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Study of rADAMTS-13 (SHP655) in the Treatment of Participants With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) (SOAR-HI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03922308
Recruitment Status : Recruiting
First Posted : April 19, 2019
Last Update Posted : February 25, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Shire )

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.

Condition or disease Intervention/treatment Phase
Acquired Thrombotic Thrombocytopenic Purpura (aTTP) Other: Placebo Drug: SHP655 Other: Standard of Care Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : October 9, 2019
Estimated Primary Completion Date : March 12, 2022
Estimated Study Completion Date : March 12, 2022


Arm Intervention/treatment
Placebo Comparator: Standard of Care (SoC) + Placebo Twice Daily
Participants will receive SoC daily plasma exchange (PEX) immediately followed by placebo (0.9% saline) and after 12 +/- 1 hours until remission is achieved.
Other: Placebo
Participants will receive injection of placebo matched to SHP655.

Other: Standard of Care
Participants will receive PEX as Standard of Care (SOC).
Other Name: PEX

Experimental: SoC + SHP655 Once Daily + Placebo 12 Hours Later
Participants will receive SoC daily PEX and intravenous (i.v.) injection of 40 +/- 4 International units per kilogram (IU/kg) of SHP655 once daily immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission is achieved.
Other: Placebo
Participants will receive injection of placebo matched to SHP655.

Drug: SHP655
Participants will receive injection of SHP655.
Other Name: rADAMTS-13

Other: Standard of Care
Participants will receive PEX as Standard of Care (SOC).
Other Name: PEX

Experimental: SoC + SHP655 Twice Daily
Participants will receive SoC daily plasma exchange and i.v. injection of 40 +/- 4 IU/kg of SHP655 twice daily (BID) immediately after PEX and 12 +/- 1 hours after completion of PEX until remission is achieved.
Drug: SHP655
Participants will receive injection of SHP655.
Other Name: rADAMTS-13

Other: Standard of Care
Participants will receive PEX as Standard of Care (SOC).
Other Name: PEX




Primary Outcome Measures :
  1. ADAMTS-13 Activity Levels [ Time Frame: Up to 6 months ]
    ADAMTS-13 Activity Levels will be assessed by daily Plasma Exchange (PEX), Immunosuppressant therapy, 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).

  2. Platelet Count [ Time Frame: Up to 6 months ]
    Platelet count will be assessed.

  3. Lactate Dehydrogenase (LDH) levels [ Time Frame: Up to 6 months ]
    LDH levels will be assessed.


Secondary Outcome Measures :
  1. Change from Baseline in the Titers of Binding and Inhibitory Antibodies to ADAMTS-13 [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
    Change from baseline in levels of ADAMTS-13 binding and inhibitory auto antibodies in response to daily Plasma Exchange (PEX), with or without SHP655 supplementation, during the acute episode and up to 30 days after the resolution of the acute aTTP episode will be assessed.

  2. Occurrence of Antibodies to SHP655 [ Time Frame: 15 minutes pre-PEX,15 minutes post-PEX, 4-6 hours post end of IP infusion #1,30 minutes pre-IP infusion #2 of Schedule A or Schedule B (up to 6 months) ]
    Occurrence of Antibodies to SHP655 will be assessed.

  3. Incidence of Incremental Recovery [ Time Frame: 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) ]
    Incremental recovery of ADAMTS-13 will be assessed.

  4. Area Under the Curve [ Time Frame: 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) ]
    AUC of ADAMTS-13 will be assessed.

  5. Systemic and Antibody Induced Clearance [ Time Frame: 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) ]
    Systemic and antibody induced clearance of ADAMTS-13 will be assessed.

  6. Trough Levels of ADAMTS-13 prior PEX [ Time Frame: 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) ]
    Trough levels of ADAMTS-13 will be assessed.

  7. ADAMTS-13 Binding and Inhibitory Autoantibody Levels in Response to Daily PEX, With or Without SHP655 Supplementation During the Acute TTP Episode and up to 30 Days After Resolution [ Time Frame: 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) ]
    ADAMTS-13 binding and inhibitory autoantibody levels in response to daily PEX, with or without SHP655 supplementation, during the acute TTP episode and up to 30 days after resolution will be assessed. Resolution is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period).

  8. ADAMTS-13 Activity Levels in Participants Receiving Additional SHP655 for up to 30 Days After Resolution [ Time Frame: Once weekly for 4 weeks ]
    ADAMTS-13 activity levels in participants receiving additional SHP655 for up to 30 days after the resolution of the TTP episode will be assessed. Resolution is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period).

  9. Dose(s) of SHP655 Needed to Achieve and Maintain Adequate Plasma Levels of rADAMTS-13 in Order to Support Induction of Remission and to Reduce the Number of PEX Procedures Needed for the Treatment of Acute aTTP Episodes [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Dose(s) of SHP655 needed to achieve and maintain adequate plasma levels of rADAMTS-13 in order to support induction of remission and to reduce the number of PEX procedures needed for the treatment of acute aTTP episodes will be assessed.

  10. Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) and Specifically Product-Related AEs and SAEs [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    An AE is defined as any untoward medical occurrence in a participants administered IP that does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) is an AE with any untoward clinical manifestation of signs, symptoms or outcomes which results in death, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, results in a congenital abnormality/birth defect, important medical event, bronchospasm associated with anaphylaxis, reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V). A product related AE is any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsens.

  11. Number of Participants with Clinically Relevant Changes in Vital Signs [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Vital signs will be assessed based on blood pressure, pulse rate, respiratory rate and body temperature.

  12. Number of Participants with Clinically Relevant Changes in Clinical Chemistry [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Clinical chemistry wiil be assessed Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.

  13. Number of Participants with Clinically Relevant Changes in Hematology [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Hematology consists of complete blood count and leukocytes with differential (basophils, eosinophils, lymphocytes,monocytes, neutrophils), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC) and platelet count.

  14. Time to Normalization of Platelet Count [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Time to normalization of platelet count, defined as platelet count greater than or equal to (>=) 150,000/μL, which must be confirmed by a second normal platelet count >= 150,000/μL and LDH lesser than (<)2 ULN 48 hours following initial normalization.

  15. Occurrence of Remission [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Remission is defined as a normal platelet count and LDH < 2 ULN for at least 48 hours following initial normalization of platelet count (acute episode period). Normalization of platelet count is defined as greater than or equal to (>=) 150,000/μL, which must be confirmed by a second normal platelet count >= 150,000/μL and LDH lesser than (<)2 upper limit of normal (ULN).

  16. Occurrence of Participants Receiving Rescue Therapy [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Rescue therapy will be defined as any product with a known interruption to the pharmacokinetic/pharmacodynamic (PK/PD) relationship between ADAMTS-13 activity, von Willebrand factor (VWF) activity, and platelet count. If rescue therapy is initiated, the administration of IP (SHP655 or placebo) will be suspended for the duration of the study. Number of participants experiencing occurrence of receiving rescue therapy will be assessed.

  17. Occurrence of Participants Meeting Rescue Criteria [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Rescue therapy will be defined as any product with a known interruption to the pharmacokinetic/pharmacodynamic (PK/PD) relationship between ADAMTS-13 activity, VWF activity, and platelet count. If rescue therapy is initiated, the administration of IP (SHP655 or placebo) will be suspended for the duration of the study. Number of participants experiencing occurrence in meeting rescue therapy criteria will be assessed.

  18. Occurrence of Exacerbation [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Occurrence of exacerbation will be determined by platelet count or the occurrence after remission of a major clinical event (e.g. MI, stroke, death) deemed by the investigator to be related to aTTP.

  19. Occurrence of Relapse [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Occurrence of relapse will be determined by platelet count or the occurrence after remission of a major clinical event (e.g. Myocardial Infraction (MI), stroke, death) deemed by the investigator to be related to aTTP.

  20. Occurrence of Major Clinical Events Related to TTP [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Major clinical events related to TTP including (Death, Stroke, MI, organ dysfunction not normalized within the 90-day observation period).

  21. Time to First Exacerbation [ Time Frame: From start of study drug administration up to 13 weeks (following remission up to 6 months) ]
    Exacerbation is defined as recurrent thrombocytopenia following a response and requiring a reinitiation of daily plasma exchange treatment after greater than or equal to (>=) 1 day but less than or equal to (<= 30) days of no plasma exchange treatment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 greater than or equal to (>=) 50% or platelet count lesser than (<) 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) greater than (>) 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 lesser than or equal to (<=) 200 cells/mm3 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03922308


Contacts
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Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

Locations
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United States, Alabama
The University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35249
Contact: Site Contact    205-934-6421    mmarques@uabmc.edu   
Principal Investigator: Marisa Marques         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21205
Contact: Site Contact    410-502-6686    schatur3@jhmi.edu   
Principal Investigator: Shruti Chaturvedi         
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Site Contact    617-732-5190    aparnes@bwh.harvard.edu   
Principal Investigator: Aric Parnes, Dr.         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Site Contact    612-624-5620    datta009@umn.edu   
Principal Investigator: Yvonne Datta         
United States, Ohio
The Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Contact    614-293-3196    spero.cataland@osumc.edu   
Principal Investigator: Spero Cataland, MD         
United States, Oklahoma
Stephenson Cancer Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Site Contact    405-271-4022    Sami-Ibrahimi@ouhsc.edu   
Principal Investigator: Sami Ibrahimi         
France
Hopital Conception Recruiting
Marseille, France, 13005
Contact: Site Contact    33491383924    Pascale.POULLIN@ap-hm.fr   
Principal Investigator: Pascale Poullin         
Chu Saint-Antoine Recruiting
Paris, France, 75012
Contact: Site Contact    33 1 49 28 26 21    paul.coppo@aphp.fr   
Principal Investigator: Paul Coppo, MD         
CHU de Rouen Recruiting
Seine Maritime, France, 76031
Contact: Site Contact    33 2 32 88 90 03    ygal.benhamou@chu-rouen.fr   
Principal Investigator: Ygal Benhamou         
Germany
Hamatologie, Onkologie, Hämostaseologie Recruiting
Frankfurt, Germany, D-60590
Contact: Site Contact    0049 69 6301 5051    Wolfgang.miesbach@kgu.de   
Principal Investigator: Wolfgang Miesbach         
Spain
Hospital General Universitario de Alicante Recruiting
Alicante, Spain, 03010
Contact: Site Contact    34609664803    marco_pas@gva.es   
Principal Investigator: Pascual Marco Vera         
Hospital General Universitario Gregorio Maranon Recruiting
Madrid, Spain, 28007
Contact: Site Contact    34915868014    crisizquierdo3@yahoo.es   
Principal Investigator: Cristina Pascual, MD, PhD         
Hospital Dr. Peset Recruiting
Valencia, Spain, 46017
Contact: Site Contact    0034 961622798    fernandez_migzar@gva.es   
Principal Investigator: Miguel Fernandez Zarzoso, MD         
Hospital Universitari i Politècnic la Fe Recruiting
Valencia, Spain, 46026
Contact: Site Contact    +34 96 1244 190    ijarqueramos@gmail.com   
Principal Investigator: Isidro Jarque Ramos, MD         
United Kingdom
Royal Liverpool University Hospital Recruiting
Liverpool, United Kingdom, L7 8XP
Contact: Site Contact    44151 282 6724    Tina.Dutt@liverpoolft.nhs.uk   
Principal Investigator: Tina Dutt         
1st Floor, UCLH-Haematology Recruiting
London, United Kingdom, WC1E 6HX
Contact: Site Contact    (+44) 203 447 9884    m.scully@nhs.net   
Principal Investigator: Marie Scully, MD         
Sponsors and Collaborators
Shire
Investigators
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Study Director: Study Director Shire
Additional Information:
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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT03922308    
Other Study ID Numbers: SHP655-201
2018-003775-35 ( EudraCT Number )
First Posted: April 19, 2019    Key Record Dates
Last Update Posted: February 25, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Purpura
Purpura, Thrombocytopenic
Purpura, Thrombotic Thrombocytopenic
Blood Coagulation Disorders
Hematologic Diseases
Hemorrhage
Pathologic Processes
Skin Manifestations
Thrombotic Microangiopathies
Thrombocytopenia
Blood Platelet Disorders
Immune System Diseases
Thrombophilia