Phase 1 Dose Escalation, Single Dose Study to Assess Safety and Pharmacokinetics of BAX930 in Hereditary Thrombotic Thrombocytopenic Purpura (TTP)

NCT02216084 | Completed Phase 1 DMC

• 2 other identifiers: 2811012012-003221-19
• Study Type: interventional
• Target: 16
• Locations: 7 countries
• Sites: 11

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.

Conditions

Hereditary Thrombotic Thrombocytopenic Purpura (TTP)

Outcome Measures

Primary Outcomes (1)

• Occurrence of adverse events (serious and non-serious), including the incidence of binding and inhibitory antibody formation

  Up to 28 (± 3) days after investigational product infusion

Secondary Outcomes (9)

• Pharmacokinetic [PK] parameter 'incremental recovery [IR]'

  Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion

• PK parameter 'maximum concentration following infusion [Cmax]'

  Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion

• PK parameter 'minimum time to reach Cmax [T max]'

  Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion

• PK parameter 'terminal or disposition half-life [T1/2]'

  Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion

• PK parameter 'mean residence time [MRT]'

  Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion

Study Arms (1)

Recombinant ADAMTS13

EXPERIMENTAL

The study is comprised of 3 dose cohorts and two dose escalation steps \[Cohort 1: 3 subjects; Cohort 2: 3 subjects; Cohort 3: 8 subjects\]. Subjects will be enrolled and dosed sequentially. Subjects will be recruited to the next dose level only after short-term safety has been demonstrated and reviewed by an independent Data Monitoring Committee (DMC) at the preceding dose level. The first 2 subjects in any cohort will be ≥ 18 years of age. The effects of the investigational product on vital signs, hematology, and clinical chemistry parameters (up to 96 ± 2 hrs blood sampling timepoint) will determine short-term safety. The DMC will recommend whether to proceed with the study or in case of a safety concern recommend remedial actions and/or to discontinue the study. Subject participation will continue until 28 ± 3 days after infusion of the investigational product. Subject participation in one Dose Cohort (1-3) is expected to be approximately 6-8 weeks.

Drug: Recombinant ADAMTS13

Interventions

Recombinant ADAMTS13 DRUG

rADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a lyophilized formulation for intravenous injection. The lyophilized rADAMTS13 is reconstituted with sterile water for injection. Subjects will receive an intravenous injection with rADAMTS13 at a dose of either 5 U/kg bodyweight (Cohort 1), or 20 U/kg bodyweight (Cohort 2), or 40 U/kg bodyweight (Cohort 3).

Recombinant ADAMTS13

Eligibility Criteria

• Age: 12 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Baxalta now part of Shire: lead

Study Sites (11)

Ohio State University Medical Center

Dublin, Ohio, 43017, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

The Methodist Hospital Research Institute

Houston, Texas, 77030, United States

Location

General Hospital Vienna (Allgemeines Krankenhaus der Stadt Wien)

Vienna, 1090, Austria

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitätsklinikum Jena

Jena, 07743, Germany

Location

• Tokyo Medical and Dental University Hospital, Faculty of Medicine

Bunkyo-ku, Tokyo, 113-8519, Japan

Location

Hyogo College of Medicine Hospital, Department of Hematology

Nishinomiya-shi, 663-8501, Japan

Location

Institute of Hematology and Transfusion Medicine

Warsaw, 02776, Poland

Location

Inselspital - Universitaetsspital Bern

Bern, 3010, Switzerland

Location

University College London Hospital NHS Foundation Trust

London, NW1 2BU, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 28912376 DERIVED

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 12, 2014
• First Posted: August 13, 2014
• Study Start: September 30, 2014
• Primary Completion: February 22, 2016
• Study Completion: February 22, 2016
• Last Updated: May 5, 2021

Record last verified: 2021-05

Locations

US (3); AU (1); PL (1); JP (2); CH (1); GB (1); DE (2)