| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
severe congenital thrombotic thrombocytopenic purpura
(cTTP, Upshaw-Schulman Syndrome [USS], hereditary thrombotic
thrombocytopenic purpura [hTTP]) |
|
| E.1.1.1 | Medical condition in easily understood language |
severe congenital thrombotic thrombocytopenic purpura
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10043562 |
| E.1.2 | Term | Thrombocytopenic purpura, thrombotic |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 |
| 1. To determine the incidence of acute TTP events in subjects with severe cTTP receiving either standard of care (SoC) or BAX 930 as a prophylactic treatment |
|
| E.2.2 | Secondary objectives of the trial |
1. Evaluate the efficacy of BAX 930 in the treatment of acute TTP events as measured by the 1)number of acute TTP events responding to treatment and 2)time to resolution in both the prophylactic and the on-demand cohorts
2. To evaluate the safety&tolerability of BAX 930 in terms of related AEs and SAEs in both the prophylactic&the on-demand cohorts
3. For both adult&pediatric subjects two crossover PK evaluations & an end-of-study ADAMTS13 PK evaluation may be performed for up to 288
hrs post-infusion in each treatment arm in the prophylactic cohort
4. To evaluate the incidence of isolated TTP manifestations including thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction, neurologic signs&symptoms, and abdominal pain in the prophylactic cohort
5. To assess the immunogenicity of BAX 930 as measured by the incidence of binding&inhibitory antibodies to ADAMTS13 in both the prophylactic&the on-demand cohorts. Full information on objectives is made in the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject or legally authorized representative has provided signed informed consent (≥18 years of age) and/or assent form (signed by legal representative if subject is <18 years of age).
2. Subject is 0 to 70 years of age, inclusive, at the time of screening. (Subjects <18 years of age will be enrolled only after at least 5 adults (≥18 years of age) each have at least 10 exposures with BAX 930 and reviewed by the DMC). In France, no subjects younger than 18 years of age will be enrolled into the study before the first adult subject has been treated with BAX 930 for a minimum of 6 months.).
3. Subject has a documented diagnosis of severe hereditary ADAMTS13 deficiency, defined as:
· Confirmed by molecular genetic testing, documented in subject history or at screening, and
· ADAMTS13 activity <10% as measured by the FRETS-VWF73 assay, documented in subject history or at screening (subjects currently receiving SoC prophylactic therapy may exceed 10% ADAMTS13 activity at screening).
Note: Subjects currently receiving prophylactic therapy will be screened immediately prior to their usual prophylactic infusion
4. Subject does not display any severe TTP symptoms signs (platelet count <100,000/µL and elevation of LDH >2×ULN) at screening. Subjects presenting with minor, but stable laboratory abnormalities at the time of screening may be enrolled (prophylactic cohort only).
5. Subject is currently on a prophylactic dosing regimen or has a documented history of at least 1 TTP event and an ability to tolerate SoC prophylactic dosing (prophylactic cohort only).
6. Subjects ≥16 years of age must have a Karnofsky score ≥70% and subjects <16 years of age must have a Lansky score ≥80%.
7. Subject is hepatitis C virus (HCV)-negative as confirmed by antibody or polymerase chain reaction testing OR HCV-positive if their disease is chronic but stable.
8. If female of childbearing potential, subject presents with a negative blood or urine pregnancy test, confirmed no more than 7 days before the first administration and agrees to employ adequate birth control measures for the duration of the study and to undergo quarterly pregnancy testing.
9. 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.
10. Subject is willing and able to comply with the requirements of the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Subject has been diagnosed with any other TTP-like disorder (microangiopathic hemolytic anemia), including acquired TTP.
2. Subject has known hypersensitivity to hamster proteins.
3. Subject has experienced an acute TTP episode less than 30 days prior to screening (prophylactic cohort only).
4. Subject has a medical history or presence of a functional ADAMTS13 inhibitor at screening.
5. 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 (HIV) positive with an absolute cluster of differentiation 4 (CD4) count <200/mm3 or who are
receiving chronic immunosuppressive drugs.
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 (ALT) ≥2xULN
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 FFP 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 (prophylaxis 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 less than 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 enrolment.
19. Any contraindication to standard of care medicinal product(s) as per local prescribing information |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Incidence of acute TTP events among subjects receiving either BAX 930 or SoC prophylactically during the corresponding treatment periods |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Interim analysis performed after all adult subjects complete Period 3 in the prophylaxis cohort and at the end of the study. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
1. Proportion of acute TTP events responding to BAX 930, defined as not requiring the use of another ADAMTS13 containing agent
2. Time to resolution of acute TTP events following initiation of treatment with BAX 930 or SoC agent
3. Incidence of thrombocytopenia defined as a drop in platelet count ≥25% of baseline or a platelet count <150,000/µL
4. Incidence of microangiopathic hemolytic anemia defined as an elevation of LDH >1.5 of baseline or >1.5×ULN
5. Incidence of neurological symptoms (e.g., confusion, dysphonia, dysarthria, focal or general motor symptoms including seizures)
6. Incidence of renal dysfunction defined as an increase in serum creatinine >1.5×baseline
7. Incidence of abdominal pain
8. Incidence of supplemental doses prompted by subacute TTP events
9. Incidence of dose modification not prompted by an acute TTP event
10. Incidence of acute TTP events while subjects are on their final dose and dosing regimen in the study
Safety/Immunogenicity
1. Incidence of product-related and unrelated AEs and SAEs during each treatment period
2. Incidence of binding and inhibitory antibodies to ADAMTS13
3. Clinically relevant changes in vital signs, clinical chemistry, and hematology
4. Estimated total quantity of ADAMTS13 administered during the treatment of acute TTP events
Pharmacokinetics/Pharmacodynamics
1. Assessment of the PK parameters (incremental recovery [IR], area under the plasma curve [AUC], terminal half-life [t1/2], mean residence time [MRT], systemic clearance [CL], steady state volume of distribution [Vss], and maximum concentration following infusion [Cmax]) for ADMATS13 activity and ADMATS13 antigen for both the SoC agent and BAX 930
2. Assessment of PD markers, such as VWF:Ag and VWF:RCo at baseline and following infusion of the SoC agent and BAX 930 treatment during the initial PK assessment
3. Assessment of ADAMTS13 activity (trough levels) and select VWF parameters prior to each PK infusion of SoC or BAX 930 and at the time of acute event presentation
4. Assessment of the impact of immunogenicity (immunogenicity status,
time of onset) on ADAMTS13 antigen and activity PK parameters |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Eifficacy analysis as above; final analysis at study end when all efficacy, safety and PK data are available |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Canada |
| Japan |
| United States |
| Austria |
| France |
| Germany |
| Italy |
| United Kingdom |
| Switzerland |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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