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

Primary Purpose

Purpura, Thrombotic Thrombocytopenic

Status
Terminated
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
IdeS (0.25 mg/kg)
IdeS (0.50 mg/kg)
Sponsored by
Hansa Biopharma AB
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Purpura, Thrombotic Thrombocytopenic focused on measuring Asymptomatic antibody-mediated TTP

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University College London Hospitals NHS

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Treatment IdeS (0.25 mg/kg)

Treatment IdeS (0.50 mg/kg)

Arm Description

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.

A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg).

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Number of Patients With Change From Baseline in ADAMTS13 Activity
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.
Number of Patients With Change From Baseline in ADAMTS13 Antibody Levels
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
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
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 Showing IdeS Immunogenicity as Measured by Anti-drug Antibodies
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.
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-point for Maximum Serum Concentration of IdeS
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
The efficacy of IdeS can be measured as change from baseline in F(ab')2 fragments (i.e. the antigen binding fragment of IgG).

Full Information

First Posted
July 27, 2016
Last Updated
September 12, 2019
Sponsor
Hansa Biopharma AB
Collaborators
University College London Hospitals
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1. Study Identification

Unique Protocol Identification Number
NCT02854059
Brief Title
IdeS in Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients
Official Title
A Phase II Pilot Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacodynamics and Pharmacokinetics of IdeS in Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients With Low ADAMTS13 Activity
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Terminated
Why Stopped
Sponsor review of initial results demonstrates a non-favourable risk benefit
Study Start Date
September 2016 (undefined)
Primary Completion Date
January 2017 (Actual)
Study Completion Date
January 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hansa Biopharma AB
Collaborators
University College London Hospitals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Purpura, Thrombotic Thrombocytopenic
Keywords
Asymptomatic antibody-mediated TTP

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment IdeS (0.25 mg/kg)
Arm Type
Experimental
Arm Description
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.
Arm Title
Treatment IdeS (0.50 mg/kg)
Arm Type
Experimental
Arm Description
A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg).
Intervention Type
Biological
Intervention Name(s)
IdeS (0.25 mg/kg)
Other Intervention Name(s)
HMed-IdeS, IgG-degrading enzyme of Streptococcus pyogenes
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
IdeS (0.50 mg/kg)
Other Intervention Name(s)
HMed-IdeS, IgG-degrading enzyme of Streptococcus pyogenes
Intervention Description
Single i.v. infusion of IdeS (0.50 mg/kg).
Primary Outcome Measure Information:
Title
Safety and Tolerability as Measured by Type, Frequency and Intensity of Adverse Events
Description
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
Secondary Outcome Measure Information:
Title
Number of Patients With Change From Baseline in ADAMTS13 Activity
Description
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.
Time Frame
From day of dosing until end of follow up on day 64
Title
Number of Patients With Change From Baseline in ADAMTS13 Antibody Levels
Description
The efficacy of IdeS on ADAMTS13 antibody cleaving was measured througout the study as change from baseline in ADAMTS13 antibody concentration.
Time Frame
From day of dosing until end of follow up on day 64
Title
Number of Patients for Whom a Decreased ADAMTS13 Activity Returned to Normal Levels at Different Time-points in the Study
Description
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.
Time Frame
From day of dosing until end of follow up on day 64
Title
Number of Patients With Change From Baseline in Pharmacodynamics as Measured by Level of IgG
Description
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.
Time Frame
From day of dosing until end of follow up on day 64
Title
Number of Patients Showing IdeS Immunogenicity as Measured by Anti-drug Antibodies
Description
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.
Time Frame
From day of dosing until end of follow up on day 64
Title
Maximum Serum Concentration (Cmax) of IdeS
Description
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
Title
Time-point for Maximum Serum Concentration of IdeS
Description
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.
Time Frame
From day of dosing until day 14
Title
Number of Patients With Change From Baseline in Pharmacodynamics as Measured by Level of F(ab')2 Fragments
Description
The efficacy of IdeS can be measured as change from baseline in F(ab')2 fragments (i.e. the antigen binding fragment of IgG).
Time Frame
From day of dosing until end of follow up on day 64

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elisabeth Sonesson, PhD
Organizational Affiliation
Hansa Biopharma AB
Official's Role
Study Director
Facility Information:
Facility Name
University College London Hospitals NHS
City
London
State/Province
Greater London
ZIP/Postal Code
NW1 2PG
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
An internal monitoring committee (IMC) at the sponsor will review available safety and tolerability data after 3 patients have received a dose of 0.25 mg/kg before proceeding to the next dose (0.5 mg/kg). Safety data collected up to and including day 14 will be evaluated.
Citations:
PubMed Identifier
30488420
Citation
Stubbs MJ, Thomas M, Vendramin C, Sonesson E, Kjellman C, Jarnum S, Stenberg Y, Elfving C, Scully M. Administration of immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) for persistent anti-ADAMTS13 antibodies in patients with thrombotic thrombocytopenic purpura in clinical remission. Br J Haematol. 2019 Jul;186(1):137-140. doi: 10.1111/bjh.15706. Epub 2018 Nov 29. No abstract available. Erratum In: Br J Haematol. 2022 Jul;198(2):405.
Results Reference
derived

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

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