Immune Globulin Intravenous (IGIV) For Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Condition(s) targeted: Polyradiculoneuropathy, Chronic Inflammatory Demyelinating

Intervention: Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified (Drug); Albumin (Human) 25%, USP (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Talecris Biotherapeutics

Official(s) and/or principal investigator(s):
Norman Latov, MD, Principal Investigator, Affiliation: Columbia University

The intent of this study is to demonstrate the efficacy and safety of Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified (IGIV-C) in newly or previously diagnosed CIDP subjects. Eight courses of treatment with either placebo or IGIV-C will occur every 3 weeks. Neurological function will be measured by INCAT scores. Patients who deteriorate or show no improvement between day 16 and month 6 will receive the alternate study drug for an additional 6 months.

Official title: Multicenter, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of IGIV-Chromatography (IGIV-C), 10% Treatment in Subjects With Chronic Inflammatory Demyelinating Polyneuropathy

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: ≥ 1 point improvement in the INCAT score relative to baseline at 6 months (without crossing over) or the last INCAT assessment after the first study drug infusion (crossing over). Any subject who crosses over will be considered a non-responder.

Secondary outcome:

Mean change in the amplitude (millivolts) in the most severely affected motor nerve

Change in grip strength

Time to relapse

Detailed description: 110 subjects, 55 per treatment group, with newly or previously diagnosed CIDP defined by INCAT neurophysiological diagnostic criteria will be enrolled into the trial. Patients will not be replaced if they discontinue prematurely.

Eligible subjects will be randomized to receive either IGIV-C at a dose of 2 g/kg body weight (bw) ideally over 2-4 days or matching placebo. Thereafter, study drug infusion (IGIV-C or matching placebo) will be administered every 3 weeks at a dose of 1 g/kg bw, given over 1-2 days for a total of 7 additional infusions. Patient's functional disability will be measured using the INCAT disability score at baseline, day 16, and at each study visit scheduled every 3 weeks for 6 months. If the INCAT score worsens by ≥1 point at any time between day 16 and month 6 (not including the month 6 visit) relative to baseline, the subject will be immediately crossed over to the other study drug. Subjects whose INCAT upper extremity score changes from 0 to 1 or from 1 to 0 will have an adjusted INCAT score calculated where this upper extremity change is not incorporated into the adjusted score. Any subject with an adjusted INCAT score change of 0 will be deemed a stable patient and will be crossed over at week 6.

Upon entering the crossover period, subjects will receive either IGIV-C at a dose of 2 g/kg bw ideally over 2-4 days or matching placebo. Thereafter, a study drug infusion (IGIV-C or matching placebo) will be administered every 3 weeks at a dose of 1 g/kg bw, given over 1-2 days for a total of 7 additional infusions. A subject will be terminated from the study any time between day 16 and 6 months during the crossover period if the INCAT score fails to improve by ≥1 point relative to INCAT score at time of crossover. Stable subjects who crossed over at Week 6 must remain in the Crossover Treatment Period for 3 weeks before being considered for withdrawal (due to lack of improvement). Any subject who has been crossed-over to the alternate study drug will be deemed a treatment failure for the primary efficacy analysis.

Randomization will be within each center. Eight randomization numbers, which constitutes one or more full random blocks, will be assigned to each center. A random number will be assigned to subjects in ascending order.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Documented diagnosis of CIDP must be made by a neurologist specializing/experienced in

neuromuscular diseases based on: a) Progressive or relapsing motor and sensory dysfunction of more than one limb resulting from neuropathy over the 2 months prior to the date informed consent is obtained, and b) Cerebrospinal fluid (CSF) less than 50 white cells/µl since CIDP diagnosis (CSF testing studies are NOT mandatory)

- Fulfillment of INCAT neurophysiological criteria for focal demyelinating

polyradiculoneuropathy

- Overall INCAT score between 2-9 and significant disability in upper or lower limb

function in at least 2 limbs. (An INCAT score of 2 must be exclusively from leg disability to qualify.)

Exclusion Criteria:

- Treatment with IGIV or plasma within 3 months prior to entry

- Steroids (Prednisolone or equivalent) > 10 mg/day or equivalent (i. e., > 20 mg every 2

days) during the last 3 months prior to entry

- Treatment with immunomodulatory/immunosuppressive agents (azathioprin,

tacrolimus,cyclosporin, OKT3, any interferon), previous lymphoid irradiation or prior treatment with cyclophosphamide, methotrexate, mitoxantrone or any other immunosuppressant drug within the past 6 months prior to entry

- Concomitant use of supplements containing any amount of fish oil within 30 days prior

to entry

- Respiratory impairment requiring mechanical ventilation

- Myelopathy or evidence of central demyelination or persisting neurological deficits

from stroke, CNS trauma or peripheral neuropathies of other cause which include diabetes mellitus (defined as a history of type 1 or type 2 diabetes with fasting plasma glucose ≥ 7. 0 mmol/L), uremic, toxic and familial neuropathies

- Pure motor syndrome fulfilling criteria for multifocal motor neuropathy with

conduction block. Lower motor neuron disorder with motor weakness in an upper limb, without sensory deficit and with proximal conduction block (50% decrease in amplitude/area with proximal distal stimulation ) in motor nerves and normal sensory nerve conduction studies.

- Clinical or known evidence of associated systemic diseases that might cause

neuropathy, including but not limited to connective tissue disease, HIV infection, hepatitis, Lyme disease, cancer (with the exception of benign skin cancer), Castleman's disease and systemic lupus erythematosus, diabetes mellitus (defined as a history of type 1 or type 2 diabetes with fasting plasma glucose ≥ 7. 0 mmol/L), a malignant plasma cell dysplasia, IgM paraproteinemia, and amiodarone therapy.

- History of anaphylaxis or severe systemic response to immunoglobulin or with a blood

product.

- Cardiac insufficiency (NYHA III/IV), cardiomyopathy, significant cardiac dysrhythmia

requiring treatment, unstable or advanced ischemic heart disease, or history of congestive heart failure, severe hypertension (diastolic pressure >120 mmHg or systolic >170 mmHg).

- Females who are pregnant, breast feeding, or if of childbearing potential, unwilling

to practice adequate contraception throughout the study.

- Known hyperviscosity.

- History of renal insufficiency or serum creatinine levels > 221 µmol/L (2. 5 mg/dL).

- Known selective IgA deficiency.

- Other investigational drugs received within the 30 days prior to entry

- Conditions whose symptoms and effects could alter protein catabolism and/or IgG

utilization (e. g. protein-losing enteropathies, nephrotic syndrome).

- Known hypercoagulable state.

- Mentally challenged adult subjects who cannot give independent informed consent.

- Subjects with uncompensated hypothyroidism (abnormally high TSH and abnormally low T4)

or vitamin B12 deficiency (abnormally low) within the last 3 months prior to entry.

Instituto de Neurociencias Buenos Aires (INEBA), Capital Federal C1192 AAW, Argentina

Hospital Frances, Buenos Aires C1221ACI, Argentina

Hospital Ramos Mejia, Buenos Aires C1221 ADC, Argentina

Fundacion para la Lucha contra Las Enfermedades Neurologicas de la Infacia (FLENI), Buenos Aires C1428 AQK, Argentina

Fakultní nemocnice Brno, Brno 625 00, Czech Republic

Fakultní nemocnice Motol, Praha 5 15600, Czech Republic

Neurologická klinika Pardubice, Pardubice 53003, Czech Republic

Fakultní nemocnice Ostrava, Ostrava-Poruba 1790, Czech Republic

Jüdisches Krankenhaus, Berlin 13347, Germany

Chaim Sheba Medical Center, Tel Hashomer, Israel

Tel Aviv Sourasky Medical Center, Tel Aviv 84101, Israel

Assaf Harofe Medical Center, Zrifin 70300, Israel

Hospital San Raffaele, Milano 20132, Italy

Dipartimento di Neuroscienze, Sezione di Neurologia, AO Chieti, Chieti, Italy

Univesita delgi Studi di Genova, Dipartimento di Scienze, Neurologiche e della Visione, Genova 16132, Italy

Hospital Central San Luis Potosi, Neurology Department, San Luis Potosi, Mexico

County Hospital, Zgierz, Poland

Central Clinical Hospital, Medical Academy Warsaw, Warsaw, Poland

Barlicki Hospital, Lodz 90-153, Poland

County Specialist Hospital, Neurology Department, Gdansk 80-803, Poland

Medical Acedemy, Clinical Hospital, Neurology Department, Lubin 20-950, Poland

Centre of Clinical Neurology, Neurology Department, Cracow 31-530, Poland

University Hospital, University of Belgrade, Belgrade 11000, Serbia and Montenegro

Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia V5Z 1M9, Canada

Yale University School of Medicine, New Haven, Connecticut 06520-8018, United States

Hospital Angel Leano, Neurology Department, Guadalajara, Jalisco, Mexico

Antiguo Hospital Civil de Guadalajara, Guadalajara, Jalisco 44280, Mexico

Saint Louis University Medical Center, St. Louis, Missouri 63110, United States

Columbia University, New York, New York 10022, United States

Wake Forest University-School of Medicine, Winston-Salem, North Carolina 27157-1078, United States

Cleveland Clinic, Cleveland, Ohio 44195, United States

University of Texas-Southwestern Medical Center at Dallas, Dallas, Texas 75390, United States

FDA Approved Product Labeling Information - Gamunex®

FDA Approved Product Labeling Information - Plasbumin®-25 (Low Aluminum)

FDA Product Approval - Gamunex

CIDP ICE Synopsis of Study Results

Starting date: April 2004
Ending date: June 2006
Last updated: April 1, 2008