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A Phase 3, Randomized, Controlled Study of Prophylactic and On-demand Treatment of cTTP With BAX 930 (rADAMTS13)

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ClinicalTrials.gov Identifier: NCT03393975
Recruitment Status : Recruiting
First Posted : January 9, 2018
Last Update Posted : June 20, 2019
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Brief Summary:
To purpose of this study is to assess safety and efficacy of BAX 930 in the prevention and treatment of acute episodes of thrombotic thrombocytopenic purpura (TTP) in subjects with severe hereditary deficiency of ADAMTS13 (cTTP; defined as plasma ADAMTS13 <10%, as measured by the fluorescent resonance energy transfer-VWF73 [FRETS] assay)

Condition or disease Intervention/treatment Phase
Congenital Thrombotic Thrombocytopenic Purpura Biological: BAX930 Biological: Standard of care Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: This is a Phase 3, prospective, randomized, controlled, open-label, multicenter, 2-period crossover study with a single arm continuation evaluating the safety and efficacy of BAX 930 in the prophylactic and on-demand treatment of subjects with severe congenital thrombotic thrombocytopenic purpura (cTTP).
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase 3, Prospective, Randomized, Controlled, Open-label, Multicenter, 2-period Crossover Study With a Single Arm Continuation Evaluating the Safety and Efficacy of BAX 930 (rADAMTS13) in the Prophylactic and On-demand Treatment of Participants With Severe Congenital Thrombotic Thrombocytopenic Purpura (cTTP) (Upshaw-Schulman Syndrome)
Actual Study Start Date : November 6, 2017
Estimated Primary Completion Date : December 16, 2022
Estimated Study Completion Date : December 16, 2022


Arm Intervention/treatment
Experimental: Prophylaxis Cohort Arm 1
(1) Pharmacokinetic (PK) Assessments: PK 1 = Investigator-recommended Standard of Care (SoC) then PK 2 = BAX930. (2) Period 1 Prophylaxis (Prophy) = BAX930; Period 2 Prophy = SoC; Period 3 Prophy = BAX930. (4) PK3 = BAX930
Biological: BAX930
A recombinant human disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13
Other Names:
  • rADAMTS13
  • SHP-655
  • recombinant ADAMTS13
  • BAX 930

Biological: Standard of care
Investigator-recommended Standard of care (SoC)

Experimental: Prophylaxis Cohort Arm 2
(1) Pharmacokinetic (PK) Assessments: PK 1 = BAX930 then PK 2 = Investigator-recommended Standard of Care (SoC). (2) Period 1 Prophylaxis (Prophy) = SoC; Period 2 Prophy = BAX930; Period 3 Prophy = BAX930. (4) PK3 = BAX930
Biological: BAX930
A recombinant human disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13
Other Names:
  • rADAMTS13
  • SHP-655
  • recombinant ADAMTS13
  • BAX 930

Biological: Standard of care
Investigator-recommended Standard of care (SoC)

Experimental: SoC On-Demand Cohort (Then prophylaxis) Arm 1
(1) On-Demand Cohort = Standard of Care (SoC). (2) Period 1 Prophylaxis (Prophy) = BAX930; Period 2 Prophy = SoC; Period 3 Prophy = BAX930. (3) Pharmacokinetic (PK) Assessment = BAX930
Biological: BAX930
A recombinant human disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13
Other Names:
  • rADAMTS13
  • SHP-655
  • recombinant ADAMTS13
  • BAX 930

Biological: Standard of care
Investigator-recommended Standard of care (SoC)

Experimental: SoC On-Demand Cohort (Then prophylaxis) Arm 2
(1) On-Demand Cohort = BAX930. (2) Period 1 Prophylaxis (Prophy) = SoC; Period 2 Prophy = BAX930; Period 3 Prophy = BAX930. (3) Pharmacokinetic (PK) Assessment = BAX930
Biological: BAX930
A recombinant human disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13
Other Names:
  • rADAMTS13
  • SHP-655
  • recombinant ADAMTS13
  • BAX 930

Biological: Standard of care
Investigator-recommended Standard of care (SoC)




Primary Outcome Measures :
  1. Incidence of acute thrombotic thrombocytopenic purpura (TTP) episodes [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of acute TTP episodes among participants receiving either BAX 930 or standard of care (SoC) prophylactically


Secondary Outcome Measures :
  1. Number of acute thrombotic thrombocytopenic purpura (TTP) episodes responding to BAX 930 [ Time Frame: Throughout the study period of approximately 60 months ]
    Defined as not requiring the use of another ADAMTS13-containing agent

  2. Incidence of acute thrombotic thrombocytopenic purpura (TTP) episodes responding to BAX 930 [ Time Frame: Throughout the study period of approximately 60 months ]
    Defined as not requiring the use of another ADAMTS13-containing agent

  3. Time to resolution of clinical symptomatology [ Time Frame: Throughout the study period of approximately 60 months ]
    Time to resolution of clinical symptomatology, if present, and normalization of laboratory parameters following initiation of treatment in acute thrombotic thrombocytopenic purpura (TTP) episodes with BAX 930 or standard of care (SoC) agent

  4. Incidence of thrombocytopenia [ Time Frame: Throughout the study period of approximately 60 months ]
    Defined as a drop in platelet count ≥25% of baseline or a platelet count <150,000/μL

  5. Incidence of microangiopathic hemolytic anemia [ Time Frame: Throughout the study period of approximately 60 months ]
    Defined as an elevation of lactate dehydrogenase (LDH) >1.5× upper limit of normal (ULN)

  6. Incidence of neurological symptoms [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of neurological symptoms (e.g., confusion, dysphonia, dysarthria, focal or general motor symptoms including seizures)

  7. Incidence of renal dysfunction [ Time Frame: Throughout the study period of approximately 60 months ]
    defined as an increase in serum creatinine >1.5×baseline

  8. Incidence of abdominal pain [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of abdominal pain

  9. Incidence of supplemental doses [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of supplemental doses prompted by subacute manifestations

  10. Incidence of dose modification [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of dose modification not prompted by an acute event

  11. Incidence of acute thrombotic thrombocytopenic purpura (TTP) episodes [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of acute TTP episodes while subjects are on their final dose and dosing regimen

  12. Incidence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of product-related and unrelated AEs and SAEs

  13. Incidence of antibodies to ADAMTS13 [ Time Frame: Throughout the study period of approximately 60 months ]
    Incidence of binding and inhibitory antibodies to ADAMTS13

  14. Clinically relevant changes in vital signs [ Time Frame: Throughout the study period of approximately 60 months ]
    Clinically relevant changes in vital signs includes: body temperature, pulse rate, respiratory rate, and blood pressure

  15. Clinically relevant changes in clinical chemistry [ Time Frame: Throughout the study period of approximately 60 months ]
    Clinically relevant changes in clinical chemistry includes: sodium, potassium, chloride, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose

  16. Clinically relevant changes in hematology [ Time Frame: Throughout the study period of approximately 60 months ]
    Clinically relevant changes in hematology includes: red blood cell (RBC) count, hemoglobin, hematocrit, haptoglobin, reticulocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), leukocytes (i.e., white blood cell count) with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, and neutrophils) and platelet counts

  17. Estimated total quantity of ADAMTS13 administered [ Time Frame: Throughout the study period of approximately 60 months. Acute events typically require 3-4 days of intensified treatment. ]
    Estimated total quantity of ADAMTS13 administered during the treatment of acute events

  18. Pharmacokinetics: Incremental Recovery (IR) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    For both the SoC agent and BAX 930

  19. Pharmacokinetics: area under the plasma curve [AUC] [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    For both the SoC agent and BAX 930

  20. Pharmacokinetics: Half Life (T-1/2) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    For both the SoC agent and BAX 930

  21. Pharmacokinetics: mean residence time (MRT) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    For both the SoC agent and BAX 930

  22. Pharmacokinetics: Clearance (CL) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    For both the SoC agent and BAX 930

  23. Pharmacokinetics: Volume at Steady State (Vss) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    For both the SoC agent and BAX 930

  24. Pharmacokinetics: Maximum Concentration (C-max) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    For both the SoC agent and BAX 930

  25. Assessment of von Willebrand factor: antigen (VWF:Ag) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    Multimer pattern at baseline and following infusion of the SoC agent and BAX 930 treatment during the initial PK assessment

  26. Assessment of von Willebrand factor: ristocetin cofactor activity (VWF: RCo) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    Multimer pattern at baseline and following infusion of the SoC agent and BAX 930 treatment during the initial PK assessment

  27. Assessment of von Willebrand factor (VWF) [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    Multimer pattern at baseline and following infusion of the SoC agent and BAX 930 treatment during the initial PK assessment

  28. Assessment of ADAMTS13 activity (pre-infusion ADAMTS13 levels) and VWF parameters [ Time Frame: Start of treatment periods and end of Treatment Period 2 prophylactic cohort. <12 years: within 60 min pre-infusion; and post-infusion at 6 timepoints up to 7 days. ≥12 years: within 60 min pre-infusion; and post-infusion at 12 timepoints up to 12 days. ]
    Assessment of ADAMTS13 activity (pre-infusion ADAMTS13 levels) and VWF parameters prior to each infusion of SoC or BAX 930 and at the time of acute event presentation

  29. Health Related Quality of Life (HRQoL): cTTP-specific patient reported outcomes (PROs) [ Time Frame: Screening visit, End of period 1 (approximately month 6), End of period 2 (approximately month 12.5), and End of period 3 (approximately month 19), or non-scheduled acute event (as needed). ]
    The cTTP PRO assessment is focused on measuring the symptoms and impacts of the disease.

  30. Health Related Quality of Life (HRQoL): 36-Item Short Form Health Survey (SF-36) [ Time Frame: Screening visit, End of period 1 (approximately month 6), End of period 2 (approximately month 12.5), and End of period 3 (approximately month 19), or non-scheduled acute event (as needed). ]
    Self-administered, validated questionnaire. A 36-item questionnaire which measures 8 domains

  31. Health Related Quality of Life (HRQoL): Abbreviated 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) [ Time Frame: Screening visit, End of period 1 (approximately month 6), End of period 2 (approximately month 12.5), and End of period 3 (approximately month 19), or non-scheduled acute event (as needed). ]
    The TSQM-9 questionnaire is a validated measure consisting of 3 domains (efficacy, convenience, and overall satisfaction) and 9 questions

  32. Health Related Quality of Life (HRQoL): EuroQol 5 Dimensions Questionnaire 3-Level (EQ-5D-3L) [ Time Frame: Screening visit, End of period 1 (approximately month 6), End of period 2 (approximately month 12.5), and End of period 3 (approximately month 19), or non-scheduled acute event (as needed). ]
    This is a generic measure of health. Self-rated health is captured using a visual analog scale.

  33. Health Related Quality of Life (HRQoL): EQ-5D-youth (EQ-5D-Y) [ Time Frame: Screening visit, End of period 1 (approximately month 6), End of period 2 (approximately month 12.5), and End of period 3 (approximately month 19), or non-scheduled acute event (as needed). ]
    This is a generic measure of health. Self-rated health is captured using a visual analog scale.

  34. Health Related Quality of Life (HRQoL): Pediatric Quality of Life Inventory (Ped QL) [ Time Frame: Screening visit, End of period 1 (approximately month 6), End of period 2 (approximately month 12.5), and End of period 3 (approximately month 19), or non-scheduled acute event (as needed). ]
    The Ped QL is a generic HRQoL instrument designed specifically for a pediatric population.

  35. Resource Utilization: hospital length of stay for acute TTP episodes [ Time Frame: Throughout the study period of approximately 60 months ]
    This information will be gathered by the sites.

  36. Resource Utilization: resource utilization during prophylaxis [ Time Frame: Throughout the study period of approximately 60 months ]
    This information will be gathered by the sites.

  37. Resource Utilization: days missed from school/work due to TTP-related illness [ Time Frame: Throughout the study period of approximately 60 months ]
    This information will be gathered by the sites.



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:   up to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant or legally authorized representative has provided signed informed consent greater than or equal to (≥)18 years of age) and/or assent form (signed by legal representative if participants is less than (<)18 years of age).
  2. Participant is 0 to 70 years of age, inclusive, at the time of screening. (Participants <18 years of age will be enrolled only after at least 5 adults (≥18 years of age) each have at least 10 exposures with BAX 930 and reviewed by the DMC. In France, no participants younger than 18 years of age will be enrolled into the study before the first adult participant has been treated with BAX 930 for a minimum of 6 months.
  3. Participant has a documented diagnosis of severe hereditary ADAMTS13 deficiency, defined as:

    • Confirmed by molecular genetic testing, documented in participant history or at screening, and
    • A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity <10% as measured by the fluorescent resonance energy transfer- von Willebrand factor73 (FRETS-VWF73) assay, documented in participant history or at screening (participants currently receiving SoC prophylactic therapy may exceed 10% ADAMTS13 activity at screening).

    Note: Participants currently receiving prophylactic therapy will be screened immediately prior to their usual prophylactic infusion

  4. Participant does not display any severe thrombotic thrombocytopenic purpura (TTP) signs (platelet count <100,000/ microliter (μL) and elevation of lactate dehydrogenase (LDH) greater than (>2)× upper limit of normal (ULN)) at screening. (Prophylactic cohort only).
  5. Participant is currently on a prophylactic dosing regimen or has a documented history of at least 1 TTP event and an ability to tolerate SoC prophylactic dosing (prophylactic cohort only).
  6. Participants ≥16 years of age must have a Karnofsky score ≥70% and participants <16 years of age must have a Lansky score ≥80 percentage (%).
  7. Participant is hepatitis C virus (HCV)-negative as confirmed by antibody or polymerase chain reaction testing OR HCV-positive if their disease is chronic but stable.
  8. If female of childbearing potential, participant presents with a negative blood or urine pregnancy test, confirmed no more than 7 days before the first administration, and agrees to employ adequate birth control measures for the duration of the study and to undergo quarterly pregnancy testing.
  9. 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.
  10. Participant is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

  1. Participant has been diagnosed with any other TTP-like disorder (microangiopathic hemolytic anemia), including acquired TTP.
  2. Participant has known hypersensitivity to hamster proteins.
  3. Participant has experienced an acute TTP episode less than 30 days prior to screening (prophylactic cohort only).
  4. Participant has a medical history or presence of a functional ADAMTS13 inhibitor at screening.
  5. Participant has a medical history of genetic or acquired immune deficiency that would interfere with the assessment of product immunogenicity, including participants who are human immunodeficiency virus (HIV)-positive with an absolute cluster of differentiation 4 (CD4) count <200/ Cubic Millimeter (mm^3) or who are receiving chronic immunosuppressive drugs.
  6. Participant has been diagnosed with severe cardiovascular disease (New York Heart Association classes 3 to 4).
  7. Participant with end stage renal disease requiring chronic dialysis.
  8. Participant has been diagnosed with hepatic dysfunction, as evidenced by, but not limited to, any of the following:

    1. Serum alanine aminotransferase (ALT) ≥2×ULN.
    2. Severe hypoalbuminemia <24 gram per liter (g/L).
    3. Portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal varices).
  9. In the opinion of the investigator, the participant has another clinically significant concomitant disease that may pose additional risks for the participant.
  10. Participant has been treated with an immunomodulatory drug, excluding topical treatment (e.g., ointments, nasal sprays), within 30 days prior to enrollment. Use of corticosteroids in conjunction with administration of fresh frozen plasma (FFP) to prevent allergic manifestations is permitted.
  11. Participant has an acute illness (e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, bronchial asthma) at the time of screening (prophylaxis cohort only).
  12. Participant is receiving or anticipates receiving another investigational drug and/or interventional drug within 30 days before enrollment.
  13. Participant has a history of drug and/or alcohol abuse within the last 2 years.
  14. Participant has a progressive fatal disease and/or life expectancy of less than 3 months.
  15. Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.
  16. 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.
  17. Participant is a family member or employee of the sponsor or investigator.
  18. If female, participant is pregnant or lactating at the time of enrollment .
  19. Any contraindication to standard of care medicinal product(s) as per local prescribing information.

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): NCT03393975


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

Locations
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United Kingdom
University College London Hospitals Recruiting
London, Greater London, United Kingdom, NW1 2PG
Sponsors and Collaborators
Baxalta now part of Shire
Baxalta Innovations GmbH, now part of Shire
Investigators
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Study Director: Study Director Shire

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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT03393975     History of Changes
Other Study ID Numbers: 281102
2017-000858-18 ( EudraCT Number )
First Posted: January 9, 2018    Key Record Dates
Last Update Posted: June 20, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided 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 in the Data Sharing section of the www.shiretrials.com website. 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://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

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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
Signs and Symptoms
Thrombotic Microangiopathies
Thrombocytopenia
Blood Platelet Disorders
Immune System Diseases
Thrombophilia