required protocol‐defined rescue treatment during Part 1. ; The proportion of subjects who required protocol‐defined rescue treatment during Part 2. ; Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the World Health Organization (WHO) Bleeding Scale for subjects receiving eltrombopag relative to placebo, during Part 1. ; Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the WHO Bleeding Scale during Part 2. ; Safety and tolerability parameters including blood pressure and heart rate, ophthalmic examinations, clinical laboratory assessments and frequency of all adverse events, categorized using Common Terminology Criteria for Adverse Events (CTCAE) v4 toxicity grades. ; PK data collected in this study will be included in a population PK analysis in order to estimate primary model‐based PK parameters such as CL/F, Q/F, Vc/F, Vp/F, and ka and the influence of potential covariates on these parameters. ; Timepoint(s) of evaluation of this end point: Secondary endpoints span up to 13 weeks in Part 1 and up to 24 weeks in Part 2.
INCLUSION CRITERIA:
1. Written informed consent must be obtained from the subject’s guardian and accompanying informed assent from the subject (for children over 6 years old). 2. Subjects must be between 1 year and <18 years of age at Day 1. 3. Subjects 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 [Rodeghiero, 2009]. 4. A peripheral blood smear or bone marrow examination will support the diagnosis of ITP with no evidence of other causes of thrombocytopenia. 5. Subjects must be refractory or have relapsed after at least one prior ITP therapy, or subjects must be unable, for a medical reason, to continue other ITP treatments. 6. Subjects must have a Day 1 (or within 48 hours prior) platelet count <30 Gi/L. 7. Previous therapy for ITP with immunoglobulins (IVIg and anti‐D) must have been completed at least 2 weeks prior to Day 1, or these therap
