Clinical trial NCT03922308: Study of rADAMTS-13 (SHP655) in the Treatment of Participants With Acquired Thrombotic Thrombocytopenic Purpura (aTTP)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acquired Thrombotic Thrombocytopenic Purpura (aTTP)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2019-04-19
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: ADAMTS-13 Activity Levels
timeFrame: Up to Days 11 or 12
measure: Platelet Count
timeFrame: Baseline and end of study (EOS) (up to approximately 15 months)
measure: Lactate Dehydrogenase (LDH) Levels
timeFrame: Baseline and EOS (up to approximately 15 months)
Secondary outcomes:
measure: Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13
timeFrame: From start of study drug administration up to 13 weeks (following remission up to 6 months)
measure: PK/PD Temporal Relationship of Safety and Efficacy Parameter as a Function of ADAMTS-13 Activity
timeFrame: Up to 6 months
measure: Number of Participants With ADAMTS-13 Binding Antibodies Per Titer
timeFrame: Baseline and EOS (up to approximately 15 months)
measure: Inhibitory Autoantibodies (Nab) Titer Levels
timeFrame: Baseline and EOS (up to approximately 15 months)
measure: ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution by Using FRETS
timeFrame: At Days 3, 7, 10, 21, 28, 42, 56 and 84
measure: Relationship Between ADAMTS-13 Activity and End-organ Disease Status
timeFrame: Up to 6 months
measure: Predose Concentration (Cpre) to Maximum Plasma Concentration (Cmax) Ratio
timeFrame: 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
measure: AUC Overall: Area Under the Plasma Concentration Time Curve ADAMTS13 Activity by Using FRETS
timeFrame: Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 1, 2, 3, 4 or 5 and 6 or 7
measure: Systemic and Antibody Induced Clearance
timeFrame: 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)
measure: Cmax: Maximum ADAMTS-13 Activity Between PEX or SHP655 Infusions by Using FRETS
timeFrame: 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
measure: Trough Levels of ADAMTS-13 Prior PEX ADAMTS13 Activity by Using FRETS
timeFrame: Within 15 min pre-PEX and at multiple timepoints Post PEX at Days 2, 3, 4 or 5 and 6 or 7
measure: Percentage of Participants With ADAMTS-13 Activity Trough Levels >10%
timeFrame: Pre-dose at Days 2, 3 4 or 5, 6 or 7, 8 or 9, and 11 or 12
measure: Number of Participants Who Achieved Remission Following Normalization of Platelet Count
timeFrame: From the start of study drug administration up to 6 months post remission
measure: Percentage of Participants Achieving Remission
timeFrame: From the start of study drug administration up to 6 months post remission
measure: Time to First Exacerbation
timeFrame: From start of study drug administration up to EOS (up to approximately 15 months)
measure: Time to Relapse
timeFrame: From start of study drug administration up to EOS (up to approximately 15 months)
measure: Percentage of Participants With Exacerbation
timeFrame: From start of study drug administration up to EOS (up to approximately 15 months)
measure: Percentage of Participants With Relapse
timeFrame: From start of study drug administration up to EOS (up to approximately 15 months)
measure: Percentage of Participants With Major Clinical Events Related to Thrombotic Thrombocytopenic Purpura (TTP)
timeFrame: From start of study drug administration up to EOS (up to approximately 15 months)
measure: Number of Participants With Major Clinical Events Related to PEX
timeFrame: Up to 6 months
measure: Number of Participants With Anti-drug Antibody (ADA) Titer of Binding Relative to Baseline
timeFrame: Baseline and EOS (at approximately Month 15)
measure: Number of Participants With Inhibitory Antibodies Relative to Baseline
timeFrame: Baseline and EOS (at approximately Month 15)
measure: Percentage of Participants With at Least One Positive Identification of Antibodies to SHP655
timeFrame: Up to 6 months
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Specifically Product-Related TEAEs and Serious TEAEs
timeFrame: From first dose of study drug until the EOS (up to approximately 15 months)
measure: Number of Participants With Clinically Relevant Changes in Vital Signs
timeFrame: From first dose of study drug until the EOS (up to approximately 15 months)
measure: Number of Participants With Clinically Relevant Changes in Clinical Chemistry
timeFrame: From first dose of study drug until the EOS (up to approximately 15 months)
measure: Number of Participants With Clinically Relevant Changes in Hematology
timeFrame: From first dose of study drug until the EOS (up to approximately 15 months)
measure: Percentage of Participants Receiving Rescue Therapy
timeFrame: From first dose of study drug until the EOS (up to approximately 15 months)
measure: Percentage of Participants Meeting Rescue Criteria
timeFrame: From first dose of study drug until the EOS (up to approximately 15 months)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham
state: Alabama
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: London
country: Canada
facility: London Health Sciences Centre (LHSC) - University Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Reims
country: France
facility: CHU de Reims - Hôpital Maison Blanche
state: Marne
city: Marseille
country: France
facility: Hopital Conception
city: Paris
country: France
facility: Chu Saint-Antoine
city: Seine Maritime
country: France
facility: CHU de Rouen
city: Frankfurt
country: Germany
facility: Hamatologie, Onkologie, Hämostaseologie
city: Milan
country: Italy
facility: Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Dr. Peset
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic la Fe
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: West Glamorgan
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: 1st Floor, UCLH-Haematology
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References: