Secondary efficacy endpoints for Part 2, the Eltrombopag-Only Period, included the proportion of subjects who

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: (Compound Number SB ) Study Number: TRA Title: A two-part, double-blind, randomized, placebo-controlled and open-label study to investigate the efficacy, safety and tolerability of eltrombopag, a thrombopoietin receptor agonist, in pediatric patients with previously treated chronic immune (idiopathic) thrombocytopenic purpura (ITP). PETIT2: in PEdiatric patients with Thrombocytopenia from ITP Rationale: The purpose of this Phase III study (TRA115450/PETIT2) was to confirm the efficacy, safety, and tolerability of eltrombopag compared with placebo in pediatric subjects with chronic ITP. Phase: Phase III Study Period: 15-Mar-2012 through 02-Jan-2014 Study Design: This was 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 subjects with previously treated chronic ITP. In Part 1, the Randomized Period, subjects were randomized 2:1 to receive eltrombopag or placebo in a 13-week double-blind, placebo-controlled treatment period. Subjects were allowed to continue on standard of care. The randomization was stratified by 3 age-defined cohorts: Cohort 1 enrolled subjects between 12 and 17 years old, Cohort 2 enrolled subjects between 6 and 11 years old, and Cohort 3 enrolled subjects between 1 and 5 years old. Subjects who completed treatment in the Randomized Period were eligible to enter Part 2. In Part 2, the -Only Period, subjects received eltrombopag in an open-label manner for 24 weeks. Subjects randomized to placebo in the Randomized Period received up to 24 weeks of eltrombopag treatment, and subjects randomized to eltrombopag in the Randomized Period received up to 37 weeks of eltrombopag treatment. After completion of the -Only Period, subjects were to complete a 24 to 28 week Follow-up Period including an ophthalmic examination 24 weeks after the last dose of study treatment. Centres: This study enrolled subjects at 38 centres in 12 countries: Argentina (1 centre); Czech Republic (4 centres); Germany (3 centres); Hong Kong (1 centre); Israel (5 centres); Italy (4 centres); Russian Federation (4 centres); Spain (3 centres); Taiwan (1 centre); Thailand (5 centres); United Kingdom (5 centres); and United States (2 centres). Indication: Chronic Immune Thrombocytopenia Treatment: Subjects were administered eltrombopag or matching placebo as tablets or powder for oral suspension (PfOS). Subjects between 6 and 17 years of age weighing 27 kg initiated study treatment at 50 mg once daily. Subjects between 6 and 17 years of age weighing <27 kg initiated study treatment at 37.5 mg once daily. The starting dose for East Asian subjects, between 6 and 17 years of age, was 25 mg. For subjects between 1 and 5 years of age, the starting dose was 1.2 mg/kg once daily, or 0.8 mg/kg once daily for East Asian subjects. Throughout the study, the dose of study treatment was titrated for each subject based upon platelet response, to a maximum of 75mg once daily. The dose of study treatment was reduced whenever the platelet count exceeded 200 Gi/L and was interrupted if the platelet count exceeded 400 Gi/L and restarted at the next lower dose. The treatment goal was to have a platelet count in a safe hemostatic range and not to normalize the platelet counts. Objectives: The primary objective of this study was 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 Period. Primary Outcome (Endpoints)/Efficacy : The primary endpoint of the study was the proportion of subjects on eltrombopag, compared to placebo, achieving platelet counts 50 Gi/L for at least 6 out of 8 weeks, between Weeks 5 to 12 of Part 1, the Randomized Period. Secondary Outcome (Endpoints)/Efficacy : Secondary efficacy endpoints for Part 1, the Randomized Period, included the odds of achieving platelet counts 50 Gi/L during the first 12 weeks; proportion of subjects achieving platelet counts 50 Gi/L at any time during the first 12 weeks; proportion of subjects achieving platelet counts 50 Gi/L at any time during the first 6 weeks; weighted mean platelet change (area under the platelet-time curve divided by duration) from baseline to Week 12; maximum period of time with platelet counts continuously 50 Gi/L during the first 12 weeks; proportion of subjects who required protocol-defined rescue treatment; and incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the WHO Bleeding Scale. Secondary efficacy endpoints for Part 2, the -Only Period, included the proportion of subjects who 1

2 achieved platelet counts 50 Gi/L at any time during Part 2; proportion of weeks in which subjects achieved platelet counts 50 Gi/L, between Weeks 4 to 24 of Part 2; maximum period of time with platelet count continuously 50 Gi/L; proportion of subjects who reduced or discontinued baseline concomitant ITP medications; proportion of subjects who required protocol-defined rescue treatment; and incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the WHO Bleeding Scale. Safety endpoints included the frequency of adverse events, categorized using Common Terminology Criteria for Adverse Events (CTCAE) v4 toxicity grades, clinical laboratory tests (hematology, chemistry, urinalysis), vital signs (blood pressure and heart rate), and ophthalmic examinations. Pharmacokinetic endpoints: PK data collected in this study were 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. Statistical Methods: The primary comparison of interest was the proportion of subjects that received eltrombopag, compared with placebo, who achieved platelet counts 50 Gi/L for at least 6 out of 8 weeks, between Weeks 5 to 12 of Part 1. The primary efficacy analysis was evaluated using stratified Cochran-Mantel-Haenszel (CMH) chi-square test statistics that adjusted for the age cohorts (1 to 5 years, 6 to 11 years and 12 to 17 years). The study was powered to demonstrate a clinically meaningful difference between eltrombopag and placebo with respect to the primary endpoint for the ITT population. A response rate of 10% for placebo and 50% for eltrombopag was assumed based on the response rates at each nominal visit during the first 10 weeks of the placebo-controlled clinical study TRA For the randomized, placebo-controlled part of the study, using a 2:1 randomization, a sample size of 66 evaluable subjects was needed in order to provide at least 90% power at the 5% level of significance (two-sided). Allowing for an additional 10% of subjects to compensate for missing data and drop-outs, approximately 75 subjects (50 eltrombopag; 25 placebo) were planned to be randomized. The intent-to-treat (ITT) population consisted of all randomized subjects and was the primary population used for assessing efficacy. The safety population consisted of all subjects who received at least one dose of the investigational product. Study Population: This study enrolled male or female subjects aged between 1 year and <18 years with a confirmed diagnosis of chronic ITP for at least 1 year and a platelet count <30 Gi/L. Subjects were to be refractory or relapsed after at least one prior ITP therapy or not eligible, for a medical reason, to continue other ITP treatments Number of Subjects: Randomized Period (Part 1) Planned, N Randomised, N Completed Randomized Period, Total Number Subjects Discontinued Study Treatment, 1 (3.4) 2 (3.2) Discontinued Study Treatment due to Adverse Events, 1 (3.4) 2 (3.2) Discontinued Study Treatment due to Lack of Efficacy, 0 0 Discontinued Study Treatment for other reasons, 0 0 Withdrawn due to Lack of Efficacy prior to Part 2, 0 2 (3.2) -Only Period (Part 2) Open-label Received Open-label (Part 2), N (%) 87 (94.6) Completed Part 1 and Part 2, 80 (87.0) Total Number Subjects Discontinued Study Treatment (Part 2), 7 (8.0) Discontinued Study Treatment due to Adverse Events, 4 (4.6) Discontinued Study Treatment due to Lack of Efficacy, 2 (2.3) Discontinued Study Treatment for other reasons, 1 (1.1) Demographics: Randomized Period (Part 1) N (ITT) Females: Males, n 14:15 30:33 Mean Age, years (Range) 9.0 (4-17) 9.0 (1-17) Race, 2

3 African American/African Heritage 0 1 (1.6) Asian 10 (34.5) 21 (33.3) White 19 (65.5) 40 (63.5) Mixed Race 0 1 (1.6) Prior ITP Medication Use 2, 26 (90) 46 (73) Actual Baseline ITP Medication Use, Yes 1 (3.4) 13 (20.6) No 28 (96.6) 50 (79.4) Actual Baseline Platelet Count, 15 Gi/L 19 (65.5) 38 (61.3) a >15 Gi/L 10 (34.5) 24 (38.7) Actual Splenectomy Status, Yes 0 4 (6.3) No 29 (100.0) 59 (93.7) a. One subject did not have a baseline platelet count value on Day 1 Primary Efficacy Results: The proportion of eltrombopag subjects compared with placebo subjects achieving a sustained platelet response in the absence of ITP rescue medication for at least 6 of 8 weeks between Weeks 5 through 12 (Randomized Period) is summarized below: Odds Ratio (E vs P) (95% Confidence Interval) a p-value b Yes 1 (3.4) 25 (39.7) (2.29, ) <0.001 No 28 (96.6) 38 (60.3) a. Adjusted for age cohort and treatment. b. Stratified CMH Chi-square test adjusted for age cohort and treatment. Secondary Outcome Results: Part 1 (Randomized Period) Repeated Measures Analysis of Odds of achieving platelet counts 50 Gi/L during the first 12 weeks (Randomized Period) is summarized below: Statistics Odds-ratio Responders / a % Confidence Interval (8.15, 78.73) a. Generalized linear mixed model with a logit canonical link function adjusted for age cohort and treatment as fixed effects, and subjects and assessments within subjects as random effects. Proportion of subjects that achieved platelet counts 50 Gi/L at any time during the first 12 weeks (Randomized Period) is summarized below: No. of Responders 6 47 Percentage of Responders Odds-ratio Responders / % Confidence Interval (3.99, 34.50) Proportion of subjects that achieved platelet counts 50 Gi/L at any time during the first 6 weeks (Randomized Period) is summarized below: 3

4 No. of Responders 5 39 Percentage of Responders Odds-ratio Responders / % Confidence Interval (2.74, 25.09) Weighted mean platelet counts (area under the platelet-time curve divided by duration) over the first 12 weeks (Randomized Period) is summarized below: Number of Subjects Baseline Mean SD Weighted mean platelet Mean counts SD Model-adjusted platelet Mean counts SE Difference from PLA Mean % Confidence Interval (24.15, 57.88) Maximum continuous duration (weeks) for which a subject continuously maintained a platelet count of 50 Gi/L (Randomized Period) is summarized below: Mean SD th Percentile Median th Percentile Min. 0 0 Max Analysis of subjects who required a protocol-defined rescue treatment (Randomized Period) Logistic Regression Model is summarized below: No. Requiring Rescue Therapy 7 12 Percentage Requiring Rescue Therapy Odds-ratio of Rescue for / % Confidence Interval (0.21, 0.93) The odds of any bleeding (dichotomized WHO Bleeding Scale grades 0 vs 1,2,3,4) during Part 1 is summarized below: Subjects with any bleeding, n(%) 28 (96.6) 51 (81.0) Odds ratio any bleeding / % Confidence Interval a (0.02, 1.25) a. Generalized linear mixed model allowing for baseline dichotomized WHO Bleeding Scale grade, age cohort and treatment as fixed effects. The odds of significant bleeding (dichotomized WHO Bleeding Scale grades 0,1 vs 2,3,4) during Part 1 is summarized below: Subjects with significant bleeding, n(%) 12 (41.4) 21 (33.3) Odds ratio significant bleeding / % Confidence Interval a (0.28, 1.79) a. Generalized linear mixed model allowing for baseline dichotomized WHO Bleeding Scale grade, age cohort and 4

5 treatment as fixed effects. Time to WHO Grade 1 to 4 bleeding data during Randomized Period is summarized below: vs. Hazard Ratio % Confidence Interval (0.70, 1.00) Time to WHO Grade 2 to 4 bleeding data during Randomized Period is summarized below: vs. Hazard Ratio % Confidence Interval (0.76, 1.93) Part 2 (-Only Period) Proportion of subjects that achieved platelet counts 50 Gi/L at any time during -Only Period is summarized below: No. of Responders 70 Percentage of Responders 80.5 Total number of cumulative weeks in which subjects achieved platelet counts 50 Gi/L between weeks 4 to 24 of -Only Period is summarized below: Mean 10.0 SD th Percentile 1.0 Median th Percentile 17.0 Min. 0 Max. a 21 a Maximum potential number of weeks of platelet response was 21 weeks The maximum continuous duration (weeks) for which a subject continuously maintained a platelet count 50 Gi/L for Weeks 1 through 24 (-Only Period) is summarized below: Mean 8.6 SD th Percentile 1.0 Median th Percentile 15.0 Min. 0 Max. 24 Proportion of subjects that had sustained reduction or discontinuation of baseline concomitant ITP medications during -Only Period is summarized below: Subjects with baseline ITP medications, N 15 8 (53.3) Proportion of subjects that required protocol-defined rescue treatment during -Only Period is summarized below: 11 (12.6) PK data analysis was not available at the time of this report, but will be amended to this document when available. Safety Results: The period for collection of AEs and SAEs was from the first dose of study treatment until the 4-week follow-up visit. In addition, any SAEs assessed as related to study participation or treatment, were recorded from the time of subject consent up to and including the 24-week follow-up period. At any time after the 4-week follow-up visit the investigator could report any adverse event that they believed possibly related to study treatment. Post therapy AEs were defined as AEs that started more than 1 day after the last dose of study treatment and up to 30 days after 5

6 the last dose of study treatment were summarized by post-treatment eltrombopag use. All Adverse Events Started On-Therapy : All Cohorts (Randomized Period) Subjects with any AE(s) 21 (72.4) 51 (81.0) Nasopharyngitis 2 (6.9) 11 (17.5) Rhinitis 2 (6.9) 10 (15.9) Epistaxis 6 (20.7) 8 (12.7) Cough 0 7 (11.1) Upper respiratory tract infection 1 (3.4) 7 (11.1) Abdominal pain 0 6 (9.5) Headache 3 (10.3) 6 (9.5) AST increased 0 4 (6.3) Pyrexia 1 (3.4) 4 (6.3) Abdominal pain upper 4 (13.8) 3 (4.8) ALT increased 0 3 (4.8) Decreased appetite 0 3 (4.8) Diarrhea 0 3 (4.8) Oropharyngeal pain 0 3 (4.8) Rash 0 3 (4.8) Toothache 0 3 (4.8) Vitamin D deficiency 0 3 (4.8) Activated partial thromboplastin time prolonged 0 2 (3.2) Blood alkaline phosphatase increased 0 2 (3.2) Blood creatinine increased 1 (3.4) 2 (3.2) Bronchitis 0 2 (3.2) Contusion 0 2 (3.2) Gingival bleeding 1 (3.4) 2 (3.2) Influenza 0 2 (3.2) Mouth haemorrhage 0 2 (3.2) Nausea 0 2 (3.2) Rhinorrhoea 0 2 (3.2) Vomiting 3 (10.3) 2 (3.2) ALT abnormal 0 1 (1.6) Allergy to chemicals 0 1 (1.6) Anemia 0 1 (1.6) AST abnormal 0 1 (1.6) Asthenia 0 1 (1.6) Back pain 0 1 (1.6) Bronchospasm 0 1 (1.6) Bulimia nervosa 0 1 (1.6) Cellulitis 0 1 (1.6) Constipation 0 1 (1.6) Dermatitis allergic 0 1 (1.6) Dyspepsia 0 1 (1.6) Ear pain 1 (3.4) 1 (1.6) Excoriation 0 1 (1.6) Furuncle 0 1 (1.6) Gastritis 1 (3.4) 1 (1.6) Gingivitis 1 (3.4) 1 (1.6) Groin pain 0 1 (1.6) Impetigo 1 (3.4) 1 (1.6) Influenza like illness 1 (3.4) 1 (1.6) Joint injury 0 1 (1.6) 6

7 Lice infestation 0 1 (1.6) Lip haemorrhage 0 1 (1.6) Meningitis aseptic 0 1 (1.6) Menorrhagia 1 (3.4) 1 (1.6) Motion sickness 0 1 (1.6) Non-cardiac chest pain 0 1 (1.6) Osteoporosis 0 1 (1.6) Pain 0 1 (1.6) Paresthesia 0 1 (1.6) Pharyngitis 0 1 (1.6) Platelet count increased 0 1 (1.6) Pneumonia 0 1 (1.6) Pneumonia fungal 0 1 (1.6) Rash pruritic 0 1 (1.6) Retinal vascular disorder 0 1 (1.6) Soft tissue injury 0 1 (1.6) Somnolence 0 1 (1.6) Subcutaneous abscess 0 1 (1.6) Tongue haemorrhage 1 (3.4) 1 (1.6) Tonsillar hypertrophy 0 1 (1.6) Viral pharyngitis 0 1 (1.6) Blood albumin increased 1 (3.4) 0 Ecchymosis 1 (3.4) 0 Eczema 1 (3.4) 0 Gastroenteritis viral 1 (3.4) 0 Haemorrhage 1 (3.4) 0 Helminthic infection 1 (3.4) 0 Hypertensive crisis 1 (3.4) 0 Ingrowing nail 1 (3.4) 0 Leukocytosis 1 (3.4) 0 Limb injury 1 (3.4) 0 Lymphadenitis 1 (3.4) 0 Nasal congestion 1 (3.4) 0 Otosalpingitis 1 (3.4) 0 Papule 1 (3.4) 0 Pericoronitis 1 (3.4) 0 Petechiae 1 (3.4) 0 Respiratory tract infection viral 1 (3.4) 0 Tongue biting 1 (3.4) 0 Urethral haemorrhage 1 (3.4) 0 Wound infection 1 (3.4) 0 Most Common Adverse Events Started On-Therapy (-Only Period) n(%) 7

8 Any event 69 (79.3) Epistaxis 12 (13.8) Upper respiratory tract infection 10 (11.5) Pyrexia 9 (10.3) Cough 8 (9.2) Headache 8 (9.2) Abdominal pain 7 (8.0) AST increased 7 (8.0) Nasopharyngitis 7 (8.0) Pharyngitis 7 (8.0) ALT increased 6 (6.9) Respiratory tract infection 6 (6.9) Vomiting 6 (6.9) Serious Adverse Events: Subjects with non-fatal SAEs (Randomized Period), N (Safety) Subjects with any SAEs 4 (13.8) 5 (7.9) ALT abnormal 0 1 (1.6) AST abnormal 0 1 (1.6) Gingivitis 0 1 (1.6) Influenza 0 1 (1.6) Meningitis aseptic 0 1 (1.6) Pneumonia 0 1 (1.6) Pneumonia fungal 0 1 (1.6) Epistaxis 1 (3.4) 0 Haemorrhage 1 (3.4) 0 Hypertensive crisis 1 (3.4) 0 Petechiae 1 (3.4) 0 Subjects with non-fatal SAEs (Etrombopag-Only Period), Any event 9 (10.3) Epistaxis 2 (2.3) Dengue fever 1 (1.1) Hematoma 1 (1.1) Hematoma infection 1 (1.1) Hemolytic anemia 1 (1.1) Pleural effusion 1 (1.1) Pneumonia 1 (1.1) Rhinitis 1 (1.1) Rhinitis allergic 1 (1.1) Thrombocytopenia 1 (1.1) Upper respiratory tract infection 1 (1.1) Subjects with non-fatal SAEs Post-therapy Randomized Period), (N=1) N=4 Any event 0 1 (25%) Subjects with non-fatal SAEs Post-therapy (-Only Period), N=87 Any event 2 (2.3%) Subjects with non-fatal SAEs Considered to be Related (Randomized Period), Any event 0 1 (1.6) ALT abnormal 0 1 (1.6) AST abnormal 0 1 (1.6) Subjects with non-fatal SAEs Considered to be Related (-Only Period), Any event 1 (1.6) 8

9 Hemolytic anemia 1 (1.6) Subjects with non-fatal SAEs Considered to be Related (Post- Therapy), Any event 0 Subjects with fatal SAEs (Randomized Period), 0 0 Subjects with fatal SAEs (-Only Period), n/a 0 Subjects with fatal SAEs (Post-Therapy)), 0 0 Conclusion: The PETIT2/TRA study demonstrated that treatment with eltrombopag when compared with placebo, resulted in a statistically significant improvements in sustained platelet response in the absence of ITP rescue medication, with 39.7% in the eltrombopag group compared with 3.4% in the placebo group achieving platelet counts 50 Gi/L for 6 of 8 weeks (between Weeks 5 to 12) of the 12-week Randomized Period (p <0.001). During the Randomized Period, the overall incidence of on-therapy AEs was 81.0% in eltrombopag subjects and 72.4% in placebo subjects. The most common AEs ( 10%) in eltrombopag subjects that occurred at a higher incidence compared with placebo subjects were nasopharyngitis, rhinitis, cough, and upper respiratory tract infection. The most common AEs ( 10%) in placebo subjects that occurred at a higher incidence compared with eltrombopag subjects were epistaxis, abdominal pain upper, headache, and vomiting. No deaths occurred at any time during the study. During the Randomized Period, the overall incidence of SAEs was 7.9% in eltrombopag subjects and 13.8% in placebo subjects. 9