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Sponsor review of initial results demonstrates a non-favourable risk benefit
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| Name | Class |
|---|---|
| University College London Hospitals | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment IdeS (0.25 mg/kg) | Experimental | 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. |
|
| Treatment IdeS (0.50 mg/kg) | Experimental | A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IdeS (0.25 mg/kg) | Biological | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | From dosing until end of follow up on day 64 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From day of dosing until end of follow up on day 64 |
| Number of Patients With Change From Baseline in ADAMTS13 Antibody Levels |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Elisabeth Sonesson, PhD | Hansa Biopharma AB | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University College London Hospitals NHS | London | Greater London | NW1 2PG | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30488420 | Derived | 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. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | IdeS (0.50 mg/kg) | A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
After review of the initial results from the study that demonstrated a non-favourable risk-benefit profile in the first 2 patients who received single i.v. infusion of IdeS (0.25 mg/kg), the study was prematurely discontinued. The potential dose escalation to i.v. infusion of IdeS (0.5 mg/kg) did not occur.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Treatment IdeS (0.50 mg/kg) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 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. | Posted | Number | Adverse Events | From dosing until end of follow up on day 64 |
|
Adverse events (AEs) were collected for a time-period of 3 months for the individual subject (i.e. from the subject signed the informed consent form (ICF) throughout the study including the follow-up period until the end of study visit).
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) was defined as any AE occurring after administration of IdeS and within the time of the residual drug effect period (i.e. 30 days after IdeS administration).
AEs reported in ClinicalTrials.gov include TEAEs and post-TEAEs, i.e. all AEs occurring after administration of IdeS until end of study
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Serum sickness | Immune system disorders | MedDRA (19.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dry mouth | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
Early termination leading to small number of subjects analyzed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Elisabeth Sonesson (Director Clinical Operations) | Hansa Biopharma AB | +46 (0)708 54 86 46 | elisabeth.sonesson@hansabiopharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 21, 2016 | Jun 10, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 22, 2017 | Jun 10, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D011697 | Purpura, Thrombotic Thrombocytopenic |
| ID | Term |
|---|---|
| D011696 | Purpura, Thrombocytopenic |
| D011693 | Purpura |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
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|
| IdeS (0.50 mg/kg) | Biological | Single i.v. infusion of IdeS (0.50 mg/kg). |
|
|
The efficacy of IdeS on ADAMTS13 antibody cleaving was measured througout the study as change from baseline in ADAMTS13 antibody concentration. |
| From day of dosing until end of follow up on day 64 |
| 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. | From day of dosing until end of follow up on day 64 |
| 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. | From day of dosing until end of follow up on day 64 |
| 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. | From day of dosing until end of follow up on day 64 |
| 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. | From day of dosing until day 14 |
| 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. | From day of dosing until day 14 |
| 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). | From day of dosing until end of follow up on day 64 |
A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg). |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 |
| 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. |
| OG001 | Treatment IdeS (0.50 mg/kg) | A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg). |
|
|
| Secondary | 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. | 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. | Posted | Count of Participants | Participants | From day of dosing until end of follow up on day 64 |
|
|
|
| Secondary | 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. | 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. | Posted | Count of Participants | Participants | From day of dosing until end of follow up on day 64 |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | From day of dosing until end of follow up on day 64 |
|
|
|
| Secondary | 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. | 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. | Posted | Count of Participants | Participants | From day of dosing until end of follow up on day 64 |
|
|
|
| Secondary | 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. | 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. | Posted | Count of Participants | Participants | From day of dosing until end of follow up on day 64 |
|
|
|
| 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. | 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. | Posted | Mean | Full Range | µg/mL | From day of dosing until day 14 |
|
|
|
| Secondary | 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. | 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. | Posted | Mean | Full Range | hours | From day of dosing until day 14 |
|
|
|
| Secondary | 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). | The concentration of F(ab')2 fragments in the patients' serum samples was not analysed 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. | Posted | From day of dosing until end of follow up on day 64 |
|
|
| 0 |
| 2 |
| 2 |
| 2 |
| 2 |
| 2 |
| EG001 | Treatment IdeS (0.50 mg/kg) | A single 30 minutes i.v. infusion of IdeS (0.50 mg/kg). | 0 | 0 | 0 | 0 | 0 | 0 |
| Thrombotic thrombocytopenic purpura | Blood and lymphatic system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA (19.0) | Systematic Assessment |
|
All MS must be sent to Sponsor for review at least 60d before submission. Sponsor may request changes. All reasonable comments will be incorporated by Investigator. If MS contains info that could impact proprietary or IP interests, the Sponsor is entitled to request a 6 mth publication delay, allowing actions to protect its interests. The Investigator/Trust shall not unreasonably withhold or delay its consent to such request from the Sponsor or for an exceptional additional delay if requested.
| D006425 |
| Hemic and Lymphatic Diseases |
| D057049 | Thrombotic Microangiopathies |
| D013921 | Thrombocytopenia |
| D001791 | Blood Platelet Disorders |
| D000095542 | Cytopenia |
| D019851 | Thrombophilia |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012877 | Skin Manifestations |
| D012816 | Signs and Symptoms |
| Title | Measurements |
|---|---|
|