TAVALISSE was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (NCT 02077192).

Randomized, Placebo-Controlled Studies

A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous treatment (which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonists) were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries. For each study, patients were randomized 2:1 to TAVALISSE or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent ITP therapy (glucocorticoids [< 20 mg prednisone equivalent per day], azathioprine, or danazol) was allowed, and rescue therapy was permitted, if needed. All patients initially received study drug at 100 mg twice daily (or matching placebo). Based on platelet count and tolerability, dose escalation to 150 mg twice daily (or matching placebo) was undertaken in 88% of patients at Week 4 or later. Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3).

Patients enrolled in the placebo-controlled studies had a median age of 54 years (range: 20 to 88), and the majority were female (61%) and were White (93%). Prior ITP treatments were varied, with the most common including corticosteroids (94%), immunoglobulins (53%), and thrombopoietin receptor agonists (TPO-RA) (48%). Most patients had chronic ITP (93%), with a median time since ITP diagnosis of 8.45 years, and 35% had undergone splenectomy. At baseline, the median platelet count was 16 × 109/L (with almost half [45]%) less than 15 × 109/L) and 47% were on stable ITP therapy.

In Study FIT-1, 76 patients were randomized; 51 to the TAVALISSE group and 25 to the placebo group. In Study FIT-2, 74 patients were randomized; 50 to the TAVALISSE group and 24 to the placebo group. The efficacy of TAVALISSE was based on stable platelet response (at least 50 ×109/L on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for FIT-1 and FIT-2 are shown in Table 5. 

In the FIT-1 and FIT-2 studies a total of 47 patients in the TAVALISSE arm had received a prior TPO-RA treatment; among these patients, 8 patients (17%) achieved a stable response to TAVALISSE. All 8 patients had previously discontinued TPO-RA due to loss of effect. Rescue medication was required by 30% and 45% of patients receiving TAVALISSE or placebo, respectively.

During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients in the TAVALISSE and placebo arms, respectively. Moderate, severe and serious bleeding events are described in Table 6. All severe events led to hospitalizations. 

Extension Study

The FIT-3 trial is an open label extension study. Patients from FIT-1 and FIT-2 who completed 24 weeks of treatment, or who did not respond to treatment any time after 12 weeks, were eligible to enroll in this study. Patients remained blinded to their treatment assignment from the previous study (TAVALISSE or placebo), so their starting dose in this study was based on their final platelet count. Patients designated as responders (defined as achievement of platelet count of at least 50 × 109/L) at the time of roll over continued in the extension study at their current trial dose and regimen. Patients who entered the extension study as non-responders (defined as platelet count less than 50 × 109/L) received TAVALISSE 100 mg twice daily regardless of their dose and regimen in the prior study.

For the FIT-3 trial, 123 patients were enrolled, 44 patients previously randomized to placebo and 79 patients previously randomized to TAVALISSE. Stable response in this study was prospectively defined as no 2 visits, at least 4 weeks apart, with a platelet count less than 50 × 109/L, without an intervening visit with a platelet count of at least 50 × 109/L (unrelated to rescue therapy), within a period of 12 weeks following initial achievement of the target platelet count. Sixty-one of the 123 subjects (50%) have discontinued from the study early.

In a prospectively defined analysis, the 44 subjects treated with placebo in the prior study were evaluated for stable response for TAVALISSE. Ten of these subjects (23%) (including a single subject who was classified as a placebo responder in the prior study) met the criteria for stable response.

Among the subjects who achieved stable response in FIT-1, FIT-2 and FIT-3 trials, 18 subjects maintained the platelet count of at least 50 × 109/L for 12 months or longer.