Table 4.

Summary of large RCTs assessing various combination therapies for subsequent treatment lines for ITP

Combination arm	Monotherapy arm	Study design	Efficacy	Remarks
rhTPO (300 ug/kg sc for up to 14 days) + rituximab (100  mg weekly x4)30	Rituximab (100  mg weekly  ×  4)	Open-label RCT with 2:1 randomization (n  =  123)	Complete response was achieved 45% vs 24% (p  =  0.02) and overall response was achieved in 79% vs 71% (p  =  0.36) of patients in the combination monotherapy groups, with the combination having significantly shorter median response time (7 vs 28 days; p < 0.01)	There was no difference in the duration of response between the two groups; side effects were generally mild
ATRA (20  mg/m2 for 12 weeks) + low dose rituximab (100  mg weekly for 6 weeks)31	Rituximab (100  mg weekly for 6 weeks)	Open-label RCT with 2:1 randomization (N  =  168)	Overall response was achieved in 80% vs 59% (between-group difference, 0.22; 95% CI, 0.07-0.36), and sustained response was achieved in 61% vs 41% (between-group difference, 0.20; 95% CI, 0.04-0.35) in combination vs monotherapy groups	Most common adverse events for the combination group were dry skin and headache/dizziness
ATRA (10  mg  ×  2/day) + danazol (200  mg  ×  2/day) for 16 weeks32	Danazol (200  mg   ×   2/day) for 16 weeks	Phase 2 open-label RCT; 1:1 randomization (N  =  96)	Sustained response at 12 months was achieved in 62% of patients receiving ATRA plus danazol vs 25% in patients receiving danazol monotherapy (OR 4.94, p  =  0.00037)	Skin desquamation was reported in 62% of patients in the combination arm
rhTPO (100 ug/kg sc for up to 14 days) + danazol (200  mg   ×   3 daily)33	Danazol (200  mg   ×   3 daily)	2 phase (14 days each), open-label RCT with 1:1 randomization (N  =  140)	Total response rate in the combination group was 60% vs 36%, p  =  0.01	Well-tolerated treatments with mild side effects