Table 3.
Protocol endpoints and statistical analysis plans
| Outcome (endpoint) statistical plan | |
| Efficacy | |
| 1. Platelet response, defined as ≥3 of 4 non-consecutive weeks with platelets >50×109/L during weeks 6–12 of therapy | Group sequential analyses, with three ‘looks’ at the data: two interim analyses (for efficacy and futility), and a final analysis (for efficacy), using a two-sided z-test with alpha=0.05 (ie, a one-sided z-test with alpha=0.025), to compare the two arms in terms of the proportion of patients who have a platelet response |
| 2. Cumulative number of rescue therapies needed during the first 12 weeks of treatment | Student’s t-test will be used to compare the two treatment arms |
| 3. Platelet response during weeks 6–12 of therapy in patients who required a rescue treatment during weeks 1–2 of study | Observed proportion and 95% CI will be calculated |
| 4. No further need for treatment after 12 weeks and 6 months of study | χ2 test will be used to compare the two treatment arms |
| 5. Treatment response* at 1 year of study | χ2 test will be used to compare the two treatment arms |
| 6. No of second-line therapies used in weeks 13–52 | Student’s t-test will be used to compare the two treatment arms |
| Safety | |
| 7. Abnormal liver function tests† (LFTs) in patients with newly diagnosed ITP treated with eltrombopag. | Frequency and proportion (with 95% CI) of patients with abnormal LFTs will be calculated |
| 8. Incidence of adverse events and serious adverse events | Adverse events will be coded by MedDRA classification term. Adverse events and serious adverse events will be tabulated by treatment group, including the number of patients for whom the event occurred, the rate of occurrence and the severity and relationship to study drug. If a patient experiences the same toxicity multiple times, a patient will be counted only once for a given toxicity at the maximum grade. |
| 9. Iron indices‡ at 12 weeks, 6 months and 1 year | Two-sided Student’s t-test will be used to compare iron indices at 12 weeks, 6 months and 1 year between the two arms |
| Patient-related outcomes assessment | |
| 10. Proportion of patients with poor bleeding scores (WHO Bleeding Scale ≥2 or Modified Buchanan Score ≥3) at 1, 2, 3, 4, 12 weeks and 1 year | χ2 test will be used to compare the two treatment arms |
| 11. Change in health-related quality of life from (A) baseline to 1 week, (B) baseline to 4 weeks, (C) baseline to 12 weeks, and, (D) baseline to 1 year, as measured by the parent-proxy report of the Kids ITP tools (KIT) | KIT scores will be calculated per the methods described in Klaassen et al.29 Spaghetti plots will be used to visualise the KIT scores over time per patient by treatment arm. Two-sided Student’s t-test will be used to compare the percentage change from baseline in KIT overall score at 1 week, 4 weeks, 12 weeks and 1 year between the two arms. |
| 12. CF atigue at 1 week, 4 weeks, 12 weeks, and 1 year as measured by the parent-proxy report of the Hockenberry Fatigue Scale-Parent | Fatigue scores will be calculated per the methods described in Hockenberry et al.30 Spaghetti plots will be used to visualise the scores over time per patient by treatment arm. A two-sided Student’s t-test will be used to compare the percentage change from baseline at 1 week, 4 weeks, 12 weeks and 1 year between the two arms. |
| Biology | |
| 13. Change in percentage of CD4+25+Foxp3+ regulatory T cells as a proportion of CD4 cells (A) from baseline to 12 weeks; and (B) from baseline to 1 year | Student’s t-test will be used to compare the two treatment arms |
*Complete response (CR) is defined as a platelet count ≥150×109/L, primary remission at 1 year is defined as CR at 1 year with no second-line agents required and ≥3 months after discontinuing most recent platelet active medication, disease resolution at 1 year is defined as CR at 1 year ≥3 months after discontinuing most recent platelet active medication (patient may have received a second-line therapy, excluding rituximab or splenectomy), disease stability at 1 year is defined as platelets ≥50×109/L but <150×109/L ≥3 months after discontinuing most recent platelet active medication.
†Alanine transaminase (ALT) ≥3x upper limit of normal (ULN) in patients with normal baseline, ALT ≥3 x baseline or ≥5x ULN (whichever is lower) in patients with abnormal baseline, ALT ≥3 x ULN and bilirubin ≥1.5x ULN (>35% direct).
‡Iron, total iron binding capacity, transferrin saturation, ferritin, mean corpuscular volume and haemoglobin.
ITP, immune thrombocytopaenia; MedDRA, Medical Dictionary for Regulatory Activities.;