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A Study of Imlifidase in Patients With Guillain-Barré Syndrome

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ClinicalTrials.gov Identifier: NCT03943589
Recruitment Status : Recruiting
First Posted : May 9, 2019
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Hansa Biopharma AB

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Guillain-Barré Syndrome (GBS) Drug: Imlifidase Phase 2

Detailed Description:

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 up to 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 6, 2019
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Experimental: Imlifidase

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
All subjects will receive imlifidase (Day 1) prior to standard care IVIg
Other Name: Hansa Medical-Immunoglobulin G degrading enzyme of Streptococcus pyogenes (HMED-IdeS), IdeS, IgG endopeptidase




Primary Outcome Measures :
  1. Safety as measured by Adverse Events (AEs) [ Time Frame: Screening up to Day 360 ]
    Safety is assessed as type, frequency and intensity of Adverse Events (AE)/Serious Adverse Events (SAEs)

  2. Improved functional outcome at 4 weeks assessed by the 6-point GBS functional score (FS) [ Time Frame: Screening and Day 29 ]

    Efficacy is assessed as proportion of subjects with improvement of one (1) or more grades in functional outcome on the 6-point GBS FS at 4 weeks.

    The 6-point Guillain-Barré Syndrome functional score (GBS FS) is a widely accepted and easily obtainable scoring system used to assess functional status of GBS subjects. The 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



Secondary Outcome Measures :
  1. Mean change in functional outcome at week 4 as assessed by the 6-point GBS FS [ Time Frame: Screening and Day 29 ]

    Efficacy is assessed as mean change from screening in GBS FS grade (on the 6-points GBS FS) at 4 weeks.

    The 6-point Guillain-Barré Syndrome functional score (GBS FS) is a widely accepted and easily obtainable scoring system used to assess functional status of GBS subjects. The 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


  2. Ability to walk unaided at 4, 8 and 26 weeks [ Time Frame: Day 29, Day 57, and Day 180 ]
    Efficacy is assessed as proportion of subjects able to walk unaided (i.e. GBS FS=2) at 4, 8 and 26 weeks

  3. Time to improvement by at least one (1) GBS FS grade [ Time Frame: Screening until Day 360 ]

    Efficacy is assessed as time to improvement by at least one (1) GBS FS grade.

    The 6-point Guillain-Barré Syndrome functional score (GBS FS) is a widely accepted and easily obtainable scoring system used to assess functional status of GBS subjects. The 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


  4. Time to walk unaided [ Time Frame: Screening until Day 360 ]
    Efficacy is assessed as time to walk unaided (i.e. GBS FS=2)

  5. Increase from baseline in R-ODS by at least 6 Points at 4, 8, and 26 weeks [ Time Frame: Screening, Day 29, Day 57, and Day 180 ]

    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).


  6. Requirement for ventilator support [ Time Frame: Screening until Day 360 ]
    Efficacy is assessed as proportion of subjects requiring ventilator support (i.e. GBS FS=5)

  7. Time in ventilator [ Time Frame: Screening until Day 360 ]
    Efficacy is assessed as time in ventilator (counted only if at least 12 hours/day)

  8. Time in an ICU [ Time Frame: Screening until Day 360 ]
    Efficacy is assessed as time in an intensive care unit (ICU)

  9. Changes in MRC sum score [ Time Frame: Screening until Day 180 ]

    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


  10. PK profile of imlifidase: Cmax [ Time Frame: Within 2 hours before imlifidase dose until Day 15 ]
    Cmax = Maximum observed plasma concentration of imlifidase following dosing

  11. PK profile of imlifidase: Tmax [ Time Frame: Within 2 hours before imlifidase dose until Day 15 ]
    Tmax = Time point for maximum observed plasma concentration of imlifidase following dosing

  12. PK profile of imlifidase: AUC [ Time Frame: Within 2 hours before imlifidase dose until Day 15 ]
    AUC = Area under the imlifidase plasma concentration versus time curve

  13. PK profile of imlifidase: t1/2 [ Time Frame: Within 2 hours before imlifidase dose until Day 15 ]
    t1/2 = terminal half-life of imlifidase

  14. PK profile of imlifidase: CL [ Time Frame: Within 2 hours before imlifidase dose until Day 15 ]
    CL = Clearance of imlifidase

  15. PK profile of imlifidase: V [ Time Frame: Within 2 hours before imlifidase dose until Day 15 ]
    V = Volume of distribution

  16. PD effect on IgG [ Time Frame: Within 2 hours before imlifidase dose until Day 15 ]
    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)

  17. Presence of ADAs [ Time Frame: Within 2 hours before imlifidase dose until Day 180 ]
    Proportion of patients with anti-imlifidase antibodies (ADAs) at different time-points during the study

  18. Quality of Life assessment [ Time Frame: Day 8, Day 15, Day 29, Day 57, Day 92, Day 180, and Day 360 ]

    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'.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed Informed Consent obtained before any study-related procedures.
  2. Willingness and ability to comply with the protocol.
  3. Male or female aged ≥18 years at the time of screening.
  4. GBS diagnosed according to National Institute of Neurological Disorders and Stroke (NINDS) diagnostic criteria (Asbury et al. 1990).
  5. Onset of weakness due to GBS is not more than 10 days prior to screening.
  6. Unable to walk unaided for >10 meters (grade ≥ 3 on GBS FS).
  7. IVIg treatment being considered.
  8. 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.
  9. 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:

  1. Previous treatment with imlifidase.
  2. Previous IVIg treatment within 28 days prior to imlifidase treatment.
  3. Subjects who are being considered for, or already on, PE.
  4. 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.
  5. Clinical evidence of a polyneuropathy of another cause e.g. diabetes mellitus (except mild sensory), alcoholism, vitamin deficiency, or porphyria.
  6. Known selective immunoglobulin A (IgA) deficiency.
  7. Hypersensitivity to IVIg or to any of the excipients.
  8. Immunosuppressive treatment (e.g. azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, sirolimus or > 20 mg prednisolone daily) during the last month.
  9. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody or human immunodeficiency virus.
  10. Subject known to have a severe concurrent disease, e.g. malignancy, severe cardiovascular disease and severe chronic obstructive pulmonary disease (COPD).
  11. 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.
  12. Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the study activities.
  13. Subjects with clinical signs of ongoing infectious diseases that requires treatment.
  14. Subjects should not have received other investigational drugs within 5 half-lives prior to imlifidase dosing.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03943589


Contacts
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Contact: Charlotte Elfving, BSc +46 705 15 29 15 charlotte.elfving@hansabiopharma.com

Locations
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France
CHU Le Kremlin-Bicêtre. Service Neurologie Not yet recruiting
Le Kremlin-Bicêtre, Paris, France, 94270
Contact: Andoni Echaniz-Laguna, Prof.    +33 145 213159    andoni.echaniz-laguna@aphp.fr   
CHU Bordeaux - Hôpital Pellegrin Tripode Not yet recruiting
Bordeaux, France, 33076
Contact: Guilhem Solé, Prof.    +33 557821380    guilhem.sole@chu.bordeaux.fr   
CHU de Limoges - Hôpital Dupuytren Not yet recruiting
Limoges, France, 87000
Contact: Laurent Magy, Prof.    +33 555 056561    laurent.magy@unilim.fr   
Hôpital de la Timone - Centre de référence des maladies neuromusculaires et de la SLA Recruiting
Marseille, France, 13385
Contact: Shahram Attarian, Professor    +33 4 9138 6569    sattarian@ap-hm.fr   
Principal Investigator: Shahram Attarian         
Sponsors and Collaborators
Hansa Biopharma AB
Investigators
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Study Chair: Elisabeth Sonesson, PhD Hansa Biopharma AB

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Responsible Party: Hansa Biopharma AB
ClinicalTrials.gov Identifier: NCT03943589     History of Changes
Other Study ID Numbers: 15-HMedIdeS-09
First Posted: May 9, 2019    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Syndrome
Guillain-Barre Syndrome
Disease
Pathologic Processes
Polyradiculoneuropathy
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Polyneuropathies
Autoimmune Diseases
Immune System Diseases
Immunoglobulins
Immunoglobulin G
Immunologic Factors
Physiological Effects of Drugs