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

• Sponsor: Baxalta now part of Shire
• Information provided by (Responsible Party): Shire ( Baxalta now part of Shire )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hereditary Thrombotic Thrombocytopenic Purpura (TTP)	Drug: Recombinant ADAMTS13	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: September 2014
• Actual Primary Completion Date: February 2016
• Actual Study Completion Date: February 2016

Arms and Interventions

Arm

Intervention/treatment

Experimental: Recombinant ADAMTS13; 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; 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).

Outcome Measures

Primary Outcome Measures :

1. Occurrence of adverse events (serious and non-serious), including the incidence of binding and inhibitory antibody formation [ Time Frame: Up to 28 (± 3) days after investigational product infusion ]

Secondary Outcome Measures :

1. Pharmacokinetic [PK] parameter 'incremental recovery [IR]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
2. PK parameter 'maximum concentration following infusion [Cmax]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
3. PK parameter 'minimum time to reach Cmax [T max]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
4. PK parameter 'terminal or disposition half-life [T1/2]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
5. PK parameter 'mean residence time [MRT]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
6. PK parameter 'systemic clearance [Cl]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
7. PK parameter 'area under the plasma/time curve [AUC]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
8. PK parameter 'steady state volume of distribution [Vss]' [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
9. Plasma von Willebrand factor: Ristocetin cofactor activity [VWF:RCo], von Willebrand factor antigen [VWF:Ag] and VWF structure analysis [ Time Frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion ]
   Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Ohio

Ohio State University Medical Center

Dublin, Ohio, United States, 43017

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

United States, Texas

The Methodist Hospital Research Institute

Houston, Texas, United States, 77030

Austria

General Hospital Vienna (Allgemeines Krankenhaus der Stadt Wien)

Vienna, Austria, 1090

Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, Germany, 20246

Universitätsklinikum Jena

Jena, Germany, 07743

Japan

• Tokyo Medical and Dental University Hospital, Faculty of Medicine

Bunkyo-ku, Tokyo, Japan, 113-8519

Hyogo College of Medicine Hospital, Department of Hematology

Nishinomiya-shi, Japan, 663-8501

Poland

Institute of Hematology and Transfusion Medicine

Warsaw, Poland, 02776

Switzerland

Inselspital - Universitaetsspital Bern

Bern, Switzerland, 3010

United Kingdom

University College London Hospital NHS Foundation Trust

London, United Kingdom, NW1 2BU

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

• Study Director: Bruce Ewenstein, MD; Shire

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Scully M, Knöbl 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.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT02216084 History of Changes
• Other Study ID Numbers: 281101; 2012-003221-19 ( EudraCT Number )
• First Posted: August 13, 2014
• Last Update Posted: October 23, 2017
• Last Verified: March 2016

Additional relevant MeSH terms:

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