[Translation] Efficacy and safety of avatrombopag in the treatment of chronic immune thrombocytopenia (ITP) in Chinese adults: a multicenter, randomized, double-blind, placebo-controlled, phase III clinical trial with extension study

主要：确定第6周的血小板反应率，证明阿伐曲泊帕对中国成人慢性ITP患者的疗效优于安慰剂。次要：根据所测量的第8天的血小板反应，证明阿伐曲泊帕优效于安慰剂。根据6周内所测定血小板反应率累积周数（定义为：在无补救治疗情况下，血小板计数≥50×109/L的累计周数），证明阿伐曲泊帕优效于安慰剂。评估阿伐曲泊帕在减少出血和补救治疗方面的疗效优于安慰剂。评估阿伐曲泊帕长期治疗的有效性。评估阿伐曲泊帕安全性和耐受性。

[Translation]

Primary: To determine the platelet response rate at week 6 and to demonstrate that avatrombopag is superior to placebo in Chinese adult patients with chronic ITP. Secondary: To demonstrate the superiority of avatrombopag over placebo based on the platelet response measured at day 8. To demonstrate the superiority of avatrombopag over placebo based on the cumulative number of weeks with platelet response rate measured within 6 weeks (defined as the cumulative number of weeks with platelet count ≥50×109/L in the absence of rescue therapy). To assess the superiority of avatrombopag over placebo in reducing bleeding and rescue therapy. To assess the effectiveness of long-term treatment with avatrombopag. To assess the safety and tolerability of avatrombopag.

Start Date02 Mar 2021

Sponsor / Collaborator

Kawashima Group Co., Ltd.

[+3]

100 Clinical Results associated with AkaRx, Inc.

0 Patents (Medical) associated with AkaRx, Inc.

Literatures (Medical) associated with AkaRx, Inc.

01 Feb 2007·Annals of PharmacotherapyQ4 · MEDICINE

Absence of Effect of Oral Rifaximin on the Pharmacokinetics of Ethinyl Estradiol/Norgestimate in Healthy Females

Q4 · MEDICINE

Article

Author: Trapnell, Carol Braun ; Connolly, Margaret ; Forbes, William P ; Bettenhausen, Doug K ; Pentikis, Helen

Background: Rifaximin is an oral rifampin analog, and its activity is targeted within the gastrointestinal tract. Some analogs induce the cytochrome P450 family of oxidative enzymes. Ethinyl estradiol (EE), commonly found in oral contraceptives (OCs), is a known CYP3A4 substrate. Objective: To determine the potential effect of rifaximin on EE and norgestimate pharmacokinetics. Methods: In an open-label, crossover study, healthy females received a single dose of OC (EE 0.07 mg/norgestimate 0.50 mg). Following a 1 week washout period, individuals received rifaximin 200 mg every 8 hours for 3 days, with a single dose of OC administered with the ninth rifaximin dose. During both treatment periods, blood samples were collected periodically for up to 96 hours after each OC dose. Plasma concentration–time profiles and pharmacokinetic parameters were characterized for EE and 2 major metabolites of norgestimate, norgestrel (NG) and 17-deacetyl norgestimate (17-DNGM). A drug–drug interaction was confirmed if the 90% CI for the 2 treatment period comparison was outside the 80–125% limit. Results: Twenty-six of 28 women completed the study. No differences in pharmacokinetic parameters were observed for EE, NG, or 17-DNGM when a single dose of the OC was administered alone or with rifaximin. In addition, the 90% CI for the bioavailability contrasts (OC alone vs OC with rifaximin) for the maximum plasma concentration, area under the plasma concentration–time curve from zero to the last measurable plasma concentration or to infinity for EE, NG. and 17-DNGM all ranged from 86–118%. These intervals were within the predefined range for equivalence; therefore, no interaction was observed between OC and rifaximin. Rifaximin was well tolerated. Conclusions: Administration of a 3 day dosing regimen of oral rifaximin was well tolerated and did not alter the pharmacokinetics of a commonly used combination OC containing EE and norgestimate.

16 Nov 2006·Blood

Single and Multiple Oral Doses of AKR-501 (YM477) Increase the Platelet Count in Healthy Volunteers.

Author: Kuter, David J. ; Tempel, Donna L. ; Lucek, Rudolph ; Desjardins, Robert E.

AbstractAKR-501 is an orally active thrombopoietin (TPO) receptor agonist that increases platelet production through stimulation of megakaryocyte proliferation and differentiation. The effect of AKR-501 in in vitro and in vivo models is additive with that of rhTPO. AKR-501 is a potential new therapy for use in the prevention or treatment of thrombocytopenia of various etiologies. We evaluated the safety, pharmacokinetics and pharmacodynamic activity of AKR-501 when administered as single and multiple oral doses to healthy volunteers. In the single dose study, 7 dose cohorts of 9 subjects each were randomized in a ratio of 2:1 to receive increasing doses (1, 3, 10, 20, 50, 75 and 100 mg) of AKR-501 or placebo. In the multiple dose study, 5 dose cohorts of 9 subjects each were to be randomized in a ratio of 2:1 to receive increasing doses (3, 10, 20, 50 and 100 mg) of AKR-501 or placebo administered daily for 14 days. All subjects were evaluated for safety and pharmacodynamic activity as assessed by peripheral blood platelet counts (PBPC). Dose escalation was stopped on Day 10 of dosing in the 3rd dose cohort (20 mg/day) when 6 of the volunteers exhibited a platelet count above 500,000/mL. The protocol defined endpoint of >50% increase over baseline platelet count was achieved in 5 of 6 volunteers given a single dose of 100 mg, and in all 6 volunteers given daily doses of 10 mg for 14 days and 20 mg for 10 days. The drug was well tolerated in both the single and multiple dose studies with no serious drug-related adverse experiences reported at any dose. AKR-501 was consistently well absorbed exhibiting dose linear pharmacokinetics following single and multiple dose administration, and a serum half-life of approximately 16 hours. The mean observed Cmax following administration of single doses increased from 5.67 ng/mL at 1 mg to 388 ng/mL at 100 mg. The mean observed AUC increased from 174 ng·hr/mL at 1 mg to 11052 ng·hr/mL at 100 mg. Accumulation to steady state with multiple dosing was consistent with predictions based on a linear model and the single dose PK parameter estimates. There was a linear correlation of individual observed peak activity with corresponding Cmax (single-dose r2=0.70 p<.0001, multiple-dose r2=0.67 p<0.0001). The mean change from baseline PBPC for each dose cohort in the single-dose (Figure 1) and multiple-dose (Figure 2) studies are shown in the following graphs.Figure 1 Figure 1. Figure 2 Figure 2.

News (Medical) associated with AkaRx, Inc.

28 Jan 2021

·www.globenewswire.com

Doptelet (Avatrombopag): A 2nd Generation, Once Daily, Orally Administered TPO Receptor Agonist Approved for the Treatment of Thrombocytopenia - Global Drug Insight and Market Forecast 2017-2030

Dublin, Dec. 30, 2020 (GLOBE NEWSWIRE) -- The "Doptelet (Avatrombopag) - Drug Insight and Market Forecast - 2030" report has been added to ResearchAndMarkets.com's offering. Doptelet (avatrombopag) - Drug Insight and Market Forecast - 2030 report by the publisher outlays comprehensive insights of the product indicated for the treatment of its approved condition. A detailed picture of the Doptelet (avatrombopag) in Seven Major Markets, i.e., United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan, for the study period 2017-2030 is provided in this report along with a detailed description of the product. The product details cover mechanism of action, dosage and administration, route of synthesis, and pharmacological studies, including product marketed details, regulatory milestones, and other development activities. Further, it also consists of market assessments inclusive of the market forecast, SWOT analysis, and detailed analyst views. It further highlights the market competitors, late-stage emerging therapies, and patent details in the global space.Doptelet (avatrombopag) is a second generation, once daily, orally administered TPO receptor agonist approved for the treatment of thrombocytopenia in adult patients with CLD who are scheduled to undergo a procedure. Doptelet is designed to mimic the effects of TPO, the primary regulator of normal platelet production. Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists. In the ADAPT-1 and ADAPT-2 clinical trials, there was 1 treatment-emergent event of portal vein thrombosis in a patient (n=1/430) with chronic liver disease and thrombocytopenia treated with Doptelet. The drug should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts. In April 2020, AkaRx announced Doptelet has been granted approval from the China National Medical Products Administration (NMPA) for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo a procedure (i.e., the CLD indication).Scope of the report Doptelet (avatrombopag) Analytical PerspectiveIn-depth Doptelet (avatrombopag) Market AssessmentThis report provides a detailed market assessment of Doptelet (avatrombopag) in Seven Major Markets, i.e., United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan. This segment of the report provides historical and forecasted sales data from 2017 to 2030.Doptelet (avatrombopag) Clinical AssessmentThe report provides the clinical trials information of Doptelet (avatrombopag) covering trial interventions, trial conditions, trial status, start and completion dates.Report highlights Key Questions Answered For more information about this report visit Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

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Avatrombopag Maleate ( TPO receptor )	Thrombocytopenia More	Approved

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