A Phase 2, Multicenter, Randomized, Placebo-Controlled, Double-blind Study in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) to Evaluate the Pharmacokinetics, Safety and Efficacy of rADAMTS-13 (SHP655) Administered in Addition to Standard Of Care (SoC) Treatment
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Shire
- 入组人数
- 28
- 试验地点
- 24
- 主要终点
- ADAMTS-13 Activity Levels
研究概览
简要总结
The purpose of this study is to evaluate the pharmacokinetics, safety, and efficacy of rADAMTS-13 (SHP655) administered in addition to standard of care (SoC) treatment of acquired thrombotic thrombocytopenic purpura (aTTP) participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant or legally authorized representative voluntarily signs informed consent. For participants unable to provide consent, a fully recognized medical proxy may be used according to local laws.
- •Participant is 18 to 75 years old at the time of screening.
- •Participant has been diagnosed with primary or secondary autoimmune acquired thrombotic thrombocytopenic purpura (aTTP) based on the following criteria:
- •a) Thrombocytopenia [drop in platelet count >=50% or platelet count <100,000/microlitre (μL)] i) No more than 3 participants per arm may be enrolled with a screening platelet count >= 50,000/μL.
- •b) Microangiopathic hemolytic anemia [elevation of lactate dehydrogenase (LDH) >2-fold or by presence or increase of schistocytes in peripheral blood smear].
- •Willingness to fully comply with study procedures and requirements, and intention to initiate plasma exchange (PEX). Participants may be provisionally entered into the trial and undergo randomization pending the results of the ADAMTS-13 activity, anti-ADAMTS-13 antibody, and genetic testing for congenital thrombotic thrombocytopenic purpura (cTTP).
- •If female of childbearing potential, participant presents with a negative pregnancy test and agrees to employ adequate birth control measures for the duration of the study. Sexually active males must use an accepted and effective method of contraception during the treatment and until a minimum of 16 days after the last dose administered.
排除标准
- •Participant has been diagnosed with congenital TTP.
- •Participant has plasma ADAMTS-13 activity > 10% of normal at the central lab; if screening samples are not taken until after the first PEX, ADAMTS-13 activity from the local lab is permitted to determine eligibility.
- •Participant has been diagnosed with another cause of thrombotic microangiopathy (TMA) including: DIC, disseminated malignancy, malignant hypertension, hematopoietic stem cell transplantation, shiga toxin related and atypical HUS, drug toxicity (e.g. gemcitabine, mitomycin C, clopidogrel) and pregnancy-related thrombocytopenia syndromes (e.g. HELLP, eclampsia).
- •Participant has been exposed to another IP within 30 days prior to enrollment or is scheduled to participate in another clinical study involving IP or investigational device during the course of the study.
- •Participant has received caplacizumab within 1 month prior to study enrollment.
- •Participant is human immunodeficiency virus positive (HIV+) with unstable disease or CD4+ count <=200 cells/mm^3 within 3 months screening.
- •Participants with conditions of severe immunodeficiency.
- •Participant has had a previous aTTP event in the past 30 days.
- •Participant has another underlying progressive fatal disease and/or life expectancy of less than 3 months.
- •Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures
- •Participant suffers from a mental condition rendering him/her unable to understand the nature, scope, and possible consequences of the study and/or evidence of an uncooperative attitude. However, a fully recognized medical proxy will be permitted to provide consent.
- •If female, participant is pregnant or lactating.
- •Participant is a family member or employee of the Sponsor or investigator.
- •Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing information.
- •Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule ADAMTS-13, hamster protein, or other constituents of SHP655.
研究组 & 干预措施
Standard of Care (SoC) + Placebo
Participants received SoC daily PEX followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
干预措施: Placebo (Other)
Standard of Care (SoC) + Placebo
Participants received SoC daily PEX followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
干预措施: Standard of Care (Other)
SoC + SHP655 + Placebo
Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
干预措施: Placebo (Other)
SoC + SHP655 + Placebo
Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
干预措施: SHP655 (Drug)
SoC + SHP655 + Placebo
Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
干预措施: Standard of Care (Other)
SoC + SHP655
Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
干预措施: SHP655 (Drug)
SoC + SHP655
Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).
干预措施: Standard of Care (Other)
结局指标
主要结局
ADAMTS-13 Activity Levels
时间窗: Up to Days 11 or 12
ADAMTS-13 Activity Levels was assessed by fluorescence resonance energy transfer (FRETS) ADAMTS13 activity, with or without SHP655 Supplementation. Schedule A (Days 1, 2, 3, 4, 6, 8, 11, and every 3 days thereafter) or Schedule B (Days 1, 2, 3, 5, 7, 9, 12, and every 3 days thereafter). Data is reported for multiple timepoints as Within 15 minutes pre-PEX and post-PEX; Within 15 minutes, 0.5-3 hours, 4-6 hours post end of investigational product (IP) infusion 1; Within 15 minutes, 0.5-3 hours post end IP infusion 2; 30 minutes pre-IP infusion 2 of Schedule A and Schedule B (up to Day 11 or 12).
Platelet Count
时间窗: Baseline and end of study (EOS) (up to approximately 15 months)
The platelet counts are reported in units of 10\^9 per liter blood.
Lactate Dehydrogenase (LDH) Levels
时间窗: Baseline and EOS (up to approximately 15 months)
The lactate dehydrogenase levels are reported.
次要结局
- Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13(From start of study drug administration up to 13 weeks (following remission up to 6 months))
- PK/PD Temporal Relationship of Safety and Efficacy Parameter as a Function of ADAMTS-13 Activity(Up to 6 months)
- Relationship Between ADAMTS-13 Activity and End-organ Disease Status(Up to 6 months)
- Predose Concentration (Cpre) to Maximum Plasma Concentration (Cmax) Ratio(Pre-PEX and post-PEX at multiple timepoints at Days 1, 2, 3, 4 or 5, 6 or 7, 8 or 9, and 11 or 12)
- Cmax: Maximum ADAMTS-13 Activity Between PEX or SHP655 Infusions by Using FRETS(Pre-PEX and post-PEX at multiple timepoints at Days 1, 2, 3, 4 or 5, 6 or 7, 8 or 9, and 11 or 12)
- Time to First Exacerbation(From start of study drug administration up to EOS (up to approximately 15 months))
- Percentage of Participants With at Least One Positive Identification of Antibodies to SHP655(Up to 6 months)
- Number of Participants With Clinically Relevant Changes in Vital Signs(From first dose of study drug until the EOS (up to approximately 15 months))
- Number of Participants With Clinically Relevant Changes in Clinical Chemistry(From first dose of study drug until the EOS (up to approximately 15 months))
- Number of Participants With ADAMTS-13 Binding Antibodies Per Titer(Baseline and EOS (up to approximately 15 months))
- ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution by Using FRETS(At Days 3, 7, 10, 21, 28, 42, 56 and 84)
- AUC Overall: Area Under the Plasma Concentration Time Curve ADAMTS13 Activity by Using FRETS(Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 1, 2, 3, 4 or 5 and 6 or 7)
- Inhibitory Autoantibodies (Nab) Titer Levels(Baseline and EOS (up to approximately 15 months))
- Number of Participants Who Achieved Remission Following Normalization of Platelet Count(From the start of study drug administration up to 6 months post remission)
- Percentage of Participants With Exacerbation(From start of study drug administration up to EOS (up to approximately 15 months))
- Systemic and Antibody Induced Clearance(15 minutes pre-PEX,15 minutes post-PEX,15 minutes, 0.5-3 hours, 4-6 hours post end of IP infusion 1,30 minutes pre-IP infusion 2,15 minutes, 0.5-3 hours post-IP infusion 2 of Schedule A or Schedule B (up to 6 months))
- Percentage of Participants Achieving Remission(From the start of study drug administration up to 6 months post remission)
- Percentage of Participants With Major Clinical Events Related to Thrombotic Thrombocytopenic Purpura (TTP)(From start of study drug administration up to EOS (up to approximately 15 months))
- Number of Participants With Treatment Emergent Adverse Events (TEAEs), Specifically Product-Related TEAEs and Serious TEAEs(From first dose of study drug until the EOS (up to approximately 15 months))
- Trough Levels of ADAMTS-13 Prior PEX ADAMTS13 Activity by Using FRETS(Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 2, 3, 4 or 5 and 6 or 7)
- Percentage of Participants With ADAMTS-13 Activity Trough Levels >10%(Pre-dose at Days 2, 3 4 or 5, 6 or 7, 8 or 9, and 11 or 12)
- Time to Relapse(From start of study drug administration up to EOS (up to approximately 15 months))
- Percentage of Participants With Relapse(From start of study drug administration up to EOS (up to approximately 15 months))
- Number of Participants With Major Clinical Events Related to PEX(Up to 6 months)
- Number of Participants With Anti-drug Antibody (ADA) Titer of Binding Relative to Baseline(Baseline and EOS (at approximately Month 15))
- Number of Participants With Inhibitory Antibodies Relative to Baseline(Baseline and EOS (at approximately Month 15))
- Number of Participants With Clinically Relevant Changes in Hematology(From first dose of study drug until the EOS (up to approximately 15 months))
- Percentage of Participants Receiving Rescue Therapy(From first dose of study drug until the EOS (up to approximately 15 months))
- Percentage of Participants Meeting Rescue Criteria(From first dose of study drug until the EOS (up to approximately 15 months))