Evaluation of Long-Term Safety and Efficacy of Recombinant ADAMTS13 (rADAMTS13) in Prophylactic and On-Demand Treatment of Congenital Thrombotic Thrombocytopenic Purpura
- Trial ID
- 2024-513839-24-00
- Protocol
- TAK-755-3002
- Sponsor
- Baxalta Innovations GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the long-term **safety** and tolerability of TAK-755 (rADAMTS13) in terms of related treatment-emergent adverse events (TEAEs) and related serious adverse events (SAEs) in both the prophylactic and on-demand cohorts. This is clinically relevant as it aims to ensure that TAK-755 is a safe treatment option for patients with severe congenital thrombotic thrombocytopenic purpura (cTTP), a rare and life-threatening condition.
Secondary objectives include:
- Evaluating the efficacy of prophylactic TAK-755 treatment for the prevention of acute TTP events.
- Assessing the efficacy of TAK-755 in controlling acute TTP events.
- Determining the proportion of subjects that require dose modification and supplemental dose in the prophylactic cohort.
- Evaluating the incidence of isolated TTP manifestations in subjects receiving prophylactic treatment.
Participants
The clinical trial involves a total of **45 participants** diagnosed with **Congenital Thrombotic Thrombocytopenic Purpura (cTTP)**. The study population includes both male and female subjects, ranging in age from 0 to 70 years. Participants were selected based on their completion of the TAK-755 Phase 3 pivotal study or their status as naïve subjects eligible for the continuation study. The trial does not include a vulnerable population. Participants are required to have a general health status that excludes severe TTP signs, such as a platelet count below 100,000/μL and elevated LDH levels. Lifestyle considerations, such as diet and physical activity, are not specified. The trial includes individuals who are willing and able to comply with the study protocol, and those who meet specific health criteria, including a Karnofsky score of at least 70% for those aged 16 and older, or a Lansky score of at least 80% for those under 16. Female participants of childbearing potential must present a negative pregnancy test and agree to use effective contraception, while sexually active males must also adhere to contraception requirements. The trial does not involve participants from an Expanded Access Program or those who had an allergic reaction to standard care prophylactic treatment unless they meet all specified criteria.
Plans and Procedures
The clinical trial is a **Phase 3b**, prospective, open-label, multicenter, single treatment arm study designed to evaluate the long-term safety and tolerability of **TAK-755 (rADAMTS13)** in subjects with severe congenital thrombotic thrombocytopenic purpura (cTTP). The trial aims to assess treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) in both prophylactic and on-demand cohorts. The study is expected to run from September 2021 to January 2027, with participant involvement potentially lasting up to 36 months, depending on individual treatment needs and response.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of severe congenital ADAMTS-13 deficiency, and absence of severe TTP signs. Following successful screening, participants will enter the treatment phase, receiving **TAK-755** either subcutaneously or intravenously, depending on the cohort. Regular follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of their health status and any long-term effects of the treatment.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in their best interest. The primary endpoint focuses on safety, with no specific efficacy endpoint, while secondary endpoints include the incidence of acute TTP events in the prophylactic cohort. The trial is not classified as low intervention, reflecting its comprehensive approach to evaluating the safety profile of **TAK-755** in this rare disease population.
Treatment
The clinical trial involves the administration of **RECOMBINANT ADAMTS13 (rADAMTS13)**, also known by the sponsor product code **TAK-755**. This experimental medication is formulated as a **powder and solvent for solution for injection**. The active substance in this formulation is **apadamtase alfa**, a protein of non-human origin. The medication is provided by Takeda Development Center Americas, Inc. and is designated as an orphan drug under the number EU/3/08/588.
Two dosing regimens are employed in the study. The first regimen involves the subcutaneous administration of rADAMTS13 at a maximum daily dose of 60 IU/kg. The treatment period for this regimen is limited to a maximum of 1 day. The second regimen involves intravenous administration, with a maximum daily dose of 40 IU/kg and a total maximum dose of 6240 IU/kg over a treatment period of up to 36 weeks. Both regimens are designed to evaluate the long-term safety and tolerability of the medication in subjects with severe congenital thrombotic thrombocytopenic purpura (cTTP).
Participant compliance with the dosing schedule is monitored throughout the trial. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is structured as a phase 3b, prospective, open-label, multicenter, single treatment arm study, focusing on both prophylactic and on-demand treatment cohorts.
Efficacy
The efficacy of TAK-755 (recombinant ADAMTS13) in the treatment of severe congenital thrombotic thrombocytopenic purpura (cTTP) will be assessed through a key secondary efficacy outcome measure. This measure focuses on the incidence of acute **thrombotic thrombocytopenic purpura (TTP)** events among subjects receiving TAK-755 prophylactically. The analysis will be conducted using the Full Analysis Set (FAS) for the prophylactic cohort. The number and incidence rate of acute TTP events will be summarized based on the enrollment status of subjects, distinguishing between those who are "naïve" and those who have completed the Phase 3 pivotal study (Study 281102), as well as providing an overall summary.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Applies to Subjects who have completed the TAK-755 Phase 3 pivotal study (Study 281102) in the prophylactic cohort Subjects who have completed TAK-755 Study 281102 (in the prophylactic cohort 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.
- Applies to naïve subjects and non-naïve on-demand cohort subjects Naïve subjects can only be enrolled in this continuation study after enrollment of the adult subjects in the prophylactic arm of the TAK-755 Phase 3 pivotal study (Study 281102) has been completed. Naïve pediatric subjects can be enrolled after enrollment of the respective age cohort into Study 281102 has been completed. The following criteria also applies to subjects who completed study 281101, but did not participate in 281102. The following criteria do not apply to subjects from the Expanded AccessProgram or subjects from 281102 who had an allergic reaction to SoC. See separate criteria below for study eligibility of EAP subjects and subjects from study 281102 who had an allergic reaction to SoC. 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 or was enrolled into the on-demand cohort of the TAK-755 Study 281102 for treatment of an acute TTP 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.
- Subjects from an Expanded Access Program or subjects in Study 281102 who had an allergic reaction to standard of care prophylactic treatment must meet ALL of the following criteria. 1. Subject or legally authorized representative has provided signed informed consent (≥18 years of age) and/or assent form (<18 years of age), as applicable. 2. Subject is 0 to 70 years of age at the time of screening. For more inclusion criteria please refer to the Protocol.
Exclusion Criteria
- The subject will be excluded from the study if any of the following exclusion criteria are met. Applies to subjects who have completed TAK-755 Phase 3 pivotal study (Study 281102): 1. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule ADAMTS-13, hamster protein, or other constituents of TAK-755. 2. Subject has presence of a functional ADAMTS-13 inhibitor at screening. 3. In the opinion of the investigator, the subject has another clinically significant concomitant disease that may pose additional risks for the subject. 4. Subject is receiving or anticipates receiving another investigational drug and/or interventional drug within 30 days before enrollment. 5. Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures. 6. 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. 7. Subject is a family member or employee of the sponsor or investigator
- The following criteria do not apply to subjects from the Expanded Access Program or subjects from 281102 who had an allergic reaction to SoC. The following criteria also applies to subjects who completed study 281101, but did not participate in 281102. 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 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 (e.g., 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 (e.g., ointments, nasal sprays), within 30 days prior to enrollment. Use of corticosteroids in conjunction with administration of fresh frozen plasma to prevent allergic reactions is permitted. 11. Subject has an acute illness (e.g., 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.
- Study 281102 who had an allergic reaction to standard of care prophylactic treatment: 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 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 09 Sept 2021 | 2 |
 France | Not Recruiting | 09 Sept 2021 | 11 |
 Germany | Not Recruiting | 09 Sept 2021 | 7 |
 Italy | Not Recruiting | 09 Sept 2021 | 1 |
 Poland | Not Recruiting | 09 Sept 2021 | 6 |
 Spain | Not Recruiting | 09 Sept 2021 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RECOMBINANT ADAMTS13rADAMTS13 | Test | POWDER AND SOLVENT FOR SOLUTION FOR INJECTION | INTRAVENOUS USE | 40 | 36 | PRD10833227 |
RECOMBINANT ADAMTS13rADAMTS13 | Test | POWDER AND SOLVENT FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 60 | 1 | PRD10833228 |