Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and Treatment With Subcutaneous Immunoglobulin (IgPro20)

Randomized, Multicenter, Double-blind, Placebo-controlled, Parallel-group Phase III Study to Investigate the Efficacy, Safety, and Tolerability of 2 Different Doses of IgPro20 (Subcutaneous Immunoglobulin) for the Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) - the PATH Study

This is a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group 3-arm study to investigate 2 different doses of subcutaneous (SC) IgPro20 compared with placebo for maintenance treatment of patients with CIDP.

Patients who received at lease 1 dose of intravenous immunoglobulin (IVIG) within 8 weeks before screening will be assessed during 4 separate study periods. Patients first undergo a Screening Period, followed by an IgG Dependency Test Period of up to 12 weeks to test for ongoing need of IgG. Those patients experiencing CIDP relapse during this test period will be administered a standardized IVIG regimen during an IVIG Re-stabilization Period. Patients with improved and maintained adjusted inflammatory neuropathy cause and treatment scale (INCAT) in the IVIG Re-stabilization Period will continue to the SC Treatment Period of the study. Patients entering the 24 week SC Treatment Period will be randomized to receive weekly infusions of 1 of 2 IgPro20 doses (0.2 or 0.4 g/kg body weight) or placebo.

The overall study duration is up to 52 weeks. Clinical outcomes will be assessed by the Inflammatory Neuropathy Cause and Treatment (INCAT) score, maximum grip strength, the Medical Research Council (MRC) sum score, the Rasch-built Overall Disability Scale (R-ODS), and electrophysiological evaluations.

Study Overview

• Status: Completed
• Conditions: Polyradiculoneuropathy; Chronic Inflammatory Demyelinating Polyneuropathy
• Intervention / Treatment: Biological: IgPro20 (low dose); Biological: IgPro10; Biological: IgPro20 (high dose); Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Southport, Australia
    • Site reference 0360008
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Site Reference 0360017
  • Victoria
    • Fitzroy, Victoria, Australia
      • Site Reference 0360011
• Belgium
  • Leuven, Belgium
    • Site reference 0560003
• Canada
  • Edmonton, Canada
    • Site reference 1240006
  • Quebec, Canada
    • Site Reference 1240007
  • Toronto, Canada
    • Site Reference 1240009
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Site Reference 1240048
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Site Reference 1240051
• Czechia
  • Hradec Kralove, Czechia
    • Site Reference 2030002
  • Hradec Kralove, Czechia
    • Site Reference 2030009
  • Prague, Czechia
    • Site reference 2030003
• Estonia
  • Tallinn, Estonia, 10138
    • Site Reference 2330002
  • Tallinn, Estonia, 10617
    • Site Reference 2330003
• Finland
  • Helsinki, Finland
    • Site reference 2460002
• France
  • Clermont-Ferrand, France
    • Site reference 2500024
  • Marseille, France
    • Site reference 2500013
  • Nice, France
    • Site Reference 2500022
  • Pessac, France
    • Site reference 2500019
• Germany
  • Berlin, Germany
    • Site reference 2760048
  • Berlin, Germany
    • Site Reference 2760069
  • Berlin, Germany
    • Site Reference 2760072
  • Bochum, Germany
    • Site Reference 2760049
  • Duesseldorf, Germany
    • Site reference 2760075
  • Essen, Germany, 45122
    • Site Reference 2760094
  • Essen, Germany
    • Site Reference 2760052
  • Göttingen, Germany
    • Site reference 2760036
  • Göttingen, Germany
    • Site reference 2760053
  • Hannover, Germany
    • Site Reference 2760054
  • Ibbenbueren, Germany, 49477
    • Site Reference 2760113
  • Koeln, Germany
    • Site reference 2760080
  • Leipzig, Germany
    • Site Reference 2760055
  • Potsdam, Germany
    • Site Reference 2760047
  • Wuerzburg, Germany
    • Site Reference 2760039
• Israel
  • Haifa, Israel
    • Site reference 3760005
  • Tel Aviv, Israel
    • Site reference 3760002
• Italy
  • Chieti, Italy
    • Site reference 3800026
  • Firenze, Italy
    • Site reference 3800027
  • Genova, Italy
    • Site reference 3800028
  • Milano, Italy
    • Site Reference 3800031
  • Roma, Italy
    • Site reference 3800035
  • Roma, Italy
    • Site reference 3800036
  • Rozzano, Italy
    • Site reference 3800030
  • Torino, Italy
    • Site reference 3800037
• Japan
  • Aomori, Japan, 030-8553
    • Site Reference 3920040
  • Aomori, Japan, 030-8553
    • Site Reference 3920042
  • Chiba, Japan
    • Site Reference 3920038
  • Kanagawa, Japan
    • Site Reference 3920061
  • Matsumoto, Japan
    • Site reference 3920045
  • Osaka, Japan
    • Site reference 3920058
  • Saitama, Japan
    • Site Reference 3920037
  • Tokushima, Japan
    • Site reference 3920034
  • Tokyo, Japan, 113-8431
    • Site Reference 3920065
  • Tokyo, Japan, 187-8551
    • Site Reference 3920062
  • Tokyo, Japan
    • Site reference 3920032
  • Yamaguchi, Japan
    • Site Reference 3920035
• Netherlands
  • Amsterdam, Netherlands
    • Site Reference 5280001
  • Maastricht, Netherlands
    • Site reference 5280005
  • Utrecht, Netherlands
    • Site reference 5280004
• Poland
  • Gdansk, Poland, 80-803
    • Site Reference 6160058
  • Lodz, Poland, 90-324
    • Site Reference 6160060
  • Lublin, Poland, 20-954
    • Site Reference 6160055
• Spain
  • Barcelona, Spain
    • Site Reference 7240010
  • Barcelona, Spain
    • Site Reference 7240011
  • Madrid, Spain
    • Site reference 7240013
  • Madrid, Spain
    • Site reference 7240014
  • Sevilla, Spain
    • Site reference 7240016
• United Kingdom
  • London, United Kingdom
    • Site Reference 8260019
  • Manchester, United Kingdom, M6 8HD
    • Site Reference 8260032
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Site Reference 8400181
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Site reference 8400173
    • Phoenix, Arizona, United States, 85018
      • Site reference 8400172
  • California
    • Los Angeles, California, United States, 90033
      • Site Reference 8400167
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Site reference 8400077
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • Site Reference 8400352
  • Florida
    • Miami, Florida, United States, 33136
      • Site reference 8400214
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Site reference 8400162
    • Chicago, Illinois, United States, 60611
      • Site Reference 8400247
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Site Reference 8400215
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Site Reference 8400166
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Site Reference 8400347
  • New York
    • New York, New York, United States, 10021
      • Site Reference 8400169
    • New York, New York, United States, 10021
      • Site reference 8400179
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Site Reference 8400182
    • Durham, North Carolina, United States, 27710
      • Site Reference 8400346
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Site reference 8400178
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Site reference 8400217
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Site Reference 8400177
  • Texas
    • Houston, Texas, United States, 77030
      • Site reference 8400164
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Site Reference 8400268
  • Washington
    • Seattle, Washington, United States, 98195
      • Site Reference 8400340

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Definite or probable CIDP according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria 2010.
• An IVIG treatment during the last 8 weeks prior to enrollment.
• Age ≥18 years.
• Written informed consent for study participation obtained before undergoing any study-specific procedures.

Exclusion Criteria:

• Any polyneuropathy of other causes
• Any other disease (mainly neurological or chronic orthopedic) that has caused neurological symptoms or may interfere with treatment or outcome assessments
• Severe diseases and conditions that are likely to interfere with evaluation of the study product or satisfactory conduct of the study
• History of thrombotic episodes within the 2 years prior to enrolment
• Known allergic or other severe reactions to blood products including intolerability to previous IVIG

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Biological: IgPro10; 10% Immunoglobulin G (IgG) liquid formulation of human normal immunoglobulin (Privigen®) administered intravenously during Restabilization Period of the study and/or as Rescue Therapy during SC Treatment Period for subjects with a CIDP relapse.; Biological: Placebo; 2% human albumin administered by weekly SC infusions during the SC treatment period of the study.
Experimental: IgPro20 low dose	Biological: IgPro20 (low dose); 20% liquid formulation (200 mg/mL) of human normal immunoglobulin for subcutaneous use administered weekly during the SC treatment period of the study according to the randomization: 0.2 g/kg body weight (low dose arm); Other Names: Hizentra; Biological: IgPro10; 10% Immunoglobulin G (IgG) liquid formulation of human normal immunoglobulin (Privigen®) administered intravenously during Restabilization Period of the study and/or as Rescue Therapy during SC Treatment Period for subjects with a CIDP relapse.
Experimental: IgPro20 high dose	Biological: IgPro10; 10% Immunoglobulin G (IgG) liquid formulation of human normal immunoglobulin (Privigen®) administered intravenously during Restabilization Period of the study and/or as Rescue Therapy during SC Treatment Period for subjects with a CIDP relapse.; Biological: IgPro20 (high dose); 20% liquid formulation (200 mg/mL) of human normal immunoglobulin for subcutaneous use administered weekly during the SC treatment period of the study according to the randomization: 0.4 g/kg body weight (high dose arm); Other Names: Hizentra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage (%) of Subjects With CIDP Relapse or Are Withdrawn for Any Other Reason During the Subcutaneous (SC) Treatment Period	Relapse is defined as an increase of at least 1 INCAT score point (except for the increase from 0 to 1 in the upper limb score). The INCAT score is a 10-point scale that covers the functionality of legs and arms, and has been successfully used to measure treatment effects in various CIDP studies. Scores for arm disability range from 0 ("No upper limb problems") to 5 ("Inability to use either arm for any purposeful movement"), and scores for leg disability range from 0 ("Walking not affected") to 5 ("Restricted to wheelchair, unable to stand and walk a few steps with help"). The INCAT (total) score is the sum of these 2 scores and ranges from 0 to 10. For the "adjusted" INCAT score, changes in the function of the upper limbs from 0 (normal) to 1 (minor symptoms) or from 1 to 0 were not recorded as deterioration or improvement because these changes are not considered clinically significant.	Up to 25 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Inflammatory Neuropathy Cause and Treatment (INCAT) Scores During the SC Treatment Period	The INCAT score is a 10-point scale that covers the functionality of legs and arms, and has been successfully used to measure treatment effects in various CIDP studies. Scores for arm disability range from 0 ("No upper limb problems") to 5 ("Inability to use either arm for any purposeful movement"), and scores for leg disability range from 0 ("Walking not affected") to 5 ("Restricted to wheelchair, unable to stand and walk a few steps with help"). The INCAT (total) score is the sum of these 2 scores and ranges from 0 to 10. For the "adjusted" INCAT score, changes in the function of the upper limbs from 0 (normal) to 1 (minor symptoms) or from 1 to 0 were not recorded as deterioration or improvement because these changes are not considered clinically significant.	Baseline and up to 25 weeks
Median Change From Baseline in the Mean Grip Strength Scores of the Dominant Hand During the SC Treatment Period	The hand-held Vigorimeter is a device that measures the strength of small muscles in the hand; ie, grip strength. Subjects squeezed a rubber bulb lying between the palm of the hand and the thumb and index fingers. The pressure was recorded via a rubber tube on a nanometer and expressed in kilopascal. At each assessment, the subjects squeezed 3 times with each hand. The mean grip strength median score of the dominant hand was determined.	Baseline and up to 25 weeks
Change in the Medical Research Council (MRC) Sum Scores During the SC Treatment Period	An adapted version of the MRC sum score was used in the study. The MRC sum score is the sum of all 16 muscle scores, and ranges from 0 (paralysis) to 80 (normal strength).	Baseline and up to 25 weeks
Change in Rasch-built Overall Disability Scale (R-ODS) Scores During the SC Treatment Period	The R-ODS centile score captures activity and social participation in subjects with CIDP. The R-ODS centile score ranges from 0 (most severe activity and social participation limitations) to 100 (no activity and social participation limitations).	Baseline and up to 25 weeks
Time to CIDP Relapse or Withdrawal Due to Any Other Reason During the SC Treatment Period		Up to 25 weeks
Number of Adverse Events Per IgPro20 Infusion During the SC Treatment Period		Up to 28 weeks
Number of Subjects With Adverse Events During the SC Treatment Period		Up to 28 weeks
Percentage of Subjects With Adverse Events During the SC Treatment Period		Up to 28 weeks
Time to Improvement During IgPro10 Re-stabilization Therapy	Improvement is defined as an INCAT score decrease by 1 point (except for the decrease from 1 to 0 in the upper limb score), R-ODS improvement by at least 4 points, Mean Grip strength improvement by at least 8 kPa in one hand, or MRC Sum score >=3.	Up to 13 weeks
Change in Mean Grip Strength During IgPro10 Re-stabilization Therapy	The hand-held Vigorimeter is a device that measures the strength of small muscles in the hand; ie, grip strength. Subjects squeezed a rubber bulb lying between the palm of the hand and the thumb and index fingers. The pressure was recorded via a rubber tube on a nanometer and expressed in kilopascal. At each assessment, the subjects squeezed 3 times with each hand. The mean grip strength median score of the dominant hand was determined.	Reference visit and up to 13 weeks
Change in MRC Sum Score During IgPro10 Re-stabilization Therapy	An adapted version of the MRC sum score was used in the study. The MRC sum score is the sum of all 16 muscle scores, and ranges from 0 (paralysis) to 80 (normal strength).	Reference visit and up to 13 weeks
Change in R-ODS During IgPro10 Re-stabilization Therapy	The R-ODS centile score captures activity and social participation in subjects with CIDP. The R-ODS centile score ranges from 0 (most severe activity and social participation limitations) to 100 (no activity and social participation limitations).	Reference visit and up to 13 weeks
Change in INCAT During IgPro10 Re-stabilization Therapy	The INCAT score is a 10-point scale that covers the functionality of legs and arms, and has been successfully used to measure treatment effects in various CIDP studies. Scores for arm disability range from 0 ("No upper limb problems") to 5 ("Inability to use either arm for any purposeful movement"), and scores for leg disability range from 0 ("Walking not affected") to 5 ("Restricted to wheelchair, unable to stand and walk a few steps with help"). The INCAT (total) score is the sum of these 2 scores and ranges from 0 to 10. For the "adjusted" INCAT score, changes in the function of the upper limbs from 0 (normal) to 1 (minor symptoms) or from 1 to 0 were not recorded as deterioration or improvement because these changes are not considered clinically significant.	Reference visit and up to 13 weeks
Number of Adverse Events Per IgPro10 Infusion During Re-stabilization Therapy		Up to 13 weeks
Number of Subjects With Adverse Events During IgPro10 Re-stabilization Therapy		Up to 13 weeks
Percent of Subjects With Adverse Events During IgPro10 Re-stabilization Therapy		Up to 13 weeks
Time to Improvement After CIDP Relapse During IgPro10 Rescue Therapy	Improvement is defined as a decrease in INCAT score (except for the decrease from 1 to 0 in the upper limb score) back to or below the baseline score..The INCAT score is a 10-point scale that covers the functionality of legs and arms, and has been successfully used to measure treatment effects in various CIDP studies. Scores for arm disability range from 0 ("No upper limb problems") to 5 ("Inability to use either arm for any purposeful movement"), and scores for leg disability range from 0 ("Walking not affected") to 5 ("Restricted to wheelchair, unable to stand and walk a few steps with help"). The INCAT (total) score is the sum of these 2 scores and ranges from 0 to 10. For the "adjusted" INCAT score, changes in the function of the upper limbs from 0 (normal) to 1 (minor symptoms) or from 1 to 0 were not recorded as deterioration or improvement because these changes are not considered clinically significant.	Up to 13 weeks
Number of Adverse Events Per IgPro10 Infusion During Rescue Therapy		Up to 13 weeks
Number of Subjects With Adverse Events During IgPro10 Rescue Therapy		Up to 13 weeks
Percent of Subjects With Adverse Events During IgPro10 Rescue Therapy		Up to 13 weeks
Change in Mean Grip Strength During IgPro10 Rescue Therapy	The hand-held Vigorimeter is a device that measures the strength of small muscles in the hand; ie, grip strength. Subjects squeezed a rubber bulb lying between the palm of the hand and the thumb and index fingers. The pressure was recorded via a rubber tube on a nanometer and expressed in kilopascal. At each assessment, the subjects squeezed 3 times with each hand. The mean grip strength median score of the dominant hand was determined.	Before first rescue IgPro10 infusion and up to 13 weeks
Change in MRC Sum Score During IgPro10 Rescue Therapy	An adapted version of the MRC sum score was used in the study. The MRC sum score is the sum of all 16 muscle scores, and ranges from 0 (paralysis) to 80 (normal strength).	Before first rescue IgPro10 infusion and up to 13 weeks
Change in R-ODS During IgPro10 Rescue Therapy	The R-ODS centile score captures activity and social participation in subjects with CIDP. The R-ODS centile score ranges from 0 (most severe activity and social participation limitations) to 100 (no activity and social participation limitations).	Before first rescue IgPro10 infusion and up to 13 weeks
Change in INCAT During IgPro10 Rescue Therapy	The INCAT score is a 10-point scale that covers the functionality of legs and arms, and has been successfully used to measure treatment effects in various CIDP studies. Scores for arm disability range from 0 ("No upper limb problems") to 5 ("Inability to use either arm for any purposeful movement"), and scores for leg disability range from 0 ("Walking not affected") to 5 ("Restricted to wheelchair, unable to stand and walk a few steps with help"). The INCAT (total) score is the sum of these 2 scores and ranges from 0 to 10. For the "adjusted" INCAT score, changes in the function of the upper limbs from 0 (normal) to 1 (minor symptoms) or from 1 to 0 were not recorded as deterioration or improvement because these changes are not considered clinically significant.	Before first rescue IgPro10 infusion and up to 13 weeks

Collaborators and Investigators

• Sponsor: CSL Behring
• Collaborators: ICON Clinical Research
• Investigators: Principal Investigator: Prof. Dr. Ivo N. van Schaik, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• van Schaik IN, Bril V, van Geloven N, Hartung HP, Lewis RA, Sobue G, Lawo JP, Praus M, Mielke O, Durn BL, Cornblath DR, Merkies ISJ; PATH study group. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2018 Jan;17(1):35-46. doi: 10.1016/S1474-4422(17)30378-2. Epub 2017 Nov 6. Erratum In: Lancet Neurol. 2018 Jan;17 (1):26. Lancet Neurol. 2018 Aug;17(8):661.
• van Schaik IN, van Geloven N, Bril V, Hartung HP, Lewis RA, Sobue G, Lawo JP, Mielke O, Cornblath DR, Merkies IS; PATH study group. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (The PATH Study): study protocol for a randomized controlled trial. Trials. 2016 Jul 25;17(1):345. doi: 10.1186/s13063-016-1466-2.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: March 1, 2012
• First Submitted That Met QC Criteria: March 5, 2012
• First Posted (Estimate): March 6, 2012

Study Record Updates

• Last Update Posted (Actual): July 5, 2018
• Last Update Submitted That Met QC Criteria: July 3, 2018
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Polyneuropathies; Polyradiculoneuropathy; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Physiological Effects of Drugs; Immunologic Factors; Immunoglobulin G
• Other Study ID Numbers: IgPro20_3003