A Study of Imlifidase in Patients With Guillain-Barré Syndrome

Study Overview
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Brief Summary
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The study participants are patients which have been diagnosed with Guillain-Barré Syndrome (GBS) and are planned to receive treatment with intravenous immunoglobulin (IVIg). IVIg is a standard of care treatment for GBS patients. The patients in this study will be treated with the study medicine imlifidase on day 1, and with IVIg on days 3-7. The purpose of this study is to investigate the safety and effectiveness of imlifidase in patients diagnosed with GBS.

Detailed Description
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This is an open-label, single arm, multi-centre, phase II study of imlifidase in combination with standard care IVIg in patients with GBS. The study will recruit approximately 30 patients who are eligible for IVIg treatment based on current practice (i.e. GBS disability score >3 and within 10 days of onset of weakness). All patients will receive imlifidase (Day 1) prior to standard care IVIg. Data from each patient enrolled in this study will be compared with a control group consisting of up to 4 subjects from the International Guillain-Barré Syndrome Outcome Study (IGOS) database (ClinicalTrials.gov identifier: NCT01582763) fulfilling a subset of the eligibility criteria in the current imlifidase GBS study protocol. Matching will be done on geographical locations, age, presence of diarrhoea, and severity of condition. There is growing body of evidence suggesting that GBS is an antibody-mediated disorder. In addition to supportive care, IVIg and Plasma Exchange (PE) are the two main immunological treatment options aimed at attenuating the autoreactive humoral immune response. Imlifidase is an IgG degrading enzyme with strict specificity. The hypothesis is that reduction of pathological antibodies may result in aborted progression, quicker recovery and less severe disease.

Official Title
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An Open-label, Single Arm, Multi-centre, Phase II Study Investigating Safety, Tolerability, Efficacy, Pharmacodynamics and Pharmacokinetics of Imlifidase in Patients With Guillain-Barré Syndrome, in Comparison With Matched Control Patients

Conditions
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Guillain-Barré Syndrome (GBS)

Intervention / Treatment
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* Drug: Imlifidase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent obtained before any study-related procedures. Willingness and ability to comply with the protocol. Male or female aged ≥18 years at the time of screening. GBS diagnosed according to National Institute of Neurological Disorders and Stroke (NINDS) diagnostic criteria (Asbury et al. 1990). Onset of weakness due to GBS is not more than 10 days prior to screening. Unable to walk unaided for >10 meters (grade ≥ 3 on GBS DS). IVIg treatment being considered. Women of child-bearing potential willing or able to use at least one highly effective contraceptive method from the day of treatment until at least 6 months after the dose of imlifidase if not abstinent. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Men willing to use double-barrier contraception from the day of treatment until at least 2 months after the dose of imlifidase if not abstinent. Exclusion Criteria: Previous treatment with imlifidase. Previous IVIg treatment within 28 days prior to imlifidase treatment. Subjects who are being considered for, or already on, PE. Women of child-bearing potential willing or able to use at least one highly effective contraceptive method from the screening visit until at least 180 days following imlifidase dosing. Breastfeeding or pregnancy Clinical evidence of a polyneuropathy of another cause e.g. diabetes mellitus (except mild sensory), alcoholism, vitamin deficiency, or porphyria. Known selective immunoglobulin A (IgA) deficiency. Hypersensitivity to IVIg or to any of the excipients. Immunosuppressive treatment (e.g. azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, sirolimus or > 20 mg prednisolone daily) during the last month. Subject known to have a severe concurrent disease, e.g. malignancy, severe cardiovascular disease and severe chronic obstructive pulmonary disease (COPD). Any condition that in the opinion of the investigator could increase the subject's risk by participating in the study or confound the outcome of the study. Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the study activities. Subjects with clinical signs of ongoing infection. Subjects should not have received other investigational drugs within 5 half-lives prior to imlifidase dosing. Present or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP. Positive PCR test for SARS-CoV-2 virus infection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Data from each patient enrolled in this study will be compared with a control group consisting of up to 4 subjects treated with IVIg only from the International Guillain-Barré Syndrome Outcome Study (IGOS) database (ClinicalTrials.gov identifier: NCT01582763) fulfilling a subset of the eligibility criteria in the current imlifidase GBS study protocol. Matching will be done on geographical locations, age, presence of diarrhoea, and severity of condition.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imlifidase<br>One (1) dose of imlifidase, 0.25 mg/kg, will be administered IV over 30 minutes, Day 1. IVIg, 0.4 g/kg, will be administered for 5 consecutive Days, starting on Day 3 at least 48 h after imlifidase administration. | Drug: Imlifidase<br>* All subjects will receive imlifidase (Day 1) prior to standard care IVIg<br>* Other names: Hansa Medical-Immunoglobulin G degrading enzyme of Streptococcus pyogenes (HMED-IdeS), IdeS, IgG endopeptidase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by Adverse Events (AEs) | Safety is assessed as type, frequency and intensity of Adverse Events (AE)/Serious Adverse Events (SAEs) | Screening up to Day 360 | 
| Changed disability outcome at 4 weeks assessed by the 6-point GBS disability score (DS) | Efficacy is assessed as proportion of subjects with improvement of one (1) or more grades in disability outcome on the 6-point GBS DS at 4 weeks. The 6-point Guillain-Barré Syndrome disability score (GBS DS) is a widely accepted and easily obtainable scoring system used to assess disability status of GBS subjects. The DS score is as follows: 0=Healthy, 1=Minor symptoms and capable of running (subjects must be asked to run), 2=Able to walk independently 10 meters or more but unable to run, 3=Able to walk more than 10 meters across an open space with help, 4=Bedridden or chair bound, 5=Needing mechanical ventilation, 6=Dead | Screening and Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in disability outcome at week 4 as assessed by the 6-point GBS DS | Efficacy is assessed as mean change from screening in GBS DS grade (on the 6-points GBS DS) at 4 weeks. The 6-point Guillain-Barré Syndrome disability score (GBS DS) is a widely accepted and easily obtainable scoring system used to assess disability status of GBS subjects. The DS score is as follows: 0=Healthy, 1=Minor symptoms and capable of running (subjects must be asked to run), 2=Able to walk independently 10 meters or more but unable to run, 3=Able to walk more than 10 meters across an open space with help, 4=Bedridden or chair bound, 5=Needing mechanical ventilation, 6=Dead | Screening and Day 29 | 
| Ability to walk unaided at 4, 8 and 26 weeks | Efficacy is assessed as proportion of subjects able to walk unaided (i.e. GBS DS=2) at 4, 8 and 26 weeks | Day 29, Day 57, and Day 180 | 
| Time to improvement by at least one (1) GBS DS grade | Efficacy is assessed as time to improvement by at least one (1) GBS DS grade. The 6-point Guillain-Barré Syndrome disability score (GBS DS) is a widely accepted and easily obtainable scoring system used to assess disability status of GBS subjects. The DS score is as follows: 0=Healthy, 1=Minor symptoms and capable of running (subjects must be asked to run), 2=Able to walk independently 10 meters or more but unable to run, 3=Able to walk more than 10 meters across an open space with help, 4=Bedridden or chair bound, 5=Needing mechanical ventilation, 6=Dead | Screening until Day 360 | 
| Time to walk unaided | Efficacy is assessed as time to walk unaided (i.e. GBS DS=2) | Screening until Day 360 | 
| Change from baseline in R-ODS by at least 6 Points at 4, 8, and 26 weeks | Efficacy is assessed as proportion of subjects with an increase from baseline in Rasch-built Overall Disability scale (R-ODS) by at least 6 Points on the centile metric score at 4, 8 and 26 weeks R-ODS is a linearly weighted disease specific scale, which captures activities and social participation limitation in patients with immune-mediated neuropathies, including GBS. The questionnaire comprises 24 items ranging from ability to read a book or newspaper (as the easiest item to accomplish) to ability to run (most difficult item to accomplish). The response options for each item are: 0=Not possible, 1=Possible with effort, 2=Easy to perform. The obtained raw summed score is subsequently translated to a centile metric ranging from 0 (most severe disability) to 100 (no disability at all). | Screening, Day 29, Day 57, and Day 180 | 
| Requirement for ventilator support | Efficacy is assessed as proportion of subjects requiring ventilator support (i.e. GBS DS=5) | Screening until Day 360 | 
| Time in ventilator | Efficacy is assessed as time in ventilator (counted only if at least 12 hours/day) | Screening until Day 360 | 
| Time in an ICU | Efficacy is assessed as time in an intensive care unit (ICU) | Screening until Day 360 | 
| Changes in MRC sum score | Efficacy is assessed as change in Medical Research Council (MRC) sum score. The MRC sum score is widely used to assess the motor impairment in subjects with peripheral neuropathies. It is a sum score of power in 6 muscle groups on each side (abduction of arm, flexion of forearm, extension of the wrist, hip flexion, and extension of knee and dorsal flexion of the foot). The sum of these scores ranges from 0 (total paralysis) to 60 (normal power). It provides valuable information about the muscle strength. Change in MRC sum score helps in identification of GBS patients with treatment related fluctuation or exacerbation. The individual MRC grades are defined as follows: 0=No visible contraction,1=Visible contraction without movement of the limb, 2=Movement of the limb but not against gravity, 3=Movement against gravity (almost full range), 4=Movement against gravity and resistance, 5=Normal | Screening until Day 180 | 
| PK profile of imlifidase: Cmax | Cmax=Maximum observed plasma concentration of imlifidase following dosing | Within 2 hours before imlifidase dose until Day 15 | 
| PK profile of imlifidase: Tmax | Tmax=Time point for maximum observed plasma concentration of imlifidase following dosing | Within 2 hours before imlifidase dose until Day 15 | 
| PK profile of imlifidase: AUC | AUC=Area under the imlifidase plasma concentration versus time curve | Within 2 hours before imlifidase dose until Day 15 | 
| PK profile of imlifidase: t1/2 | t1/2=Terminal half-life of imlifidase | Within 2 hours before imlifidase dose until Day 15 | 
| PK profile of imlifidase: CL | CL=Clearance of imlifidase | Within 2 hours before imlifidase dose until Day 15 | 
| PK profile of imlifidase: V | V=Volume of distribution | Within 2 hours before imlifidase dose until Day 15 | 
| PD effect on IgG | The PD effect on IgG will be described qualitatively on a scale. The scale range from score=0 (no intact IgG, single cleaved IgG (scIgG) or F(ab')2 to score=5 (only intact IgG) | Within 2 hours before imlifidase dose until Day 15 | 
| Presence of ADAs | Proportion of patients with anti-imlifidase antibodies (ADAs) at different time-points during the study | Within 2 hours before imlifidase dose until Day 180 | 
| Patient's health state as assessed by EQ-5D Quality of Life questionnaire | Quality of Life will be assessed using the EurQol group's EurQol - 5 dimension (EQ-5D) Health questionnaire. The EQ-5D consists of 2 parts: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient indicates health state in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions are combined into a 5-digit number that describes the patient's health state. The EQ VAS records the patient's self-rated health on a vertical scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. | Day 8, Day 15, Day 29, Day 57, Day 92, Day 180, and Day 360 |