IdeS in Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients

Conditions

Purpura, Thrombotic Thrombocytopenic

Keywords

Asymptomatic antibody-mediated TTP

Brief summary

The main purpose of this study is to evaluate safety and tolerability in patients diagnosed with asymptomatic antibody-mediated TTP with low ADAMTS13 activity after receiving single intravenous dose of IdeS.

Detailed description

Immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) is an IgG specific endopeptidase which cleaves IgG molecules and efficiently neutralizes Fc-mediated activities. IdeS-mediated IgG degradation constitutes a novel therapeutic principle for the treatment of IgG-driven human diseases. In addition to assessing the safety and tolerability of IdeS the study will also assess the efficacy of IdeS to significantly increase the ADAMTS13 activity and decrease the anti-ADAMTS13 antibody levels in patients diagnosed with asymptomatic antibody-mediated TTP with low ADAMTS13 activity.

Related papers

No related papers found yet.

Interventions

BIOLOGICALIdeS (0.25 mg/kg)

Single i.v. infusion of IdeS (0.25 mg/kg). Following an evaluation of efficacy and safety in the first 3 patients the dose may be increased in the following 3 patients to 0.5 mg/kg.

BIOLOGICALIdeS (0.50 mg/kg)

Single i.v. infusion of IdeS (0.50 mg/kg).

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Age 18 years or above * Diagnosed with acquired TTP with ADAMTS13 levels of ≤ 10 % in clinical remission and with measurable or previously confirmed ADAMTS13 antibodies

Exclusion criteria

* Prior malignancy within 5 years * Test positive for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus (HIV) * Ongoing infectious disease including P-CRP \>10 * Test positive for IgE antibodies against IdeS * Secondary cause of TTP * Rituximab treatment or other antibody-based therapy within 7 days prior to IdeS dosing * Treatment with investigational medicinal product within the last 12 weeks proceeding screening * Severe other conditions requiring treatment and close monitoring, e.g. cardiac failure \> NYHA (New York Heart Association) grade 3, unstable coronary disease or oxygen dependent COPD * History of any other clinically significant disease or disorder which may either put the patient at increased risk because of participation in the study, or influence the results or the patient's ability to participate in the study * Hypogammaglobulinemia defined as any values of P-total IgG less than 3 g/L * History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to IdeS (e. g. streptokinase and/or staphylokinase) * Substance abuse or other concurrent medical condition that could confound study interpretation or affect the patient's ability to tolerate or complete the study * Breast feeding women or women with a positive pregnancy test * Previously received IdeS treatment

Design outcomes

Primary

Measure	Time frame	Description
Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	From dosing until end of follow up on day 64	Data on AEs were obtained if spontaneously reported by the patient, if reported in response to an open question from the study personnel or if revealed by observation. A treatment emergent AE (TEAE) is defined as any AE occurring after administration of the IMP and within the time of the residual drug effect period (i.e. 30 days after IMP administration). AEs reported in ClinicalTrials.gov include TEAEs and post-treatment AEs, i.e. all AEs occurring after administration of IdeS until end of study. Please refer to Adverse Event section for details on reported AEs

Secondary

Measure	Time frame	Description
Number of Patients With Change From Baseline in ADAMTS13 Antibody Levels	From day of dosing until end of follow up on day 64	The efficacy of IdeS on ADAMTS13 antibody cleaving was measured througout the study as change from baseline in ADAMTS13 antibody concentration.
Number of Patients for Whom a Decreased ADAMTS13 Activity Returned to Normal Levels at Different Time-points in the Study	From day of dosing until end of follow up on day 64	The ADAMTS13 activity in TTP patients is decreased. The efficacy of IdeS on ADAMTS13 activity was assessed throughout the study to identify the time-point of return to normal levels.
Number of Patients With Change From Baseline in Pharmacodynamics as Measured by Level of IgG	From day of dosing until end of follow up on day 64	IdeS cleaves IgG molecules. The concentration of uncleaved IgG in the patient's serum was measured throughout the study to determine change from baseline following IdeS administration.
Number of Patients With Change From Baseline in ADAMTS13 Activity	From day of dosing until end of follow up on day 64	ADAMTS13 is an enzyme which is inhibited in patients with TTP. The efficacy of IdeS on ADAMTS13 activity was measured througout the study as change from baseline.
Maximum Serum Concentration (Cmax) of IdeS	From day of dosing until day 14	The concentration of IdeS in serum was measured to identify the pharmacokinetic parameter Cmax of IdeS in TTP patients.
Time-point for Maximum Serum Concentration of IdeS	From day of dosing until day 14	The concentration of IdeS in serum was measured to identify the pharmacokinetic parameter Tmax of IdeS in TTP patients. Tmax refers to the time-point when the serum concentration of IdeS reaches maximum.
Number of Patients With Change From Baseline in Pharmacodynamics as Measured by Level of F(ab')2 Fragments	From day of dosing until end of follow up on day 64	The efficacy of IdeS can be measured as change from baseline in F(ab')2 fragments (i.e. the antigen binding fragment of IgG).
Number of Patients Showing IdeS Immunogenicity as Measured by Anti-drug Antibodies	From day of dosing until end of follow up on day 64	Most humans have been infected with S. pyogenes which is the origin of IdeS. It was therefore expected that patients in this study might have antibodies against IdeS before being exposed to IdeS in the study. The concentration of ant-IdeS antibodies was measured before dosing and throughout the study.

Countries

United Kingdom

Participant flow

Participants by arm

Arm	Count
Treatment IdeS (0.25 mg/kg) A single 30 minutes i.v. infusion of IdeS (0.25 mg/kg). Following an evaluation of safety and efficacy in 3 patients receiving 0.25 mg/kg there will be a potential to increase the IdeS dose to 0.5 mg/kg for the remaining 3 patients.	2
Treatment IdeS (0.50 mg/kg) A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg).	0
Total	2

Baseline characteristics

Characteristic	Treatment IdeS (0.25 mg/kg)	Total
Age, Categorical <=18 years	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	2 Participants	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants
Race (NIH/OMB) White	1 Participants	1 Participants
Region of Enrollment United Kingdom	2 participants	2 participants
Sex: Female, Male Female	1 Participants	1 Participants
Sex: Female, Male Male	1 Participants	1 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 2	0 / 0
other Total, other adverse events	2 / 2	0 / 0
serious Total, serious adverse events	2 / 2	0 / 0

Outcome results

Primary

Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events

Data on AEs were obtained if spontaneously reported by the patient, if reported in response to an open question from the study personnel or if revealed by observation. A treatment emergent AE (TEAE) is defined as any AE occurring after administration of the IMP and within the time of the residual drug effect period (i.e. 30 days after IMP administration). AEs reported in ClinicalTrials.gov include TEAEs and post-treatment AEs, i.e. all AEs occurring after administration of IdeS until end of study. Please refer to Adverse Event section for details on reported AEs

Time frame: From dosing until end of follow up on day 64

Population: Because of the premature termination of the study due to the non-favourable risk-benefit profile in the first 2 patients and since the sponsor will no longer pursue the indication, the analyses as described in the protocol were not performed. Instead, data collected for the 2 enrolled subjects were listed and/or presented graphically.

Arm	Measure	Group	Value (NUMBER)
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	TEAEs	10 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Mild TEAEs (Grade=1)	7 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Moderate TEAEs (Grade=2)	1 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Severe TEAEs (Grade=3)	1 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Life threatening TEAEs (Grade=4)	1 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Related TEAEs	4 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Serious TEAEs	2 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Post-TEAEs	2 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Mild Post-TEAEs (Grade=1)	1 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Moderate Post-TEAEs (Grade=2)	1 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Related Post-TEAEs	0 Adverse Events
Treatment IdeS (0.25 mg/kg)	Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events	Serious Post-TEAEs	2 Adverse Events

Secondary

Maximum Serum Concentration (Cmax) of IdeS

The concentration of IdeS in serum was measured to identify the pharmacokinetic parameter Cmax of IdeS in TTP patients.

Time frame: From day of dosing until day 14

Population: Because of the premature termination of the study due to the non-favourable risk-benefit profile in the first 2 patients and since the sponsor will no longer pursue the indication, the analyses as described in the protocol were not performed. Instead, data collected for the 2 enrolled subjects were listed and presented graphically.

Arm	Measure	Value (MEAN)
Treatment IdeS (0.25 mg/kg)	Maximum Serum Concentration (Cmax) of IdeS	6.64 µg/mL

Secondary

Number of Patients for Whom a Decreased ADAMTS13 Activity Returned to Normal Levels at Different Time-points in the Study

The ADAMTS13 activity in TTP patients is decreased. The efficacy of IdeS on ADAMTS13 activity was assessed throughout the study to identify the time-point of return to normal levels.