E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
congenital Thrombotic thrombocytopenic purpura (TTP) |
|
E.1.1.1 | Medical condition in easily understood language |
congenital Thrombotic thrombocytopenic purpura |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the long-term safety and tolerability of TAK-755 (rADAMTS-13) in terms of related adverse events (AEs) and serious adverse events (SAEs) in both the prophylactic and the on-demand cohorts. |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of TAK-755 in the treatment of acute thrombotic thrombocytopenic purpura (TTP) episodes as measured by the a) number of acute TTP events responding to treatment and b) time to resolution of the acute TTP in either the prophylactic or the on-demand cohorts. 2. To evaluate the incidence of isolated TTP manifestations including thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction, neurologic signs and symptoms, and abdominal pain in the prophylactic cohort. 3. To evaluate the proportion of subjects that require dose modification and supplemental dose in the prophylactic cohort. 4. To evaluate the incidence of subacute manifestations in subjects receiving prophylactic treatment. For more secondery objectives please refer to Protocol pages 10,11. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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/µL 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 highly effective 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 naïve 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 naïve pediatric subjects can be enrolled after enrollment of the respective age cohort into the pivotal Phase 3 study (281102) has been completed. Subjects in the UK who are naïve to TAK-755 may not be enrolled in this study. TAK-755 naïve 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 naïve 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/µL 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 highly effective birth control measures for the duration of the study and to undergo quarterly pregnancy testing. 10. Sexually active males must use an accepted and effective method of contraception during treatment and until a minimum of 16 days after the last dose administered. 11. Subject is willing and able to comply with the requirements of the protocol. |
|
E.4 | Principal 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 naïve 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. 19. In the UK only: Subjects who are naive to TAK-755. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
There is no primary efficacy endpoint for this study, as the primary objective of the study is long-term safety. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Various timepoints throughout the study |
|
E.5.2 | Secondary end point(s) |
1. Prophylactic cohort: Efficacy analysis for the prophylactic cohort will provide the number and incidence rate of acute TTP events in total and by enrollment status (“Naïve” or having completed the Phase 3 pivotal study [281102]), with the corresponding 95%, 2-sided confidence intervals (CIs). 2. Prophylactic and on-demand cohorts: For acute TTP events, the number and proportion of acute events responding to treatment will be summarized, along with the 2-sided 95% CIs for the pooled prophylactic and on-demand cohort data as well as by cohort.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various timepoints throughout the study |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Brazil |
Canada |
China |
Colombia |
Czechia |
Denmark |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Poland |
Portugal |
Russian Federation |
Serbia |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 10 |