HumRes40653
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EUCTR2017-000858-18
A Phase 3, randomized, controlled study of severe congenital thrombotic thrombocytopenic purpura, with Bax 930.
Studientyp
Interventional clinical trial of medicinal product
(ICTRP)
Untersuchte Intervention
Product Name: Recombinant A Disintegrin and Metalloproteinase with Thrombospondin Type-1 Motifs 13
Product Code: BAX930 or SHP655
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: apadamtase alfa
Current Sponsor code: SHP655 (BAX930)
Other descriptive name: Recombinant A Disintegrin and Metalloproteinase with Thrombospondin Type-1 Motifs
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 1500-
(ICTRP)
Untersuchte Krankheit(en)
severe congenital thrombotic thrombocytopenic purpura(cTTP, Upshaw-Schulman Syndrome [USS], hereditary thromboticthrombocytopenic purpura [hTTP])
MedDRA version: 20.0Level: LLTClassification code 10043562Term: Thrombocytopenic purpura, thromboticSystem Organ Class: 100000013328
(ICTRP)
Kriterien zur Teilnahme
Gender:
Female: yes
Male: yes
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 10 exposures with BAX 930 have been completed in at least 5 subjects over 18 years of age and reviewed by the study medical director).
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/?L 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 pregnancy test and agrees to employ adequate birth control measures for the duration of the study and to undergo quarterly pregnancy testing.
9. Subject is willing and able to comply with the requirements of the protocol.
Are the trial subjects under 18? yes
Number of subjects for this age range: 9
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1
(ICTRP)
Ausschlusskriterien
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. International normalized ratio >1.5
c. Severe hypoalbuminemia <24 g/L
d. 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 manifestations 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.
(ICTRP)
Gender:
Female: yes
Male: yes
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 10 exposures with BAX 930 have been completed in at least 5 subjects over 18 years of age and reviewed by the study medical director).
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/?L 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 pregnancy test and agrees to employ adequate birth control measures for the duration of the study and to undergo quarterly pregnancy testing.
9. Subject is willing and able to comply with the requirements of the protocol.
Are the trial subjects under 18? yes
Number of subjects for this age range: 9
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1
(ICTRP)
Ausschlusskriterien
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. International normalized ratio >1.5
c. Severe hypoalbuminemia <24 g/L
d. 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 manifestations 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.
(ICTRP)
Studienstandort
Schweiz, Deutschland, Frankreich, Vereinigte Staaten, Vereinigtes Königreich, Österreich, Italien, Kanada, Polen, Spanien, Japan
(ICTRP)
Wissenschaftlicher Titel
A phase 3, prospective, randomized, controlled, open-label, multicenter, 2-period crossover study with a single arm continuation evaluating the safety and efficacy of BAX 930 (rADAMTS13) in the prophylactic and on-demand treatment of subjects with severe congenital thrombotic thrombocytopenic purpura (cTTP, Upshaw-Schulman Syndrome [USS], hereditary thrombotic thrombocytopenic purpura [hTTP]) - A phase 3, randomized, controlled study of prophylactic and on-demand treatment of cTTP with BAX 930 (ICTRP)
Studiendesign
Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: yes Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2 (ICTRP)
Primäre und sekundäre Endpunkte
Main Objective: 1. To determine the incidence of acute TTP episodes in subjects with severe cTTP receiving either standard of care (SoC) or BAX 930 as a prophylactic treatment;Secondary Objective: 1. To evaluate the efficacy of BAX 930 in the treatment of acute TTP episodes 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 and tolerability of BAX 930 in terms of related adverse events (AEs) and serious adverse events (SAEs) in both the prophylactic and the on-demand cohorts
3. To evaluate the pharmacokinetics (PK) of ADAMTS13 for up to 288 hours post-infusion in each treatment arm (BAX 930 and SoC) in the prophylactic cohort
4. 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
5. To assess the immunogenicity of BAX 930 as measured by the incidence of binding and inhibitory antibodies to ADAMTS13 in both the prophylactic and the on-demand cohorts;Primary end point(s): 1.Incidence of acute TTP episodes among subjects receiving either BAX 930 or SoC prophylactically during the corresponding treatment periods;Timepoint(s) of evaluation of this end point: After first 24 subjects completed the 2x2 crossover phase of the study (interim analysis) and at the end of the study (ICTRP)
Secondary end point(s): Efficacy
1.Number and incidence of acute TTP episodes responding to BAX 930, defined as not requiring the use of another ADAMTS13 containing agent
2.Time to resolution of clinical symptomatology, if present, and normalization of laboratory parameters (platelet count =150,000/?L; LDH =1.5?ULN) following initiation of treatment in acute TTP episodes 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/?L
4.Incidence of microangiopathic hemolytic anemia defined as an elevation of LDH >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 manifestations
9.Incidence of dose modification not prompted by an acute event
10.Incidence of acute TTP episodes while subjects are on their final dose and dosing regimen
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 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 both the SoC agent and BAX 930 at the beginning of the respective treatment periods with each agent and for BAX 930 at the conclusion of Treatment Period 2 in the prophylactic cohort
2.Assessment of VWF:Ag, VWF:RCo, and VWF multimer pattern 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 VWF parameters prior to each infusion of SoC or BAX 930 and at the time of acute event presentation;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 (ICTRP)
Registrierungsdatum
18.09.2017 (ICTRP)
Einschluss des ersten Teilnehmers
27.11.2017 (ICTRP)
Sekundäre Sponsoren
nicht verfügbar
Weitere Kontakte
Frank Stout, frank.stout@shire.com, +34665 850140, Baxalta Innovation GmbH (ICTRP)
Sekundäre IDs
281102, 2017-000858-18-GB (ICTRP)
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar
Weitere Informationen zur Studie
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000858-18 (ICTRP)
Ergebnisse der Studie
Zusammenfassung der Ergebnisse
nicht verfügbar
Link zu den Ergebnissen im Primärregister
nicht verfügbar