Gastroenterology 2018;155:705–718 CLINICAL—LIVER Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia Norah Terrault,1 Yi-Cheng Chen,2 Namiki Izumi,3 Zeid Kayali,4 Paul Mitrut,5 Won Young Tak,6 Lee F. Allen,7 and Tarek Hassanein8

1University of California San Francisco, San Francisco, California; 2Chang Gung Memorial Hospital and University, Taoyuan, Taiwan; 3Musashino Red Cross Hospital, Tokyo, Japan; 4Inland Empire Liver Foundation, Rialto, California; 5University of Medicine and Pharmacy of Craiova, Craiova, Romania; 6Kyungpool National University, Daegu, Korea; 7Dova Pharmaceuticals, Durham, North Carolina; and 8Southern California GI and Liver Centers, Coronado, California CLINICAL LIVER

BACKGROUND & AIMS: Patients with thrombocytopenia and endpoint compared with 22.9% and 38.2% of patients chronic liver disease (CLD) may require platelet transfusions receiving placebo, respectively (P < .0001 for both). In the before scheduled procedures to decrease risk of . We ADAPT-2 study, 68.6% of patients who received 60 mg ava- performed 2 randomized, placebo-controlled, phase 3 trials in trombopag and 87.9% of patients who received 40 mg ava- patients with thrombocytopenia and CLD undergoing sched- trombopag met the primary endpoint compared with 34.9% uled procedures to evaluate the safety and efficacy of ava- and 33.3% of patients who received placebo, respectively (P < trombopag in increasing platelet counts in this patient .001 for both). Avatrombopag led to a measured increase in population. METHODS: In the ADAPT-1 and ADAPT-2 studies, platelet counts and increased the proportion of patients who adults with thrombocytopenia and CLD (n ¼ 231 and n ¼ 204, achieved the target platelet count 50 109/L on procedure respectively) were in 1 of 2 cohorts according to their baseline day vs placebo. The incidence and severity of adverse events platelet count (below 40 109/L or 40 to below 50 109/L) were similar for the avatrombopag and placebo groups and and within each cohort were randomized (2:1) to receive 5 were consistent with those expected in the CLD population. daily doses of avatrombopag (60 mg if baseline platelet count CONCLUSIONS: In2phase3randomizedtrials,avatrombopag below 40 109/L or 40 mg if 40 to below 50 109/L) or was superior to placebo in reducing the need for platelet placebo. ADAPT-1 was conducted at 75 study sites in 20 transfusions or rescue procedures for bleeding in patients countries, from February 2014 through January 2017, and with thrombocytopenia and CLD undergoing a scheduled ADAPT-2 was conducted at 74 sites in 16 countries, from procedure. ClinicalTrials.gov nos.: NCT01972529 and December 2013 through January 2017. The primary endpoint NCT01976104. was the proportion of patients not requiring platelet trans- fusions or rescue procedures for bleeding up to 7 days after a scheduled procedure. RESULTS: In the ADAPT-1 study, 65.6% Keywords: Cirrhosis; ; Thrombopoietin Receptor of patients who received 60 mg avatrombopag and 88.1% of Agonist; Thrombosis. patients who received 40 mg avatrombopag met the primary 706 Terrault et al Gastroenterology Vol. 155, No. 3

Avatrombopag (previously known as E5501, YM477, and WHAT YOU NEED TO KNOW AKR501) is a novel, oral, small-molecule thrombopoietin BACKGROUND AND CONTEXT receptor agonist being developed to provide a predictable The efficacy of platelet transfusions to reduce bleeding increase in platelet counts as an alternative to platelet 30,31 risks in patients with thrombocytopenia and liver transfusions. Two identically designed, randomized, disease undergoing a scheduled procedure is variable placebo-controlled, phase 3 trials were conducted in pa- and may be associated with potentially fatal tients with thrombocytopenia and CLD undergoing sched- complications. uled procedures to evaluate the safety and efficacy of NEW FINDINGS avatrombopag in increasing platelet counts in this patient population (ADAPT-1 and ADAPT-2). Avatrombopag, a thrombopoietin receptor agonist, was well tolerated and superior to placebo in increasing The primary endpoint of these studies was the propor- platelet counts with significantly less patients requiring a tion of patients who did not require a platelet transfusion or platelet transfusion or rescue procedure for bleeding. rescue procedure for bleeding after randomization and up to 7 days after a scheduled procedure. LIMITATIONS

LNCLLIVER CLINICAL The inability to demonstrate a difference in bleeding rates between treatment groups and the relatively small number Materials and Methods of patients in the subgroup analyses may be limitations of these studies. Study Design IMPACT ADAPT-1 and ADAPT-2 were identically designed, global, multicenter, randomized, double-blind, placebo-controlled Avatrombopag may be an alternative therapy to platelet phase 3 studies that assessed the efficacy and safety of ava- transfusions for patients with thrombocytopenia and trombopag in adults with thrombocytopenia and CLD under- liver disease undergoing scheduled procedures as a A means to minimize bleeding and improve clinical going a scheduled procedure (Figure 1 ). ADAPT-1 was management. conducted at 75 study sites across 20 countries between February 2014 and January 2017; ADAPT-2 was conducted at 74 sites in 16 countries from December 2013 through January hrombocytopenia is common in patients with 2017. Study sites were located in Argentina, Australia, Austria, T chronic liver disease (CLD), affecting up to 84% of Belgium, Brazil, Canada, Chile, China, Czech Republic, France, – patients1 6 and worsens with the degree of cirrhosis.7,8 Germany, Hungary, Israel, Italy, Japan, Mexico, Republic of Ko- Severe thrombocytopenia is associated with poor clinical rea, Romania, Russia, Poland, Portugal, Spain, Taiwan, Thailand, outcomes,5,9 including both an increased risk of the United Kingdom, and the United States. Studies were con- bleeding8,10,11 and mortality.5,9 For patients with CLD and ducted under the World Medical Association Declaration of severe thrombocytopenia (platelet count < 50 109/L) Helsinki and Good Clinical Practice guidelines, protocols were undergoing scheduled procedures, platelet transfusions are approved by local institutional review boards or independent administered prophylactically to mitigate the risk of ethics committees, and written informed consent was obtained bleeding.2,12 The risk of bleeding during or after invasive from all patients before screening. Both trials were registered procedures in patients with CLD varies with the patient’s at Clinicaltrials.gov (NCT01972529, NCT01976104). platelet count, status, and type of procedure, although there is no universal consensus regarding the use Patient Population of prophylactic platelet transfusions. An increased risk of Eligible patients were adults (18 years of age) with CLD bleeding with invasive procedures in these patients has (Model for End-Stage Liver Disease [MELD] score 24) and 3,4,8 been reported, and some clinical guidelines recommend thrombocytopenia with a mean baseline platelet count of 13–18 prophylactic platelet transfusions. < 50 109/L. Platelet counts were measured during the Once the decision has been made to use platelets, it is screening period and at baseline at least 1 day apart, and the important to appreciate that the efficacy of platelet trans- mean value used to determine eligibility and assignment to fusions in increasing platelet counts is variable19,20 and may either the low (<40 109/L) or high (40 to <50 109/L) be associated with serious complications, including trans- baseline platelet count cohort; neither platelet count was fusion reactions; the transmission of infectious agents, permitted to be > 60 109/L. Per the study inclusion criteria, which can be fatal in rare cases; and the development of all patients were scheduled to undergo a procedure with an refractoriness to subsequent platelet transfusion.12,21–23 associated risk of bleeding that would require a platelet Although 2 thrombopoietin-receptor agonists,

and , are approved to increase platelet counts in Abbreviations used in this paper: 24–28 AE, adverse event; AESI, adverse event adults with chronic immune thrombocytopenia, no of special interest; CLD, chronic liver disease; MELD, Model for End-Stage product is approved for the treatment of thrombocytopenia Liver Disease; TEAE, treatment-emergent adverse event. associated with CLD in patients undergoing scheduled Most current article procedures. Eltrombopag was studied in this patient popu- © 2018 by the AGA Institute. Published by Elsevier Inc. This is an open lation, but the trial was terminated early because of safety access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). concerns, that is, an increased incidence of thromboembolic 0016-5085 29 events with eltrombopag. https://doi.org/10.1053/j.gastro.2018.05.025 September 2018 Avatrombopag Before Procedures in CLD 707 CLINICAL LIVER

Figure 1. Overview of the phase 3 studies ADAPT-1 and ADAPT-2 (A) Study design. aVisit 3 occurred on day 4 (±1 day) during the treatment period. (B) Patient disposition. PLT, platelet count; R, ratio. transfusion, unless there was a clinically significant increase in dental procedures, renal biopsy, biliary interventions, neph- platelet counts from baseline. Permitted procedures were rostomy tube placement, radiofrequency ablation, laparoscopic classified by the associated bleeding risk based on the pub- interventions).32 lished literature and investigator input into 3 categories: low Key exclusion criteria included a history of thrombosis; risk (paracentesis, thoracentesis, gastrointestinal endoscopy), hematologic disorders; significant cardiovascular disease; por- moderate risk (liver biopsy, bronchoscopy, ethanol ablation tal or splenic mesenteric system thrombosis at screening; therapy, chemoembolization), and high risk (vascular cathe- portal vein blood flow < 10 cm/s at screening; platelet trans- terization, transjugular intrahepatic portosystemic shunt, fusion or receipt of blood products containing platelets within 7 708 Terrault et al Gastroenterology Vol. 155, No. 3

days of screening; use of heparin, warfarin, nonsteroidal Platelet count and change from baseline in platelet count at anti-inflammatory drugs, aspirin, verapamil, or antiplatelet each visit were assessed as exploratory outcome measures. therapy with ticlopidine or glycoprotein IIb/IIIa antagonists, or Efficacy assessments included platelet counts at screening, erythropoietin-stimulating agents within 7 days of screening; baseline, procedure day, 7 days after procedure, and on day 35 and previous use of avatrombopag. In addition, to minimize during the follow-up phase and the use of platelet transfusions confounding of the study results, patients were excluded from or any rescue procedure for bleeding (platelet, whole blood, or the study if they had advanced hepatocellular carcinoma packed red cell transfusions; plasma; cryoprecipitate; vitamin (Barcelona Clinic liver cancer staging classification C or D), K; desmopressin; recombinant activated factor VII; amino- because these patients had a higher risk of developing throm- caproic acid; tranexamic acid; surgical intervention; or inter- boembolic events. ventional radiology). All adverse events (AEs) were recorded, regardless of relationship to study drug or procedure, and fi Randomization included prede ned adverse events of special interest (AESI). After trial commencement, amendments were made to the A computer-generated randomization schedule was study protocol for both ADAPT-1 and ADAPT-2, as follows: (1) administered by an interactive voice and Web response system addition of eltrombopag and romiplostim as prohibited medi- using permuted-block randomization. The randomization

LNCLLIVER CLINICAL cations if used off-label; (2) updates to the bleeding risk scheme and identification for each patient were kept strictly categories and revision of the exclusion criteria, based on confidential before database lock and final unblinding. A pa- feedback received from the investigators; (3) and the addition tient’s treatment could be unblinded only when knowledge of of tranexamic acid as a rescue procedure for bleeding. the treatment was essential for further management of the patient. A patient whose treatment was unblinded did not receive any further study medication. Determination of Sample Size Originally, 150 patients were to be enrolled in each of the 2 Procedures baseline platelet count cohorts based on an expected placebo response rate of 18%.29 The treatment difference was assumed Patient eligibility was assessed during the pre- 33 randomization phase (days –14 to –1). Patients meeting entry to be similar to that in a phase 2 avatrombopag study. As > criteria were enrolled into 1 of 2 cohorts according to their mean originally sized, each study had 99% power for the assessment fi baseline platelet count. Within each cohort, patients were further of ef cacy. Because of the lower-than-expected incidence of AESI, stratified by the procedure bleeding risk (low, moderate, or high) the total sample size was reduced. The reduced sample size of and presence of hepatocellular carcinoma (yes or no). Patients in 100 patients per baseline platelet count cohort (approximately > the low baseline platelet count cohort were randomized 2:1 to 67 avatrombopag and 33 placebo) retained 90% power to receive 60 mg avatrombopag (3 20-mg tablets) or placebo (3 detect an absolute difference of 35% between the avatrombopag matching-placebo tablets) once daily with a meal on days 1–5. response rate and the projected 18% placebo response rate us- a Patients in the high baseline platelet count cohort were ran- ing Fisher exact tests with a 2-sided of .05 domized 2:1 to receive 40 mg avatrombopag (2 20-mg tablets) or placebo (2 matching-placebo tablets) once daily with a meal on Statistical Analysis fi days 1 through 5. To maintain the double-blind con guration, The full analysis set included all randomized patients and avatrombopag and matching placebo were supplied by the was used for all efficacy analyses; the safety analysis set con- fi sponsor in containers labeled speci cally for this study in a sisted of patients who received at least 1 dose of study drug blinded manner. Avatrombopag doses were selected based on and had at least 1 post-dose safety assessment. No interim ef- pharmacokinetic/pharmacodynamic modeling and simulations ficacy analysis was planned or conducted and, therefore, no 33 fi of phase 2 study data. Doses were selected to achieve suf cient adjustment of the P value for the final efficacy analysis was fi > ef cacy while limiting patients achieving platelet counts 200 needed. All authors had access to the study data and reviewed 9 – – 10 /L. Procedure days (days 10 13) were scheduled 5 8 days and approved the final manuscript. after the last dose of study drug but could be delayed if pre- procedural platelet counts were 200 109/L. Results Study Endpoints Patients The primary endpoint for both studies was the proportion ADAPT-1 screened 370 patients, of whom 231 met of patients who did not require a platelet transfusion or rescue eligibility criteria and were randomized. A total of 149 pa- procedure for bleeding after randomization and up to 7 days after a scheduled procedure. The primary efficacy analysis was tients were randomized to avatrombopag and 82 to placebo also assessed for each of the following subgroups: age, sex, race, in the 2 baseline platelet count cohorts; 12/370 (3.2%) fl region, bleeding risk, MELD score, Child-Turcotte-Pugh class, subjects were excluded for low portal vein ow. In ADAPT- and disease etiology. Secondary efficacy endpoints were also 2, 346 patients were screened and 204 randomized: 128 to the same in the 2 studies and included: (1) the proportion of avatrombopag and 76 to placebo (Figure 1B); 14/346 patients achieving the target platelet count of 50 109/L on (4.0%) subjects were excluded for low portal vein blood procedure day and (2) the change in platelet count from flow. Patient demographics and disease characteristics were baseline to procedure day. The secondary endpoints were to be balanced between treatment groups in both ADAPT-1 and analyzed only if the primary efficacy endpoint was statistically ADAPT-2, with 94% of patients completing each study significant for both baseline platelet cohorts in each study. (Table 1). The categories of procedure bleeding risk for the etme 08Aarmoa eoePoeue nCD709 CLD in Procedures Before Avatrombopag 2018 September

Table 1.Patient Demographics and Disease Characteristics

ADAPT-1 ADAPT-2

<40 109/L 40 to <50 109/L <40 109/L 40 to <50 109/L

Avatrombopag Placebo Avatrombopag Placebo Avatrombopag Placebo Avatrombopag Characteristic Placebo (n ¼ 48) 60 mg (n ¼ 90) (n ¼ 34) 40 mg (n ¼ 59) (n ¼ 43) 60 mg (n ¼ 70) (n ¼ 33) 40 mg (n ¼ 58)

Mean age, y (±SD) 55.1 (±11.0) 55.6 (±9.1) 57.8 (±11.1) 57.5 (±10.1) 57.3 (±12.0) 58.6 (±14.2) 59.2 (±10.3) 57.9 (±11.1) Age > 65 years, % 14.6 14.4 29.4 25.4 30.2 35.7 30.3 25.9 Median age, y (min, max) 55 (25, 76) 57 (29, 78) 59 (30, 76) 58 (19, 77) 58 (27, 77) 62 (20, 86) 60 (39, 81) 59 (29, 77) Male, % 66.7 72.2 70.6 62.7 62.8 71.4 51.5 56.9 Weight, kg,mean(±SD) 78 (±23) 80 (±19) 79 (±25) 78 (±17) 80 (±21) 77 (±22) 74 (±22) 78 (±17) Mean baseline platelet count (±SD) 31 (±7) 31 (±7) 45 (±3) 44 (±3) 33 (±6) 33 (±5) 45 (±3) 44 (±4) Median baseline platelet count (min, max) 32 (12, 45) 33 (10, 40) 44 (41, 51) 44 (40, 50) 34 (12, 40) 34 (18, 40) 45 (36, 49) 44 (37, 50) Disease etiology, n (%) Alcoholic liver disease 7 (14.6) 13 (14.6) 2 (5.9) 11 (19.3) 7 (16.3) 12 (17.1) 5 (15.2) 6 (10.3) Chronic viral hepatitis 30 (62.5) 50 (56.2) 27 (79.4) 36 (63.2) 26 (60.5) 34 (48.6) 18 (54.5) 29 (50.0) Nonalcoholic steatohepatitis 4 (8.3) 6 (6.7) 0 4 (7.0) 5 (11.6) 10 (14.3) 5 (15.2) 6 (10.3) Other 7 (14.6) 20 (22.5) 5 (14.7) 6 (10.5) 5 (11.6) 14 (20.0) 5 (15.2) 17 (29.3) Hepatocellular carcinoma, n (%) 11 (22.9) 21 (23.6) 7 (20.6) 17 (9.3) 14 (32.6) 21 (30.0) 11 (33.3) 15 (25.9) MELD score, mean (±SD) 11 (±3) 11 (±3) 10 (±3) 12 (±4) 11 (±3) 11 (±3) 11 (±4) 11 (±4) MELD score, median (min, max) 11 (6, 20) 10 (6, 22) 10 (7, 18) 11 (6, 21) 11 (6, 19) 11 (6, 19) 10 (6, 19) 10 (4, 23) Child-Turcotte-Pugh class, n (%) Class A 30 (62.5) 49 (55.1) 20 (60.6) 31 (53.4) 21 (48.8) 44 (63.8) 16 (48.5) 32 (55.2) Class B 17 (35.4) 38 (42.7) 12 (36.4) 22 (37.9) 21 (48.8) 20 (29.0) 12 (36.4) 22 (37.9) Class C 1 (2.1) 2 (2.2) 1 (3.0) 5 (8.6) 1 (2.3) 5 (7.2) 5 (15.2) 4 (6.9) Level of bleeding risk of scheduled procedure, n (%)a Low 27 (67.5) 56 (66.7) 21 (65.6) 33 (58.9) 21 (52.5) 40 (59.7) 17 (53.1) 33 (57.9) Moderate 8 (20.0) 10 (11.9) 3 (9.4) 11 (19.6) 9 (22.5) 11 (16.4) 9 (28.1) 9 (15.8) High 5 (12.5) 18 (21.4) 8 (25.0) 12 (21.4) 10 (25.0) 16 (23.9) 6 (18.8) 15 (26.3)

NOTE. Percentages were based on the total number of patients with nonmissing values in relevant treatment group. max, maximum; MELD, Model for End-Stage Liver Disease; min, minimum; SD, standard deviation. aProportion of patients undergoing a scheduled procedure associated with a low, moderate, or high bleeding risk.

CLINICAL LIVER 710 Terrault et al Gastroenterology Vol. 155, No. 3

scheduled procedures was also balanced between treatment and high (70.5% [43/61] vs 20.7% [6/29], respectively) groups with most patients (60.8%) undergoing low bleeding bleeding risk procedure categories. The proportion of pa- risk procedures as predefined in the study protocol tients not requiring a platelet transfusion or rescue pro- (Table 2). cedure for bleeding was also consistently higher in the avatrombopag-treated patients across subgroups in both ADAPT-1 and ADAPT-2 compared with placebo regardless Efficacy of age, sex, race, region, MELD score category, Child- Primary Efficacy Endpoint. In both studies, the 2 Turcotte-Pugh class, or disease etiology. avatrombopag dose groups were shown to be superior to Secondary Efficacy Endpoints. In the low baseline placebo in increasing the proportion of patients who did platelet count cohort in ADAPT-1, 68.9% (62/90) of not require a platelet transfusion or rescue procedure for avatrombopag-treated patients achieved the target platelet bleeding. In ADAPT-1, 65.6% (59/90) of avatrombopag- count of 50 109/L on procedure day vs only 4.2% treated patients compared with 22.9% (11/48) of (2/48) of placebo-treated patients (P < .0001); in ADAPT-2, placebo-treated patients in the low baseline platelet count it was 67.1% [47/70] vs 7.0% [3/43] (P < .0001) cohort did not require a platelet transfusion or rescue (Figure 2B). In the high baseline platelet count cohort in LNCLLIVER CLINICAL procedure for bleeding (P < .0001; Figure 2A). Similarly, in ADAPT-1, 88.1% (52/59) of avatrombopag-treated patients the ADAPT-2 low baseline platelet count cohort, 68.6% achieved platelet counts 50 109/L on procedure day (48/70) of avatrombopag-treated patients and 34.9% compared with 20.6% (7/34) of placebo-treated patients (15/43) of placebo-treated patients did not require a (P < .0001); in ADAPT-2, this was 93.1% [54/58]) vs 39.4% platelet transfusion or rescue procedure (P ¼ .0006). In the (13/33), respectively (P < .0001). high baseline platelet count cohort in both studies, a The mean change in platelet count from baseline to significantly higher proportion of patients treated with procedure day in the low baseline platelet count cohort avatrombopag compared with placebo achieved the pri- was significantly greater for avatrombopag-treated mary endpoint (ADAPT-1: 88.1% [52/59] vs 38.2% compared with placebo-treated patients in both ADAPT-1 [13/34], respectively [P < .0001]; ADAPT-2: 87.9% (32.0 109/L vs 0.8 109/L, respectively; P < .0001) [51/58] vs 33.3% [11/33], respectively [P < .0001]). and ADAPT-2 (31.3 109/L vs 3.0 109/L, respectively; Subgroup analyses of the ADAPT-1 and ADAPT-2 data by P < .0001) (Figure 2C). Similarly, in the high baseline procedure bleeding risk category showed the consistency platelet count cohort, a greater mean change in platelet of the avatrombopag treatment effect vs placebo across the count from baseline to procedure day was seen in both low (84.0% [136/162] vs 40.7% [35/86], respectively), studies among patients treated with avatrombopag moderate (75.6% [31/41] vs 31.0% [9/29], respectively), compared with placebo (ADAPT-1: 37.1 109/L vs 1.0

Table 2.Summary of Procedures Performed in ADAPT-1 and ADAPT-2 Pooled Study Data

Placebo (N ¼ 158) Avatrombopag (N ¼ 277) Total (N ¼ 435) Procedure n(%a) n(%a) n(%a)

Subjects with nonmissing values 144 (100) 264 (100) 408 (100) Low bleeding risk 86 (59.7) 162 (61.4) 248 (60.8) Paracentesis 2 (1.4) 3 (1.1) 5 (1.2) Endoscopy 75 (52.1) 137 (51.9) 212 (52.0) Upper GI endoscopy without biopsy 30 (20.8) 46 (17.4) 76 (18.6) Upper GI endoscopy with biopsy, 45 (31.3) 91 (34.5) 136 (33.3) variceal banding, or sclerotherapy Colonoscopy 9 (6.3) 22 (8.3) 31 (7.6) Colonoscopy with polypectomy/biopsy 8 (5.6) 10 (3.8) 18 (4.4) Colonoscopy without polypectomy/biopsy 1 (0.7) 12 (4.5) 13 (3.2) Moderate bleeding risk 29 (20.1) 41 (15.5) 70 (17.2) Liver biopsy 6 (4.2) 10 (3.8) 16 (3.9) Ethanol ablation 0 2 (0.8) 2 (0.5) Chemoembolization for HCC 23 (16.0) 29 (11.0) 52 (12.7) High bleeding risk 29 (20.1) 61 (23.1) 90 (22.1) Dental procedures 13 (9.0) 26 (9.8) 39 (9.6) Transjugular intrahepatic portosystemic shunt 3 (2.1) 0 3 (0.7) Laparoscopic interventions 0 1 (0.4) 1 (0.2) Radiofrequency ablation 8 (5.6) 24 (9.1) 32 (7.8) Vascular catheterization 5 (3.5) 10 (3.8) 15 (3.7)

GI, gastrointestinal; HCC, hepatocellular carcinoma. aPercentages based on number of patients who had nonmissing bleeding risk data. September 2018 Avatrombopag Before Procedures in CLD 711 CLINICAL LIVER

Figure 2. ADAPT-1 and ADAPT-2 efficacy endpoints. (A) Proportion of patients not requiring a platelet transfusion or any rescue procedure for bleeding. (B) Proportion of pa- tients who achieved platelet counts 50 109/L on procedure day. (C) Magnitude of change in platelet count from baseline to procedure day. Full analysis set. Difference in change from baseline of platelet count for avatrombopag vs placebo within each cohort was based on Hodges-Lehmann estimation. 712 Terrault et al Gastroenterology Vol. 155, No. 3

109/L, respectively [P < .0001]; ADAPT-2: 44.9 109/vs similar (Figure 3). Platelet counts increased by day 4, 5.9 109/L [P < .0001]). peaked at days 10–13, and then returned to baseline levels by day 35. In total, only 3 avatrombopag-treated Exploratory Endpoints patients had platelet counts > 200 109/L at any In both studies, the time course for the increase in time during the 2 studies, all of whom were platelet counts after avatrombopag administration was asymptomatic. LNCLLIVER CLINICAL

Figure 3. Mean platelet counts by treatment group and visit day. (A) ADAPT-1. (B) ADAPT-2. September 2018 Avatrombopag Before Procedures in CLD 713

Safety 36, 31 days after the last dose of avatrombopag that was Exposure to treatment was similar in the ava- assessed as serious but not related. This patient had a trombopag and placebo treatment groups in ADAPT-1 (4.9 mean baseline platelet count of 13 109/L that increased ± 0.36 vs 5.0 ± 0.0 days) and ADAPT-2 (5.0 ± 0.18 vs 5.0 to 23 109/L on procedure day (scheduled procedure ± 0.26 days). Overall, the safety profile of avatrombopag was splenic artery embolization) and received 2 units of in both studies was similar to placebo, with a comparable blood/platelets before undergoing the procedure. Post- overall incidence of treatment-emergent AEs (TEAEs) in procedurecoursewascomplicatedbypainandsepsis, avatrombopag- and placebo-treated patients in both the with platelet counts of 86 109/L on day 15, 178 low and high baseline platelet count cohorts (Table 3). 109/L on day 26, and 93 109/L on day 36 (31 days from Most reported AEs across both studies were mild to last avatrombopag dose). moderate in severity in all treatment groups. The most common TEAEs were similar between patients treated with avatrombopag or placebo and included abdominal Discussion pain, dyspepsia, nausea, pyrexia, dizziness, and headache Thrombocytopenia can adversely affect the management (Table 4). of patients with CLD, delaying necessary diagnostic or The overall incidence of serious AEs in both studies was therapeutic procedures because of the increased bleeding low and similar in both the combined avatrombopag- and risk.2,8,34 There is a lack of consensus in the field regarding placebo-treatment groups, with all serious AEs in the appropriate target platelet counts in these patients, the

avatrombopag-treated patients being reported in only in- bleeding risk of individual procedures, and the variability in CLINICAL LIVER dividual patients with the exception of gastrointestinal the use of prophylactic platelet transfusions. In addition, the hemorrhage and hyponatremia in 2 patients each (Table 3). prophylactic use of platelet transfusions for these patients is Two avatrombopag-treated patients in the high baseline complicated by their variable efficacy and potential AEs, platelet count cohort of ADAPT-1 experienced serious AEs which include transfusion reactions, sepsis, and refractori- that resulted in death (hepatic coma, multi-organ system ness to further platelet transfusions, the last of which is failure), neither of which was assessed to be study related. associated with decreased survival, prolonged hospitaliza- In addition, 2 avatrombopag-treated patients in the low tions, and increased health care costs.12,21–23,35–37 Also, baseline platelet count cohort of ADAPT-1 had TEAEs that patients with CLD require multiple procedures; therefore, resulted in withdrawal of study drug (myalgia and anemia an unintended consequence of the recurrent use of platelet [possibly related to study treatment], pyrexia [unrelated to transfusions is the potential development of platelet study treatment]). refractoriness, which reduces the options to treat sponta- In ADAPT-1 and ADAPT-2, there were no meaningful neous, uncontrolled bleeding or bleeding with major surgi- differences in the incidence of AESI in avatrombopag- cal procedures (eg, liver transplantation). Furthermore, the compared with placebo-treated patients, which included need for platelet transfusions adds to the logistical World Health Organization Grade 2 bleeding events, complexity of outpatient management with scheduled recurrence of thrombocytopenia, and thromboembolic procedures.2,36,38 events. Overall across the 2 studies, the incidence of Thefocusofthese2phase3studieswastoshowthe bleeding events (World Health Organization Grade 2) was potential for avatrombopag to reduce the need for comparable between the avatrombopag and placebo treat- platelet transfusions or rescue procedures for bleeding in ment groups in both the low and high baseline platelet patients who were scheduled to undergo a procedure count cohorts (3.8% vs 3.3% and 2.6% vs 4.6%, that, in the opinion of the investigator, would otherwise respectively). require a platelet transfusion to address the risk of pro- In ADAPT-2, 3 patients developed thromboembolic cedural bleeding. Data from these 2 randomized, double- TEAEs in the high baseline platelet count cohort: 1 blind, placebo-controlled phase 3 studies consistently avatrombopag-treated patient (partial portal vein throm- show the efficacy and safety of avatrombopag in bosis) and 2 placebo-treated patients (acute myocardial increasing the proportion of patients with thrombocyto- infarction, disseminated intravascular coagulation and pul- penia associated with CLD undergoing a procedure who monary embolism). No thromboembolic TEAEs were re- did not require a platelet transfusion or rescue procedure ported in ADAPT-1. The TEAE of partial portal vein for bleeding. Previously published phase 3 data on the thrombosis in the avatrombopag group (40 mg) was iden- use of a thrombopoietin receptor agonist to mitigate tified on day 18 (13 days after the last dose) and assessed as thrombocytopenia in these patients showed efficacy, but nonserious and possibly related. This patient had a baseline this was also associated with an increased risk of portal platelet count of 45 109/L that increased to 77 109/L on vein thromboses that halted its further development for procedure day (scheduled procedure was upper gastroin- this indication.29 The thromboembolic events in that testinal endoscopy with variceal bleeding) and then study were attributed to the high (>200 109/L) and decreased to 61 109/L on day 18 and 45 109/L on sustained increase in platelet counts in eltrombopag- day 37. treated patients. There was also 1 non-TEAE of portal vein thrombosis By design, the magnitude and duration of the platelet in the avatrombopag group (60 mg) in ADAPT-1 on day count increase with avatrombopag in the ADAPT trials was LNCLLIVER CLINICAL 1 erute al et Terrault 714

Table 3.TEAE Categories

ADAPT-1 ADAPT-2

<40 109/L 40 to <50 109/L <40 109/L 40 to <50 109/L

Placebo Avatrombopag Placebo Avatrombopag Placebo Avatrombopag Placebo Avatrombopag (N ¼ 48) 60 mg (N ¼ 89) (N ¼ 32) 40 mg (N ¼ 58) (N ¼ 43) 60 mg (N ¼ 70) (N ¼ 33) 40 mg (N ¼ 57) AE n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

TEAEs 31 (64.6) 53 (59.6) 18 (56.3) 31 (53.4) 22 (51.2) 36 (51.4) 15 (45.5) 28 (49.1) Treatment-related TEAEsa 7 (14.6) 12 (13.5) 2 (6.3) 4 (6.9) 9 (20.9) 6 (8.6) 2 (6.1) 4 (7.0) TEAEs with CTCAE Grade 3, 4, 5 8 (16.7) 7 (7.9) 0 10 (17.2) 4 (9.3) 6 (8.6) 4 (12.1) 7 (12.3) Serious TEAEs 11 (22.9) 10 (11.2) 1 (3.1) 8 (13.8) 1 (2.3) 1 (1.4) 1 (3.0) 1 (1.8) Deathsb 0 0 0 2 (3.4) 0 0 1 (3.0) 0 Other SAEsc 11 (22.9) 10 (11.2) 1 (3.1) 6 (10.3) 1 (2.3) 1 (1.4) 0 1 (1.8) Life threatening 0 1 (1.1) 0 0 0 0 0 0 Requires hospitalization 9 (18.8) 10 (11.2) 1 (3.1) 6 (10.3) 1 (2.3) 1 (1.4) 0 0 Persistent or significant disability or incapacity 0 0 0 0 0 0 0 0 Important medical events 3 (6.3) 0 0 0 0 0 0 0 TEAEs leading to study drug withdrawal 0 2 (2.2) 0 0 0 0 0 0

NOTE. A TEAE is defined as an AE that started on or after the date of first dose of study drug, up to 30 days after the last dose of study drug. For each row category, a patient with 2 or more AEs in that category is counted only once. AE, adverse event; CTCAE, common terminology criteria for adverse events; SAE, serious adverse event; TEAE, treatment-emergent adverse event. aIncludes TEAEs considered by the investigator to be related to study drug or TEAEs with missing causality. b

Includes all patients with SAE resulting in death. 3 No. 155, Vol. Gastroenterology cIncludes all patients with nonfatal SAEs only. If a patient had both fatal and nonfatal SAEs, the patient is counted in the previous row and not in this row. etme 08Aarmoa eoePoeue nCD715 CLD in Procedures Before Avatrombopag 2018 September

Table 4.Frequently Reported TEAEs

ADAPT-1 ADAPT-2

<40 109/L 40–50 109/L <40 109/L 40–50 109/L

Placebo Avatrombopag Placebo Avatrombopag Placebo Avatrombopag Placebo Avatrombopag (N ¼ 48) 60 mg (N ¼ 89) (N ¼ 32) 40 mg (N ¼ 58) (N ¼ 43) 60 mg (N ¼ 70) (N ¼ 33) 40 mg (N ¼ 57) AE preferred term n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Patients with any TEAE 31 (64.6) 53 (59.6) 18 (56.3) 31 (53.4) 22 (51.2) 36 (51.4) 15 (45.5) 28 (49.1) Abdominal pain 3 (6.3) 8 (9.0) 3 (9.4) 6 (10.3) 3 (7.0) 2 (2.9) 1 (3.0) 2 (3.5) Abdominal pain, upper ————5 (11.6) 2 (2.9) 3 (9.1) 1 (1.8) Diarrhea 1 (2.1) 4 (4.5) 2 (6.3) 1 (1.7) 3 (7.0) 3 (4.3) 0 2 (3.5) Dyspepsia 2 (4.2) 0 2 (6.3) 0 ———— Nausea 2 (4.2) 4 (4.5) 2 (6.3) 5 (8.6) 5 (11.6) 6 (8.6) 6 (8.6) 3 (5.3) Fatigue 1 (2.1) 6 (6.7) 1 (3.1) 1 (1.7) 3 (7.0) 1 (1.4) 0 2 (3.5) Edema peripheral 2 (4.2) 3 (3.4) 1 (3.1) 3 (5.2) 2 (6.1) 0 3 (9.1) 0 Pyrexia 6 (12.5) 7 (7.9) 2 (6.3) 5 (8.6) 2 (4.7) 11 (15.7) 4 (12.1) 4 (7.0) Gastroenteritis 0 0 2 (6.3) 0 ———— Procedural pain 0 7 (7.9) 0 0 ———— Transfusion reactions 3 (6.3) 0 0 0 1 (2.3) 0 2 (6.1) 0 Dizziness ————3 (7.0) 3 (4.3) 1 (3.0) 0 Headache 3 (6.3) 5 (5.6) 2 (6.3) 6 (10.3) 4 (9.3) 2 (2.9) 1 (3.0) 2 (3.5) Hematuria ———— 0 0 2 (6.1) 0

NOTE. A TEAE is defined as an AE that started on or after the date of first dose of study drug, up to 30 days after the last dose of study drug. For each row category, a patient with 2 or more AEs in that category is counted only once. Table 4 shows TEAEs occurring in >5% of patients in treatment group. AE, adverse event; TEAE, treatment-emergent adverse event.

CLINICAL LIVER 716 Terrault et al Gastroenterology Vol. 155, No. 3

predictable and of short duration, making it ideal for pro- there was a positive treatment effect shown for ava- phylactic use for scheduled procedures. Platelet counts trombopag in all subgroups, the confidence intervals peaked 5–8 days after the last dose of avatrombopag and were wider for those subgroups with the smallest num- then consistently declined within 7 days of the procedure, ber of patients. returning to baseline within 30 days of the last dose. The In conclusion, avatrombopag has been developed as an timeline for the peak increase in platelet counts after alternative to platelet transfusions for patients with avatrombopag treatment provided a procedure window thrombocytopenia and CLD scheduled for a procedure to from days 10–13 from the first avatrombopag dose, in minimize bleeding and other safety risks and improve contrast to the very narrow window with platelet trans- clinical management. Avatrombopag (Doptelet; AkaRx Inc,) fusions. Importantly with the recommended dosing regi- was approved by FDA on May 21, 2018 for the treatment of mens, only 3 avatrombopag-treated patients had platelet thrombocytopenia in adult patients with chronic liver dis- counts 200 109/Loverthecourseofthe2phase3 ease who are scheduled to undergo a procedure. The effi- studies, proactively mitigating an increased risk of throm- cacy and safety profiles shown in the phase 3 ADAPT-1 and boembolic events. The ability to limit the magnitude and ADAPT-2 studies strongly support a positive benefit–risk duration of the platelet count increase with avatrombopag profile of avatrombopag, and offer the opportunity to LNCLLIVER CLINICAL is likely directly related to its predictable pharmacoki- change the standard of care for the treatment of thrombo- netic/pharmacodynamic profile and to the use of a robust cytopenia in patients with CLD who are scheduled to un- pharmacokinetic/pharmacodynamic model and simula- dergo a procedure and for whom the clinician has decided tions based on phase 2 data to select the phase 3 ava- that an increased platelet count is required; avatrombopag trombopag dosing regimens.33 may provides physicians with a safe and effective alterna- In both ADAPT-1 and ADAPT-2, avatrombopag was tive to platelet transfusions, simplifying the clinical man- reproducibly shown to be superior to placebo across all agement of these patients. primary and secondary efficacy endpoints, with clinically fi meaningful and statistically signi cant results. 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Bleeding after transfusions: utilization and associated costs in a tertiary invasive procedures is rare and unpredicted by platelet care hospital. Am J Hematol 2000;64:251–256. counts in cirrhotic patients with thrombocytopenia. Eur J 37. Toor AA, Choo SY, Little JA. Bleeding risk and platelet Intern Med 2017;38:79–82. transfusion refractoriness in patients with acute myeloge- 20. Slitcher SJ, Kaufman RM, Assmann SF, et al. Dose of nous leukemia who undergo autologous stem cell trans- prophylactic platelet transfusions and prevention of plantation. Bone Marrow Transplant 2000;26:315–320. hemorrhages. N Engl J Med 2010;362:600–613. 38. Hayashi H, Beppu T, Shirabe K, et al. Management of 21. Kerkhoffs JL, Eikenboom JC, van de Watering LM, et al. thrombocytopenia due to liver cirrhosis: A review. World The clinical impact of platelet refractoriness: correlation with J Gastroenterol 2014;20:2595–2605. bleeding and survival. Transfusion 2008;48:1959–1965. 22. Valsami S, Dimitroulis D, Gialeraki A, et al. Current trends in platelet transfusions practice: The role of ABO-RhD Received March 2, 2018. Accepted May 11, 2018. and human leukocyte antigen incompatibility. Asian J Reprint requests Transfus Sci 2015;9:117–123. Address requests for reprints to: Norah Terrault, MPH, MD, University of 23. Novotny VM. Prevention and management of platelet California San Francisco, San Francisco, California 94143. e-mail: [email protected]; fax: (415) 4760-0659. transfusion refractoriness. Vox Sang 1999;76:1–13. 24. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and effi- Acknowledgments Medical writing support, under the direction of the authors, was provided by cacy of long-term treatment with romiplostim in throm- Paul O’Neill, PhD, and Gemma McGregor, PhD, of CMC AFFINITY, a division bocytopenic patients with chronic ITP. Blood 2009; of Complete Medical Communications Ltd, Glasgow, UK, funded by Dova 113:2161–2171. Pharmaceuticals, Durham, North Carolina, in accordance with Good Publication Practice (GPP3) guidelines. 25. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romi- The authors would like to thank the sponsor’s responsible medical officer, plostim in patients with chronic immune thrombocyto- Francesco Bibbiani, MD, for his assistance in conducting both studies. Author contributions: Norah Terrault made substantial contributions to the penic purpura: a double-blind randomised controlled study concept and design; acquisition of data; analysis and interpretation of trial. Lancet 2008;371:395–403. data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and administrative, technical, and material 26. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for support. Yi-Cheng Chen made substantial contributions to the acquisition of the treatment of chronic idiopathic thrombocytopenic data and critically revised the manuscript for important intellectual content. purpura. N Engl J Med 2007;357:2237–2247. Namiki Izumi made substantial contributions to the acquisition of data and critically revised the manuscript for important intellectual content. Zeid Kayali 27. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for made substantial contributions to the acquisition of data and critically management of chronic immune thrombocytopenia revised the manuscript for important intellectual content. Paul Mitrut made substantial contributions to the acquisition of data and critically revised the (RAISE): a 6-month, randomised, phase 3 study. Lancet manuscript for important intellectual content. Wong Young Tak made 2011;377:393–402. substantial contributions to the acquisition of data and critically revised the 718 Terrault et al Gastroenterology Vol. 155, No. 3

manuscript for important intellectual content. Lee F. Allen made substantial Gilead, Otsuka, and Shionogi. Zeid Kayali has received grants from BMS, contributions to the analysis and interpretation of the data from both phase 3 Eisai, Exelixis, Gilead, Intercept, Merck, Novartis, Pfizer, Shionogi, and Shire. studies, participated in drafting and revising the article’s content, and gave Tarek Hassanein has received research grants from AbbVie, Boehringer final approval of the version to be submitted for publication. Tarek Hassanein Ingelheim, Boston Biomedical, Bristol-Myers Squibb, CymaBay, Eisai, made substantial contributions to the acquisition of data; critical revision of GenFit, Gilead, Idenix, Ikaria, Intercept, Janssen, La Jolla, Madrigal, the manuscript for important intellectual content; and administrative, Mallinckrodt, Merck, Mochida, NGM Biopharmaceuticals, Novartis, Obalon, technical, and material support. Roche, Ocera, Sunrise, Salix, Shire, Taigen, Takeda, Tobria, Trek, Vertex, and Vital Therapies; has been a speaker at sponsored lectures for AbbVie, Conflicts of interest Baxter, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Salix; and has Norah Terrault has received research grants from AbbVie, Allergan, BMS, Eisai, served on the advisory board for AbbVie, Bristol-Myers Squibb, Gilead, Gilead, and Merck. Namiki Izumi has received grants from AbbVie, Bayer, Merck, and Trek. The remaining authors disclose no conflicts. LNCLLIVER CLINICAL