LIME Study (LFB IVIg MMN Efficacy Study)

Condition(s) targeted: Motor Neuron Disease

Intervention: Biological : I10E (Human normal Immunoglobulin for intravenous administration 100mg/mL) (Drug); Biological: Kiovig® (Human normal Immunoglobulin for intravenous administration 100mg/mL) (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Laboratoire français de Fractionnement et de Biotechnologies

Official(s) and/or principal investigator(s):
Jean-Marc LEGER, MD, Principal Investigator, Affiliation: Hôpital de la Pitié Salpêtrière - Paris 75013

Overall contact:
Witold MALYSZCZAK, MD, Phone: +33 1 69 82 17 14, Email: malyszczakw@lfb.fr

The aim of this study is to evaluate the efficacy and safety of I10E (LFB 10% ready-to-use liquid human intravenous immunoglobulin) compared to Kiovig® for the maintenance treatment of MMN in a randomized, double-blind, active comparator-controlled, cross-over trial.

Official title: A European, Randomised, Double-blind, Active Comparator Controlled, Cross-over, Efficacy and Safety Study of a New 10% Ready To-use Liquid Human Intravenous Immunoglobulin (I10E) Versus Kiovig® in Patients With Multifocal Motor Neuropathy

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Change between I10E and Kiovig® in the original MMRC 10 sum score described by Cats 2008

Secondary outcome:

Change between I10E and Kiovig® in: MMRC 10 new sum score (10 slightly different muscles on both sides)

AEs observed and reported TAAEs (temporally associated AE) beginning at infusion or within 72H after infusion

Change between I10E and Kiovig® in : Rasch built MMRC sum score (Cats 2008)

Change between I10E and Kiovig® in : INCAT: upper and lower limbs

Change between I10E and Kiovig®: Grip strength

Change between I10E and Kiovig® in: MMRC 14 sum score

Detailed description: Multifocal motor neuropathy (MMN) is a chronic acquired, probably autoimmune, demyelinating, motor neuropathy. It is a rare disease, variable in its clinical features. The disease course is usually steadily progressive. Intravenous immunoglobulin (IVIg) is the standard and the first line treatment for MMN. The Cochrane review of four randomized placebo-controlled studies showed a significant clinical improvement in muscle strength from IVIg in 78% of patients with MMN versus 4% with placebo but a non-significant improvement in disability (39% versus 11%) (van Schaik IN, 2005). However, IVIg treatment does not prevent a mild gradual decline in muscle strength which is probably due to ongoing axonal degeneration. In addition to its efficacy, IVIg is also a safe treatment with a positive benefit-risk ratio in MMN. Muscle strength measured with the Modified Medical Research Council (MMRC 10) sum score as described in the study of Cats (Cats EA, 2008) including 20 movements i. e. 10 muscle groups of the upper and lower limbs on each side was selected as the primary endpoint. Other

parameters of muscle strength such as measurement of grip strength by dynamometer - and

functional disability will also be evaluated to reinforce the robustness of the study and substantiate the efficacy of I10E in MMN patients.

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Male or female patient aged 18 to 80 years. 2. Written informed consent obtained prior to any study-related procedures. 3. Diagnosis of definite or probable MMN according to the EFNS/PNS Guideline 2010, First revision made by neuromuscular disease specialists with specific electrodiagnostic expertise. 4. Patients treated with a stable maintenance dose within 15% of any brand of IVIg (Kiovig® excluded) at 1 g/kg for 1-3 days up to 2 g/Kg for 2-5 days every 4 to 8 weeks (+/- 7 days), according to the EFNS/PNS Guideline 2010, First revision for at least 3 months prior to enrolment. 5. Covered by national health care insurance system if required by local regulations. Exclusion Criteria: 1. Upper motor neuron, bulbar, cranial nerve or significant sensory deficit. 2. CSF protein >100 mg/dL (if available and done as part of a previous evaluation). 3. Any other ongoing disease that may cause neuropathy, such as toxin exposure, dietary difficency, uncontrolled diabetes, hyperthyroidism, cancer, systemic lupus erythematosus or other connective diseases, infection with HIV, hepatitis B virus (HBV), or hepatitis C (HCV), Lyme disease, multiple myeloma, Waldenström's macroglobulinemia, amyloid, and hereditary neuropathy. 4. BMI >= 40 kg/m2. 5. Known hypersensitivity to the active substance or to any of the excipients of I10E (glycine and polysorbate 80) or Kiovig(glycine). 6. Patient who have been treated with Kiovig shall not have received Kiovig during the last 6 months prior to enrolment. 7. History of IgA deficiency, except if the absence of anti-IgA antibodies is documented. 8. Protein-losing enteropathy characterised by serum protein levels <60 g/l and serum albumin levels <30 g/l or nephrotic syndrome characterised by proteinuria >=3. 5 g/24 hours, serum protein levels <60 g/l and serum albumin levels <30 g/l. 9. History of cardiac insufficiency (New York Heart Association (NYHA) III/IV), uncontrolled cardiac arrythmia, unstable ischemic heart disease, or uncontrolled hypertension. 10. History of venous thrombo-embolic disease, myocardial infarction, or cerebrovascular accident. 11. Risk factor for blood hyperviscosity such as cryoglobulinemia or haematological malignancy with monoclonal gammopathy. 12. Glomerular filtration rate <80 ml/min/1. 73m2 measured according to the Modified Diet in Renal Disease (MDRD) calculation. 13. Serum levels of AST, ALT >2 times upper limit of normal range. 14. Treatment within 12 months prior to screeening with immunomodulator or immunosuppressant agent (including but not limited to cyclophosphamide, cyclosporine, interferon-a, interferon-b 1a, anti-CD20, alemtuzumab, azathioprine, etanarcept, mycophenolate mofetil, methotrexate, haematopoietic stem cell transplantation). 15. Administration of another investigational product within the last month prior to inclusion. 16. Plasma exchange, blood products or derivatives administered with the last 3 months prior to screening. 17. Woman with positive results of pregnancy test or breast-feeding woman or woman of childbearing potential without an effective contraception. Effective contraception are injectible, patch or combined oestro-progestative or progestative contraceptives, Cooper T or levonorgest releasing intra-uterine devices, depot intramuscular medroxyprogesterone, subcutaneous progestative contraceptive implants, condoms or occlusive caps (diaphragm or cervical/vault caps) with spermicide, true abstinence (when this is in line with the preferred and usual lifestyle of the patient). 18. Any serious medical condition that would interfere with the clinical assessment of I10E or prevent the patient from complying with the protocol requirements. 19. Anticipated poor compliance of patient with study procedures during the 12 month duration of the study. 20. Drug or alcohol abuse.

Witold MALYSZCZAK, MD, Phone: +33 1 69 82 17 14, Email: malyszczakw@lfb.fr

CHU de Bordeaux -Hôpital Haut-Lévêque, Bordeaux 33604, France; Recruiting
Gwendal LE MASSON, MD, PhD, Principal Investigator

CHU Créteil - Groupe Hospitalier Henri Mondor, Creteil 94010, France; Recruiting
Alain CREANGE, MD, PhD, Principal Investigator

CHRU Lille - Hôpital Roger Salengro, Lille 59037, France; Recruiting
Arnaud LACOUR, MD, Principal Investigator

CHU de Lyon - Hôpital Pierre Wertheimer, Lyon 69677, France; Recruiting
Christophe VIAL, MD, Principal Investigator

CHU de Marseille - Hôpital de La Timone, Marseille 13385, France; Recruiting
Jean POUGET, MD, PhD, Principal Investigator

CHU de Nice - Hôpital l'Archet, Nice 06202, France; Recruiting
Claude DESNUELLE, MD, PhD, Principal Investigator

CHU Paris - Hôpital Pitié Salpétrière, Paris 75651, France; Recruiting
Jean-Marc LEGER, MD, Principal Investigator

CHU de Saint Etienne - Hôpital Nord, Saint Etienne 42055, France; Recruiting
Jean-Christophe ANTOINE, MD, PhD, Principal Investigator

Università di Genova - Ospedale San Martino, Genova 16132, Italy; Recruiting
Angelo SCHENONE, Prof., Principal Investigator

IRCCS Istituto Clinico Humanitas, Milan 20089, Italy; Recruiting
Eduardo NOBILE-ORAZIO, MD, PhD, Principal Investigator

Università Cattolica del Sacro Cuore, Roma 00168, Italy; Recruiting
Luca PADUA, Prof., Principal Investigator

Azienda Ospedaliero Universitaria San Giovanni Battista, Turin 10126, Italy; Recruiting
Dario COCITO, MD, Principal Investigator

Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain; Recruiting
Ricardo ROJAS-GARCIA, MD, Principal Investigator

Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela 15706, Spain; Recruiting
Julio PARDO-FERNANDEZ, MD, Principal Investigator

Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain; Recruiting
Celedonio MARQUEZ-INFANTE, MD, Principal Investigator

Hospital Universitari i Politècnic La Fe, Valencia 46026, Spain; Recruiting
Teresa SEVILLA, MD, Principal Investigator

Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Recruiting
Yusuf RAJABALLY, MD, Principal Investigator

Southampton General Hospital, Southampton SO16 6YD, United Kingdom; Recruiting
Haider KATIFI, MD, Principal Investigator

Starting date: December 2013
Last updated: July 6, 2015