14 CLINICAL STUDIES

14.1 Patients with Chronic Liver Disease

The efficacy of DOPTELET for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was established in 2 identically-designed multicenter, randomized, double-blind, placebo-controlled trials (ADAPT-1 [NCT01972529] and ADAPT-2 [NCT01976104]). In each trial, patients were assigned to the Low Baseline Platelet Count Cohort (<40×109/L) or the High Baseline Platelet Count Cohort (≥40 to <50×109/L) based on their platelet count at baseline. Patients were then randomized in a 2:1 ratio to either DOPTELET or placebo. Patients were stratified according to hepatocellular cancer (HCC) status and risk of bleeding associated with the elective procedure (low, moderate, or high). Patients undergoing neurosurgical interventions, thoracotomy, laparotomy or organ resection were not eligible for enrollment.

Patients in the Low Baseline Platelet Count Cohort received 60 mg DOPTELET or matching placebo once daily for 5 days, and patients in the High Baseline Platelet Count Cohort received 40 mg DOPTELET or matching placebo once daily for 5 days. Eligible patients were scheduled to undergo their procedure (low, moderate, or high bleeding risk) 5 to 8 days after their last dose of treatment. Patient populations were similar between the pooled Low and High Baseline Platelet Count Cohorts and consisted of 66% male and 35% female; median age 58 years and 61% White, 34% Asian, and 3% Black.

In ADAPT-1, a total of 231 patients were randomized, 149 patients were treated with DOPTELET and 82 patients were treated with placebo. In the Low Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated group was 31.1×109/L and for the placebo-treated patients was 30.7×109/L. In the High Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated patients was 44.3×109/L and for placebo-treated patients was 44.9×109/L.

In ADAPT-2, a total of 204 patients were randomized, 128 patients were treated with DOPTELET and 76 patients were treated with placebo. In the Low Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated group was 32.7×109/L and for the placebo-treated patients was 32.5×109/L. In the High Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated patients was 44.3×109/L and for the placebo-treated patients was 44.5×109/L.

Across both baseline platelet count cohorts and the avatrombopag and placebo treatment groups, patients underwent a broad spectrum of types of scheduled procedures that ranged from low to high bleeding risk. Overall, the majority of patients (60.8% [248/430] subjects) in all treatment groups underwent low bleeding risk procedures, 17.2% (70/430) of patients underwent procedures associated with moderate bleeding risk, and 22.1% (90/430) of subjects underwent procedures associated with high bleeding risk. The proportions of patients undergoing low, moderate, and high-risk procedures were similar between the avatrombopag and placebo treatment groups.

The major efficacy outcome was the proportion of patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure. Additional secondary efficacy outcomes were the proportion of patients who achieved platelet counts of >50×109/L on the day of procedure, and the change in platelet count from baseline to procedure day.

Responders were defined as patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure. The following were considered rescue therapies to manage the risk of bleeding associated with a procedure: whole blood transfusion, packed red blood cell (RBC) transfusion, platelet transfusion, fresh frozen plasma (FFP) or cryoprecipitate administration, Vitamin K, desmopressin, recombinant activated factor VII, aminocaproic acid, tranexamic acid, or surgical or interventional radiology procedures performed to achieve hemostasis and control blood loss. In both baseline platelet count cohorts, patients in the DOPTELET treatment groups had a greater proportion of responders than the corresponding placebo treatment groups that was both clinically meaningful and statistically significant as detailed in Table 8.

Table 8: Proportion of Patients Not Requiring a Platelet Transfusion or Any Rescue Procedure for Bleeding by Baseline Platelet Count Cohort and Treatment Group – ADAPT-1 and ADAPT-2

Low Baseline Platelet Count Cohort (<40×109/L)
Category	ADAPT-1		ADAPT-2
	DOPTELET 60 mg (n=90)	Placebo (n=48)	DOPTELET 60 mg (n=70)	Placebo (n=43)
Responders 95% CI a	66% (56, 75)	23% (11, 35)	69% (58, 79)	35% (21, 49)
Difference of Proportion vs. Placebob 95% CI c	43% (27, 58)		34% (16, 52)
p-valued	˂0.0001		0.0006
High Baseline Platelet Count Cohort (≥40 to <50×109/L)
Category	ADAPT-1		ADAPT-2
	DOPTELET 40 mg (n=59)	Placebo (n= 34)	DOPTELET 40 mg (n=58)	Placebo (n=33)
Responders 95% CI a	88% (80, 96)	38% (22, 55)	88% (80, 96)	33% (17, 49)
Difference of Proportion vs. Placebob 95% CI c	50% (32, 68)		55% (37, 73)
p-valued	˂0.0001		˂0.0001

Two-sided 95% confidence interval based on normal approximation.
Difference of Proportion vs. placebo = Proportion of Responders for DOPTELET – Proportion of Responders for placebo.
95% confidence interval calculated based on normal approximation.
By Cohhran-Mantel-Haenszel Testing stratified by bleeding risk for the procedure.

In addition, both trials demonstrated a higher proportion of patients who achieved the target platelet count of ≥50×109/L on the day of procedure, a secondary efficacy endpoint, in both DOPTELET-treated groups versus the placebo-treated groups for both cohorts (Low Baseline Platelet Count Cohort – ADAPT-1: 69% vs 4%, respectively; p˂0.0001, ADAPT-2: 67% vs 7%, respectively; p <0.0001; High Baseline Platelet Count Cohort – ADAPT-1: 88% vs 21%, respectively; p <0.0001: ADAPT-2: 93% vs 39%, respectively; p <0.0001). Further, both trials demonstrated a greater mean change in platelet counts from baseline to the day of the procedure, a secondary efficacy endpoint, in both DOPTELET-treated groups versus the placebo-treated groups for both cohorts (Low Baseline Platelet Count Cohort – ADAPT-1: 32×109/L vs 0.8×109/L, respectively; p<0.0001; ADAPT-2: 31.3×109/L vs 3.0×109/L, respectively; p <0.0001; High Baseline Platelet Count Cohort – ADAPT-1: 37.1×109/L vs 1.0×109/L, respectively; p <0.0001; ADAPT-2: 44.9×109/L vs 5.9×109/L, respectively; p <0.0001).

A measured increase in platelet counts was observed in both DOPTELET treatment groups over time beginning on Day 4 post-dose, that peaked on Day 10-13, decreased 7 days post-procedure, and then returned to near baseline values by Day 35.

14.2 Patients with Chronic Immune Thrombocytopenia

Randomized Phase 3 Clinical Trial

The efficacy of DOPTELET in adult patients with chronic immune thrombocytopenia was evaluated in a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT01438840). Patients had previously received one or more prior chronic immune thrombocytopenia therapies and had an average of screening and baseline platelet counts <30×109/L. Patients were centrally stratified by splenectomy status, baseline platelet count (≤15×109/L or >15×109/L to <30×109/L), and use of concomitant chronic immune thrombocytopenia medication, and then randomized (2:1) to receive either DOPTELET or placebo for 6 months. Patients received a starting dose of 20 mg once daily, with doses subsequently titrated based on platelet response.

Forty-nine patients were randomized, 32 to DOPTELET and 17 to placebo, with similar mean [SD] baseline platelet counts in the 2 treatment groups (14.1 [8.6]×109/L and 12.7 [7.8]×109/L, respectively). The median age was 44 years, 63% were female, and 94% were Caucasian, 4% Asian and 2% Black. The median duration of exposure was 26 weeks for DOPTELET-treated patients and 6 weeks for placebo-treated patients. The major efficacy outcome in this trial was the cumulative number of weeks in which the platelet count was ≥50×109/L during the 6-month treatment period in the absence of rescue therapy. DOPTELET-treated patients had a longer duration of platelet counts ≥50×109/L in the absence of rescue therapy than those who received placebo (median 12.4 [0, 25] vs 0 [0, 2] weeks, respectively, p<0.0001) (see Table 9).

Table 9: Cumulative Number of Weeks of Platelet Response – Phase 3 Trial in Patients with Chronic Immune Thrombocytopenia

Primary Efficacy Analysis	DOPTELET (n=32)	Placebo (n=17)
Cumulative Number of Weeks with a Platelet Response*
Mean (SD)	12.0 (8.75)	0.1 (0.49)
Median	12.4	0.0
Min, Max	0, 25	0, 2
p-value of Wilcoxon rank sum test	<0.0001

Max=maximum, Min=minimum, SD=Standard deviation.

*Cumulative number of weeks of platelet response is defined as the total numbers of weeks in which the platelet count was ≥50×109/L during 6 months of treatment in the absence of rescue therapy.

In addition, a larger proportion of patients in the DOPTELET treatment group had platelet counts ≥50×109/L at Day 8 compared to placebo (21/32; 66% vs 0/17; 0.0%, respectively; p<0.0001).

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