Trial Summary
What is the purpose of this trial?Thrombotic thrombocytopenic purpura (or TTP for short) is a condition where blood clots form in small blood vessels throughout the body. The clots can limit or block the flow of oxygen-rich blood to the body's organs, such as the brain, kidneys, and heart. As a result, serious health problems can develop. The increased clotting that occurs in TTP uses up the cells that help the blood to clot, called platelets. With fewer platelets available in the blood, bleeding problems can also occur. People who have TTP may bleed underneath the skin forming purple bruises, or purpura. TTP also can cause anemia, a condition in which red blood cells break apart faster than the body can replace them, leading to fewer red blood cells than in normal.
TTP is caused by a lack of activity in the ADAMTS13 enzyme, a protein in the blood involved in controlling clotting of the blood. The ADAMTS13 enzyme breaks up another blood protein called von Willebrand factor that forms blood clots by clumping together with platelets. Some people are born with this condition, while others develop the condition during their life. Many people who are born with TTP experience frequent flare-ups that need to be treated right away. TAK-755 is a medicine that replaces ADAMTS13 and may prevent or control TTP flare-ups, called acute TTP events.
The main aim of the study is to check for side effects of long-term treatment with TAK-755. Treatment will be given in 2 ways:
1. TAK-755 treatment given either every week or every other week to prevent acute TTP events from happening (the "prophylactic" cohort).
2. TAK-755 treatment given to control an acute TTP event when it happens (the "on-demand" cohort).
Participants in the prophylactic cohort will receive treatment in the clinic or at home for up to approximately 3 years. They will visit the clinic at least every 12 weeks. Participants in the on-demand cohort will receive daily treatment for the acute TTP event until the flare-up has gotten better. They will have a follow-up visit at the clinic 4 weeks later.
Will I have to stop taking my current medications?
The trial protocol does not specify whether you need to stop taking your current medications. However, if you are taking immunomodulatory drugs (medications that modify the immune system), you must stop them at least 30 days before enrolling in the study, except for certain topical treatments and corticosteroids used with fresh frozen plasma.
What data supports the effectiveness of the drug TAK-755 for treating Purpura?
The research highlights the importance of ADAMTS13 activity in diagnosing and predicting outcomes for thrombotic thrombocytopenic purpura (TTP), suggesting that treatments targeting ADAMTS13, like TAK-755, could be effective in managing this condition.
12345Is TAK-755 (recombinant ADAMTS13) safe for humans?
In a study with 15 patients, TAK-755 (also known as BAX 930) was well tolerated with no serious side effects, and no antibodies against the treatment were found. Additionally, animal studies showed no increased risk of bleeding, even at high doses.
678910How is the drug TAK-755 unique in treating Purpura?
TAK-755 is unique because it is a recombinant form of the enzyme ADAMTS13, which helps break down von Willebrand factor to prevent excessive blood clotting, specifically targeting the underlying cause of thrombotic thrombocytopenic purpura (TTP). This approach directly addresses the enzyme deficiency that leads to TTP, unlike other treatments that may not target this specific mechanism.
1341112Eligibility Criteria
This trial is for individuals aged 0-70 with severe congenital ADAMTS-13 deficiency, a condition leading to excessive blood clotting and bleeding issues. Participants must be in good health otherwise, not pregnant, agree to use birth control, and have no history of drug/alcohol abuse or immune deficiencies. They cannot have other TTP-like disorders or life-threatening reactions to similar treatments.Inclusion Criteria
I have been diagnosed with severe congenital ADAMTS-13 deficiency.
My doctor says I am mostly active and can care for myself.
I am not pregnant and use birth control.
I don't have severe blood clotting issues or very high LDH levels.
I am over 16 and can care for myself, or I am under 16 and mostly active.
I am between 0 and 70 years old.
I have been diagnosed with severe congenital ADAMTS-13 deficiency.
I use effective birth control methods.
I am between 0 and 70 years old.
I have signs of TTP (a rare blood disorder).
Exclusion Criteria
I am currently sick.
I have been diagnosed with a condition similar to TTP.
I haven't taken any immune system modifying drugs in the last 30 days.
My doctor expects I have 3 months or less to live due to my illness.
I have severe heart problems or kidney failure needing regular dialysis.
I have a history of immune deficiency or significant neurological events.
I have never received TAK-755 before.
Participant Groups
TAK-755 is being tested as a replacement therapy for the ADAMTS13 enzyme in patients with congenital thrombotic thrombocytopenic purpura (TTP). The study has two parts: one where TAK-755 is given regularly to prevent flare-ups ('prophylactic' cohort) and another where it's given during acute flare-ups ('on-demand' cohort).
2Treatment groups
Experimental Treatment
Group I: Prophylactic Cohort: TAK-755Experimental Treatment1 Intervention
All participants will receive prophylactic treatment with 40 IU/kg TAK-755 intravenous (IV) infusions once every week or once every other week for the duration of the study.
Participants who are naïve will receive an initial IV dose of 40 IU/kg TAK-755 to allow measurement of the pharmacokinetics of TAK-755, followed by prophylactic treatment with 40 IU/kg TAK-755 by IV infusion once every week or once every other week for the duration of the study.
Group II: On-Demand Cohort: TAK-755Experimental Treatment1 Intervention
Participants will receive daily IV infusions of TAK-755 when experiencing an acute thrombotic thrombocytopenic purpura (TTP) event until 2 days after the acute TTP event is resolved.
Participants will receive 40 IU/kg TAK-755 on the first day, followed by 20 IU/kg on Day 2, and then 15 IU/kg daily until 2 days after the acute TTP event has resolved. Upon resolution of the acute TTP event, participants may choose to move to the prophylactic cohort of the study or discontinue entirely from the study.
TAK-755 is already approved in United States, European Union, Japan for the following indications:
🇺🇸 Approved in United States as TAK-755 for:
- Congenital Thrombotic Thrombocytopenic Purpura (cTTP)
🇪🇺 Approved in European Union as TAK-755 for:
- Thrombotic thrombocytopenic purpura
🇯🇵 Approved in Japan as TAK-755 for:
- Thrombotic thrombocytopenic purpura
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Mid Ohio Heart Clinic IncDublin, OH
University of Minnesota Health Clinical Research UnitMinneapolis, MN
University of OklahomaOklahoma City, OK
Roswell Park Comprehensive Cancer CenterBuffalo, NY
More Trial Locations
Loading ...
Who is running the clinical trial?
TakedaLead Sponsor
Takeda Development Center Americas, Inc.Industry Sponsor
ShireIndustry Sponsor
References
Diagnostic relevance of ADAMTS13 activity: evaluation of 28 patients with thrombotic thrombocytopenic purpura - hemolytic uremic syndrome clinical diagnosis. [2019]The significance of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) is still a controversial issue.
Predictive Values of ADAMTS13, TBIL, and D-D for Prognosis of Patients with Thrombotic Thrombocytopenic Purpura. [2023]The aim of the study was to investigate the levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), total bilirubin (TBIL), and D-dimer (D-D) in thrombotic thrombocytopenic purpura (TTP) and their values for predicting the prognosis.
Incidence of obstetrical thrombotic thrombocytopenic purpura in a retrospective study within thrombocytopenic pregnant women. A difficult diagnosis and a treatable disease. [2018]Thrombotic thrombocytopenic Purpura (TTP) defined as ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 domain 13) activity
Clinical features and outcomes in patients with thrombotic microangiopathy not associated with severe ADAMTS13 deficiency. [2018]The a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 (ADAMTS13) activity assay has become important in distinguishing autoimmune thrombotic thrombocytopenic purpura from other forms of thrombotic microangiopathy (TMA). Although the significance of severe deficiency in ADAMTS13 (activity levels 10% or less) has been well defined, little data are available on the clinical importance of mild to moderate deficiency (activity levels 11%-70%) among patients with TMA.
A multi-center evaluation of TECHNOSCREEN® ADAMTS-13 activity assay as a screening tool for detecting deficiency of ADAMTS-13. [2023]Quantifying A disintegrin-like and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS-13) activity enhances thrombotic thrombocytopenic purpura (TTP) diagnosis but most assays are time consuming, technically demanding, and mainly available in reference centers.
ADAMTS-13 assays in thrombotic thrombocytopenic purpura. [2023]ADAMTS-13, the thirteenth member of the ADAMTS (A Disintegrin And Metalloprotease with Thrombo-Spondin 1 repeats) family, is the plasma metalloprotease responsible for regulating the multimeric structure of VWF. In congenital or acquired deficiency it is actively involved in the pathophysiology of thrombotic thrombocytopenic purpura (TTP), a rare but life threatening disease characterized by microangiopathic haemolytic anaemia and consumptive thrombocytopenia leading to disseminated microvascular thrombosis and variable signs and symptoms of organ ischemia and damage. In the last few years, a number of in house and commercial laboratory assays for ADAMTS-13 and its autoantibodies have been developed. The features and clinical utility of ADAMTS-13 assays are summarized in this review.
Relation between ADAMTS13 activity and ADAMTS13 antigen levels in healthy donors and patients with thrombotic microangiopathies (TMA). [2019]We have established a new, enzyme-linked immunosorbent assay (ELISA) for the detection of ADAMTS13 antigen using purified polyclonal rabbit anti-human ADAMTS13 IgG. Normal plasma ADAMTS13 antigen levels span a concentration of 740-1420 ng/ml (median 1080 ng/ml) resulting in an ADAMTS13 activity to antigen ratio of 0.48 to 1.68 U/mug. In a cohort of HUS patients, ADAMTS13 antigen was in the normal range, whereas in hereditary TTP patients antigen levels were low to undetectable, in concordance with severe deficient ADAMTS13 activity. Plasma of acquired TTP patients was found to contain free as well as autoantibody-bound ADAMTS13. We also present evidence for circulating anti-ADAMTS13 antibody/ADAMTS13 antigen immune complexes not only in acutely ill or actively treated patients but also in patients who have already achieved clinical remission. This new developed ADAMTS13 antigen ELISA assay allows rapid determination of ADAMTS13 antigen levels in human plasma but is of limited predictive value for the diagnosis or treatment of acquired TTP due to the detection of ADAMTS13 in antibody complexes.
Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura. [2022]Safety, tolerability, and pharmacokinetics of recombinant ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity <6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. After single-dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to maximum plasma concentration (Cmax [U/mL]) and area under the concentration-time curve (AUC [h∙U/mL]). Dose-related increases of individual ADAMTS-13:Ag and activity were observed and reached a maximum within 1 hour. With escalating BAX 930 doses administered, a dose-dependent persistence of ADAMTS-13-mediated von Willebrand factor (VWF) cleavage products and reduced VWF multimeric size were observed. This study demonstrated that pharmacokinetic parameters of BAX 930 were comparable to those estimated in previous plasma infusion studies and provided evidence of pharmacodynamic activity. This study was registered at www.clinicaltrials.gov as #NCT02216084.
The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura. [2016]Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy often associated with a severely decreased activity of ADAMTS13. In plasma of the majority of patients with TTP, antibodies are present that inhibit the von Willebrand factor (VWF) processing activity of ADAMTS13. We describe a sensitive assay that monitors binding of recombinant ADAMTS13 to immobilized IgG derived from patient plasma. Analysis of fifteen patients with TTP and severely reduced ADAMTS13 activity revealed that in all patients antibodies directed to ADAMTS13 were present. Levels of anti-ADAMTS13 antibodies varied considerably among patients, specific antibody levels in plasma range from less than 100 ng/ml to over 1 microg/ml. Longitudinal analysis in three patients revealed that anti-ADAMTS13 antibody levels declined with different kinetics. For further characterization of anti-ADAMTS13 antibodies, we prepared a series of recombinant fragments corresponding to the various ADAMTS13 domains. All seven TTP plasma samples tested, showed reactivity of antibodies towards a fragment consisting of the disintegrin/TSR1/cysteine-rich/spacer domains. In one patient, we also observed reactivity towards the TSR2-8 repeats. No binding of antibodies to propeptide, metalloprotease and CUB domains was detected. To further delineate the binding site in the disintegrin/TSR1/cysteine-rich/spacer region, we prepared additional ADAMTS13 fragments. Antibodies directed towards the cysteine-rich/spacer fragment were found in all plasma samples analyzed. No antibodies reacting with the disintegrin/TSR1 domains were detected. A recombinant fragment comprising the spacer domain was recognized by all patients samples analyzed, suggesting that the 130-amino-acid spacer domain harbors a major binding site for anti-ADAMTS-13 antibodies.
Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey. [2023]Insufficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif repeats-13) is the cause of thrombotic thrombocytopenic purpura (TTP) and contributes in microangiopathy in sickle cell disease (SCD). Recombinant ADAMTS13 effectively cleaves prothrombotic ultra-large von Willebrand factor (VWF) multimers. It is being tested as replacement therapy for TTP, and at supra-physiologic concentrations, for moderating vaso-occlusive crisis in SCD. Deficiencies of VWF, or concomitant treatment with antithrombotic drugs, could pose risks for increased bleeds in these patient populations. The purpose of the experiments was to evaluate the potential of exaggerated pharmacology and temporary bleeding risks associated with rADAMTS13 administration. We utilized safety studies in monkey and tested the effects of administering maximum-feasible doses of rADAMTS13 on nonclinical safety and spontaneous or aggressive bleeds in the rat model. Evaluation of pharmacokinetics, toxicity profiles, and challenge in a tail-tip bleeding model show that treatment with rADAMTS13 did not increase bleeding tendency, either alone, or in combination with enoxaparin or acetylsalicylic-acid. These novel findings demonstrate absence of rADAMTS13 exaggerated pharmacology without spontaneous or aggravated bleeds even at supra-physiologic (>100-fold) plasma concentrations.
Reference range for ADAMTS13 antigen, activity and anti-ADAMTS13 antibody in the healthy adult Singapore population [2022]ADAMTS13 (a disintegrin-like and metalloproteinase with a thrombospondin Type 1 motif, member 13) plays a fundamental role in the regulation of haemostasis and thrombosis. Its deficiency leads to an accumulation of ultra-large von Willebrand multimers, inducing spontaneous platelet aggregation, thrombosis in the microvasculature, and thrombotic thrombocytopenic purpura (TTP), a condition with 90% mortality when left untreated. Prompt quantification of ADAMTS13 antigen, activity and autoantibody plays a crucial role in the diagnosis and management of TTP and can help differentiate it from other thrombotic microangiopathies (TMAs). Reference ranges for ADAMTS13 are generally derived from Caucasian patients. Given that polymorphism in the ADAMTS13 gene can be associated with variable ADAMTS13 levels, we aimed to establish the first reference range in Singapore and provide a crucial laboratory test for institutions here and elsewhere.
Measurement of ADAMTS13. [2020]ADAMTS13, encoded on chromosome 9q34, is a member of the ADAMTS (a disintegrin and metalloprotease with thrombospondin type 1 motif) metalloprotease family, containing the common domain structure of (from the amino terminus) signal peptide, propeptide, reprolysin type metalloprotease, thrombospondin type 1 motif, cysteine-rich region, and spacer domain. ADAMTS13 cleaves von Willebrand factor (VWF) in a shear stress dependent manner. Deficiency of the enzyme causes the platelet aggregation of thrombotic thrombocytopenic purpura (TTP). Inhibitory antibodies of ADAMTS13 are detected in patients with acquired TTP, while homozygous or double heterozygous mutations of the ADAMTS13 gene cause the hereditary form of the disease 1. Targeting of the ADAMTS13 gene by recombinant technology has reproduced the phenotype of human TTP in ADAMTS13-null mice 2. Despite these advances, intense controversy and confusion persist regarding the role of ADAMTS13 assays in the diagnosis of TTP. This brief review highlights some of the contentious issues and proposes steps to improve the diagnostic value of ADAMTS13 assays.