Clinical trial NCT02216084: Phase 1 Dose Escalation, Single Dose Study to Assess Safety and Pharmacokinetics of BAX930 in Hereditary Thrombotic Thrombocytopenic Purpura (TTP)
Official title: BAX930 (rADAMTS13): A Phase 1 Prospective, Uncontrolled, Open-Label, Multicenter, Dose-Escalation Study Evaluating the Safety and Pharmacokinetics in Hereditary Thrombotic Thrombocytopenic Purpura (TTP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hereditary Thrombotic Thrombocytopenic Purpura (TTP)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-08-13
Enrollment: 16
Sex: ALL
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this Phase 1, prospective, uncontrolled, open-label, multicenter, dose-escalation study is to evaluate the safety, including immunogenicity, and pharmacokinetics of BAX930 (rADAMTS13) in a total of 14 evaluable subjects diagnosed with severe hereditary thrombotic thrombocytopenic purpura (TTP) (plasma ADAMTS13 activity \<6%) who are assigned to one of three dose cohorts.


Eligibility criteria: Inclusion Criteria:

* Subject is between 12 and 65 years of age, inclusive. (The first 2 subjects in any cohort will be ≥ 18 years of age.)
* Subject and/or legally authorized representative has provided written informed consent.
* Subject has a documented diagnosis of severe hereditary ADAMTS13 deficiency, defined as 1) confirmed by genetic testing, documented in patient history or at screening, and 2) ADAMTS13 activity \< 6%, documented in patient history or at screening. NOTE: In patients receiving prophylactic therapy with fresh frozen plasma (FFP) or other ADAMTS13 containing products, the levels of plasma ADAMTS13 activity may exceed 6% at screening.
* Cryoprecipitate, FFP, or other ADAMTS13 containing products interfering with ADAMTS13 PK have to be paused at least 10 days prior to infusion of the investigational product.
* The subject is not displaying any severe TTP symptoms at screening. Patients presenting with minor, but stable laboratory abnormalities (LDH not higher than 3 times the upper limit of normal; platelet count not lower than 100,000 per μl) at screening may be enrolled.
* Subjects ≥18 years of age have a Karnofsky score ≥ 60%, and subjects \< 18 years of age have a Lansky score ≥ 70%.
* Subject is hepatitis C virus negative (HCV-) as confirmed by antibody or polymerase chain reaction (PCR) testing; HCV positive (HCV+) subjects are eligible for inclusion if their disease is chronic but stable.
* If female of childbearing potential, subject presents with a negative serum pregnancy test and agrees to employ adequate birth control measures for the duration of the study.
* Subject is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

* Subject has been diagnosed with any other TTP-like disorder (for example, microangiopathic hemolytic anemia), including acquired TTP.
* Subject has known hypersensitivity to hamster proteins or other components of the investigational product.
* Subject has a medical history or presence of a functional neutralizing ADAMTS13 inhibitor at screening.
* Subject has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis/mild asthma, food allergies or animal allergies.
* Subject has a medical history of hematological disorders, in particular systemic lupus erythematosus, amyloidosis, antiphospholipid antibody syndrome, vasculitis, other hemolytic anemia, disseminated intravascular coagulation, and systemic scleroderma.
* Subject has a history of significant neurological events, such as major stroke, indicating that a relapse might have severe consequences, as judged by the investigator.
* Subject is HIV positive with an absolute CD4 count \< 200/mm3.
* Subject has been diagnosed with a cardiovascular disease \[New York Heart Association (NYHA) classes 3-4\].
* Subject is scheduled to undergo elective surgery during study participation.
* Subject has been diagnosed with severe liver disease, as evidenced by, but not limited to, any of the following: serum ALT 3 times the upper limit of normal, international normalized ratio (INR) \> 1.5, hypoalbuminemia, portal vein hypertension (e.g. presence of otherwise unexplained splenomegaly, history of esophageal varices).
* Subject has been diagnosed with severe glomerular disease, with gross proteinuria and a serum creatinine level ≥ 2.5 mg/dL.
* Subject has been treated with an immunomodulatory drug, in case of corticoids with an equivalent to hydrocortisone greater than 10 mg /day, excluding topical treatment (e.g. ointments, nasal spray), within 30 days prior to enrollment.
* Subject has a history of drug and/or alcohol abuse within the last 6 months prior to study enrollment.
* Subject has a life expectancy of less than 3 months.
* Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures.
* Subject is a family member or employee of the investigator.
* Subject 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.
* If female, subject is pregnant or lactating at the time of study enrollment.
* Subject has participated in another clinical study involving an investigational product or device within 30 days prior to study enrollment.
* Subject is scheduled to participate in another clinical study involving an investigational product or device during the course of this study.

Primary outcomes:
measure: Occurrence of adverse events (serious and non-serious), including the incidence of binding and inhibitory antibody formation
timeFrame: Up to 28 (± 3) days after investigational product infusion
Secondary outcomes:
measure: Pharmacokinetic [PK] parameter 'incremental recovery [IR]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: PK parameter 'maximum concentration following infusion [Cmax]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: PK parameter 'minimum time to reach Cmax [T max]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: PK parameter 'terminal or disposition half-life [T1/2]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: PK parameter 'mean residence time [MRT]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: PK parameter 'systemic clearance [Cl]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: PK parameter 'area under the plasma/time curve [AUC]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: PK parameter 'steady state volume of distribution [Vss]'
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
measure: Plasma von Willebrand factor: Ristocetin cofactor activity [VWF:RCo], von Willebrand factor antigen [VWF:Ag] and VWF structure analysis
timeFrame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
Other outcomes:
Locations:
city: Dublin
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Houston
country: United States
facility: The Methodist Hospital Research Institute
state: Texas
city: Vienna
country: Austria
facility: General Hospital Vienna (Allgemeines Krankenhaus der Stadt Wien)
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Bunkyo-ku, Tokyo
country: Japan
facility: • Tokyo Medical and Dental University Hospital, Faculty of Medicine
city: Nishinomiya-shi
country: Japan
facility: Hyogo College of Medicine Hospital, Department of Hematology
city: Warsaw
country: Poland
facility: Institute of Hematology and Transfusion Medicine
city: Bern
country: Switzerland
facility: Inselspital - Universitaetsspital Bern
city: London
country: United Kingdom
facility: University College London Hospital NHS Foundation Trust
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Scully M, Knobl P, Kentouche K, Rice L, Windyga J, Schneppenheim R, Kremer Hovinga JA, Kajiwara M, Fujimura Y, Maggiore C, Doralt J, Hibbard C, Martell L, Ewenstein B. Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura. Blood. 2017 Nov 9;130(19):2055-2063. doi: 10.1182/blood-2017-06-788026. Epub 2017 Sep 14.