Eine offene Fortsetzungsstudie der Phase IIIb zur prophylaktischen und Bedarfsbehandlung von cTTP mit TAK-755 (rADAMTS-13, auch bekannt als BAX 930/SHP655)

Product Name: Recombinant A Disintegrin and Metalloproteinase Thrombospondin Type-1 Motifs 13
Product Code: TAK-755 or BAX930 or SHP655
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: Apadamtase alfa
Current Sponsor code: TAK-755 (SHP655 or BAX930)
Other descriptive name: Recombinant A Disintegrin and Metalloproteinase with Thrombospondin Type-1 Motifs
Concentration unit: IU/ml international unit(s)/millilitre
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: Apadamtase alfa
Current Sponsor code: TAK-755 (BAX930 or SHP655)
Other descriptive name: Recombinant A Disintegrin and Metalloproteinase with Thrombospondin Type-1 Motifs
Concentration unit: IU/ml international unit(s)/millilitre
Concentration type: equal
Concentration number: 300-

Gender:
Female: yes
Male: yes

Inclusion criteria:
Subjects who have completed TAK-755 Phase 3 pivotal study (281102) and who meet ALL of the following criteria are eligible for this study:
1. Subject or legally authorized representative has provided signed informed consent (=18 years of age) and/or assent form (<18 years of age).
2. Subject is 0 to 70 years of age at the time of screening of the 281102 study.
3. Subject has been diagnosed with severe congenital ADAMTS-13 deficiency.
4. Subject does not display any severe TTP signs (platelet count <100,000/?L and elevation of LDH >2 ? upper limit of normal [ULN]) at screening (prophylactic cohort only).
5. Subjects =16 years of age must have a Karnofsky score =70% and subjects <16 years of age must have a Lansky score =80%.
6. If female of childbearing potential, subject presents with a negative serum or urine pregnancy test confirmed not more than 7 days before the first IP administration and agrees to employ adequate birth control measures for the duration of the study and to undergo quarterly pregnancy testing.
7. 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.
8. Subject is willing and able to comply with the requirements of the protocol.

TAK-755 na?ve subjects can only be enrolled in this continuation after enrollment of the adult subjects in the prophylactic arm of the TAK-755 Phase 3 pivotal study (281102) has been completed. TAK-755 na?ve pediatric subjects can be enrolled after enrollment of the respective age cohort into the pivotal Phase 3 study (281102) has been completed.
TAK-755 na?ve subjects and subjects who were enrolled into the on-demand cohort of the TAK-755 Phase 3 pivotal study (281102) who meet ALL of the following criteria are eligible for this study:
1. Subject is na?ve to TAK-755 or was enrolled into the on-demand cohort of the TAK-755 Phase 3 pivotal study (281102) for treatment of an acute event but did not receive prophylactic treatment.
2. Subject or legally authorized representative has provided signed informed consent (=18 years of age) and/or assent form (<18 years of age).
3. Subject is 0 to 70 years of age at the time of screening.
4. Subject has been diagnosed with severe congenital ADAMTS-13 deficiency defined as:
a. Confirmed by molecular genetic testing, documented in subject history or at screening, and
b. ADAMTS-13 activity <10% as measured by the fluorescence resonance energy transfer (FRETS)-Von Willebrand factor (VWF)73 assay, documented in subject history or at screening. Subjects currently receiving standard of care prophylactic therapy may exceed 10% ADAMTS 13 activity at screening.
5. Subjects currently receiving prophylactic therapy will be screened immediately prior to their usual prophylactic infusion.
6. Subject does not display any severe TTP signs (platelet count <100,000/?L and elevation of LDH >2 ? ULN) at screening (prophylactic cohort only).
7. Subjects =16 years of age must have a Karnofsky score =70% and subjects <16 years of age must have a Lansky score =80%.
8. Subject is hepatitis C virus negative (HCV?) as confirmed by antibody or polymerase chain reaction testing OR HCV positive (HCV+) if their disease is chronic but stable.
9. If female of childbearing potential, subject presents with a negative serum or urine pregnancy test confirmed not more than 7 days before the first IP administration and agrees to employ adequate birth control measures for the dur
Exclusion criteria:
The subject will be excluded from the study if any of the following exclusion criteria are met.
For both subjects who have completed TAK-755 Phase 3 pivotal study (281102) and TAK 755 na?ve subjects:
1. Subject has been diagnosed with any other TTP-like disorder (microangiopathic hemolytic anemia), including immune-mediated TTP.
2. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule ADAMTS-13, hamster protein, or other constituents of TAK-755.
3. Subject has a medical history or presence of a functional ADAMTS-13 inhibitor at screening.
4. Subject has a medical history of a genetic or acquired immune deficiency that would interfere with the assessment of product immunogenicity, including subjects who are human immunodeficiency virus positive with an absolute cluster of differentiation 4 (CD4) count <200/mm3 or who are receiving chronic immunosuppressive drugs.
5. 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.
6. Subject has been diagnosed with severe cardiovascular disease (New York Heart Association classes 3 to 4).
7. Subject with end stage renal disease requiring chronic dialysis.
8. Subject has been diagnosed with hepatic dysfunction, as evidenced by, but not limited to, any of the following:
a. Serum alanine aminotransferase =2 ? ULN
b. Severe hypoalbuminemia <24 g/L
c. Portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices).
9. In the opinion of the investigator, the subject has another clinically significant concomitant disease that may pose additional risks for the subject.
10. Subject has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to enrollment. Use of corticosteroids in conjunction with administration of fresh frozen plasma to prevent allergic manifestations is permitted.
11. Subject has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, bronchial asthma) at the time of screening (prophylactic cohort only).
12. Subject is receiving or anticipates receiving another investigational drug and/or interventional drug within 30 days before enrollment.
13. Subject has a history of drug and/or alcohol abuse within the last 2 years.
14. Subject has a progressive fatal disease and/or life expectancy of =3 months.
15. Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures
16. 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.
17. Subject is a family member or employee of the sponsor or investigator.
18. If female, subject is pregnant or lactating at the time of enrollment.