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Efficacy and Safety of IGIV-C in Corticosteroid Dependent Patients With Generalized Myasthenia Gravis

Primary Purpose

Myasthenia Gravis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
IGIV-C
Placebo
Sponsored by
Grifols Therapeutics LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myasthenia Gravis

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Anti-acetylcholine receptor antibody positive
  • Confirmed diagnosis of generalized MG historically meeting the clinical criteria for diagnosis of MG defined by the Myasthenia Gravis Foundation of America (MGFA) classification of Class II, III, IV, or V historically
  • At Screening, subjects may have symptoms controlled by CS or were MGFA Class II-IVa inclusive (Class IVb and Class V excluded). Subjects who only have a history of ocular MG may not enroll.
  • On systemic CS for a minimum period of at least 3 months and on a stable CS dose of >=15 mg/day and <=60 mg/day (prednisone equivalent) for the month prior to Screening.
  • Had a tapering CS dose that the study investigator considered to be appropriate.
  • At least 1 previous completed attempt to taper CS in order to minimize CS dose (lowest feasible dose based on observed MG signs and symptoms)

Exclusion Criteria:

  • Any dose change in concomitant immunosuppressant therapy, other than CS, in the prior 6 months
  • Any change in CS dose or acetylcholinesterase inhibitor (e.g., pyridostigmine) dose in the 1 month prior to Screening
  • A 3-point change in Quantitative Myasthenia Gravis score, increased or decreased, between the Screening/Week -3 (Visit 0) and Baseline (Week 0 [Visit 1])
  • Any episode of myasthenic crisis (MC) in the 1 month prior to Screening, or (at any time in the past) MC or hospitalization for MG exacerbation associated with a previous CS taper attempt
  • Evidence of malignancy within the past 5 years (non-melanoma skin cancer, carcinoma in situ of cervix is allowed) or thymoma potentially requiring surgical intervention during the course of the trial (intent to perform thymectomy)
  • Thymectomy within the preceding 6 months prior to Screening
  • Rituximab, belimumab, eculizumab or any monoclonal antibody used for immunomodulation within the past 12 months prior to Screening
  • Have received immune globulin treatment given by IV, subcutaneous, or intramuscular route within the last 3 months prior to Screening
  • Received plasma exchange performed within the last 3 months prior to Screening
  • History of anaphylactic reactions or severe reactions to any blood-derived product
  • History of recent (within the last year) myocardial infarction or stroke
  • Uncontrolled congestive heart failure; embolism; or historically documented (within the last year) electrocardiogram changes indicative of myocardial ischemia or atrial fibrillation
  • Current known hyperviscosity or hypercoagulable state
  • Currently receiving anti-coagulation therapy. Oral anti-platelet agents are allowed (e.g., aspirin, clopidogrel, ticlopidine)
  • Females of child-bearing potential who are pregnant, have a positive serum pregnancy test, breastfeeding, or are unwilling to practice a highly effective method of contraception throughout the study.
  • Renal impairment
  • Aspartate aminotransferase or alanine aminotransferase levels exceeding more than 2.5 times the upper limit of normal for the expected normal range for the testing laboratory.
  • Hemoglobin (Hb) levels <9 g/dL

Sites / Locations

  • University of California-Irvine
  • Yale University School of Medicine, Department of Neurology
  • University of Florida at Shands Jacksonville
  • University of South Florida
  • Georgia Regents University
  • Indiana University
  • University of Kansas Medical Center Research Institute, Inc.
  • Rutgers New Jersey Medical School
  • Columbia University Medical Center
  • Ohio State University Wexner Medical Center, Neurology Department
  • Thomas Jefferson University Hospital
  • Houston Methodist Neurological Institute
  • University of Vermont Medical Center
  • University of Washington Medical Center
  • UZ Leuven
  • London Health Sciences Centre- University Hospital
  • University Health Network (UHN) - Toronto General Hospital
  • Fakultni nemocnice Brno, Dept of Neurologicka klinika
  • Fakultni nemocnice Ostrava
  • Vseobecna fakultni nemocnice v Praze, Dept of Neurologicka klinika
  • East Tallinn Central Hospital
  • CHU Strasbourg - Nouvel Hôpital Civil, Clinique Neurologique
  • CHU de Toulouse - Hôpital Purpan, Service de Neurologie Générale
  • Universitaetsklinikum Regensburg, Parent
  • Universitaetsklinikum Giessen und Marburg GmbH Standort Marburg
  • Universitaetsmedizin Goettingen, Parent
  • Krankenhaus Martha-Maria Halle-Doelau, Klinik fuer Neurologie
  • Fachkrankenhaus Hubertusburg gGmbH, Klinik f. Neurologie
  • Universitaetsklinikum Jena, Klinik fuer Neurologie
  • Charité Universitaetsmedizin Berlin, Klinik für Neurologie
  • Universitaetsklinikum Hamburg-Eppendorf, Klinik und Poliklinik
  • Jahn Ferenc Del-pesti Korhaz es Rendelointezet, Neurologiai Osztaly
  • Pest Megyei Flor Ferenc Korhaz, Neurologia es Stroke Osztaly
  • Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
  • Hospital of Lithuanian University of Health Sciences Kaunas Clinics
  • Uniwersyteckie Centrum Kliniczne, Dept of Neurology
  • Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej
  • III Szpital Miejski w Lodzi im. Dr K. Jonschera
  • Samodzielny Publiczny Centralny Szpital Kliniczny

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

IGIV-C

Placebo

Arm Description

An IGIV-C loading dose of 2 g/kg and maintenance dose of 1 g/kg will be administered in CS dependent subjects with MG.

0.9% sodium chloride injection, USP or equivalent

Outcomes

Primary Outcome Measures

Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39
The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. Subjects who discontinued the study early with adverse outcomes related to MG were considered as not achieving a 50% or greater reduction. The missing dose reduction at Week 39 was imputed using the worst observation carried forward (WOCF) method. For subjects who did not have CS dose prescribed at Week 39 due to other reasons, the last observation carried forward (LOCF) method was used to impute the prescribed CS dose at Week 39. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The percent of subjects achieving ≥50% reduction in CS dose from baseline to Week 39 is presented for each treatment group overall and for the baseline daily prednisone equivalent dose level stratification categories.

Secondary Outcome Measures

Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39
The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. For subjects who discontinued the study early with adverse outcomes related to MG, the missing dose reduction at Week 39 was imputed using the WOCF method. For subjects who had missing CS dose reduction at Week 39 due to other reasons, the missing CS dose was imputed using the LOCF method. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The least squares (LS) mean percent change from baseline in daily CS dose to Week 39 is presented for each treatment group.
Median Time to First Episode of MG Worsening
The time to the first episode of MG worsening was defined as the time between baseline and the first instance of QMG total score increase by ≥4 points relative to Baseline/Week 0. The QMG total score is the sum of all 13 items and ranges from 0 to 39. Higher values represent greater severity of illness. If one or more items were missing at a given assessment, the total score was set to missing. The median time to MG worsening was calculated based on Kaplan-Meier methodology. Baseline was defined as the last non-missing measurement taken prior to the first dose of study medication.

Full Information

First Posted
June 14, 2015
Last Updated
March 13, 2020
Sponsor
Grifols Therapeutics LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02473965
Brief Title
Efficacy and Safety of IGIV-C in Corticosteroid Dependent Patients With Generalized Myasthenia Gravis
Official Title
A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of lGIV-C as a Corticosteroid Sparing Agent in Corticosteroid Dependent Patients With Generalized Myasthenia Gravis
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
June 2015 (undefined)
Primary Completion Date
February 2019 (Actual)
Study Completion Date
February 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grifols Therapeutics LLC

4. Oversight

5. Study Description

Brief Summary
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) as a corticosteroid (CS)-sparing agent in subjects with CS-dependent Myasthenia Gravis (MG).
Detailed Description
This study consists of 2 phases: IGIV-C Run-in Phase and Corticosteroid Tapering/IGIV-C Maintenance Phase. In the Run-in Phase, subjects will receive a total of 3 doses of IGIV-C (1 loading dose of 2 g/kg and 2 maintenance doses of 1 g/kg) while maintaining a stable dose of corticosteroids. In the CS Tapering/IGIV-C Maintenance Phase, subjects will continue 1 g/kg IGIV-C and begin a prescribed CS tapering regimen where the CS dose is decreased every 3 weeks. Approximately 60 subjects are planned to be enrolled in the study across multiple centers in North America and Europe. The total duration of study participation for each subject is up to 45 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myasthenia Gravis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IGIV-C
Arm Type
Experimental
Arm Description
An IGIV-C loading dose of 2 g/kg and maintenance dose of 1 g/kg will be administered in CS dependent subjects with MG.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
0.9% sodium chloride injection, USP or equivalent
Intervention Type
Drug
Intervention Name(s)
IGIV-C
Intervention Description
Run-Phase: 1 loading dose of 2 g/kg IGIV-C and 2 maintenance doses of 1 g/kg IGIV-C Corticosteroid Tapering/IGIV-C Maintenance Phase: 1 g/kg IGIV-C every 3 weeks for up to 36 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39
Description
The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. Subjects who discontinued the study early with adverse outcomes related to MG were considered as not achieving a 50% or greater reduction. The missing dose reduction at Week 39 was imputed using the worst observation carried forward (WOCF) method. For subjects who did not have CS dose prescribed at Week 39 due to other reasons, the last observation carried forward (LOCF) method was used to impute the prescribed CS dose at Week 39. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The percent of subjects achieving ≥50% reduction in CS dose from baseline to Week 39 is presented for each treatment group overall and for the baseline daily prednisone equivalent dose level stratification categories.
Time Frame
Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).
Secondary Outcome Measure Information:
Title
Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39
Description
The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. For subjects who discontinued the study early with adverse outcomes related to MG, the missing dose reduction at Week 39 was imputed using the WOCF method. For subjects who had missing CS dose reduction at Week 39 due to other reasons, the missing CS dose was imputed using the LOCF method. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The least squares (LS) mean percent change from baseline in daily CS dose to Week 39 is presented for each treatment group.
Time Frame
Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).
Title
Median Time to First Episode of MG Worsening
Description
The time to the first episode of MG worsening was defined as the time between baseline and the first instance of QMG total score increase by ≥4 points relative to Baseline/Week 0. The QMG total score is the sum of all 13 items and ranges from 0 to 39. Higher values represent greater severity of illness. If one or more items were missing at a given assessment, the total score was set to missing. The median time to MG worsening was calculated based on Kaplan-Meier methodology. Baseline was defined as the last non-missing measurement taken prior to the first dose of study medication.
Time Frame
From Baseline/Week 0 (Visit 1) to Week 39 (Visit 14).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Anti-acetylcholine receptor antibody positive Confirmed diagnosis of generalized MG historically meeting the clinical criteria for diagnosis of MG defined by the Myasthenia Gravis Foundation of America (MGFA) classification of Class II, III, IV, or V historically At Screening, subjects may have symptoms controlled by CS or were MGFA Class II-IVa inclusive (Class IVb and Class V excluded). Subjects who only have a history of ocular MG may not enroll. On systemic CS for a minimum period of at least 3 months and on a stable CS dose of >=15 mg/day and <=60 mg/day (prednisone equivalent) for the month prior to Screening. Had a tapering CS dose that the study investigator considered to be appropriate. At least 1 previous completed attempt to taper CS in order to minimize CS dose (lowest feasible dose based on observed MG signs and symptoms) Exclusion Criteria: Any dose change in concomitant immunosuppressant therapy, other than CS, in the prior 6 months Any change in CS dose or acetylcholinesterase inhibitor (e.g., pyridostigmine) dose in the 1 month prior to Screening A 3-point change in Quantitative Myasthenia Gravis score, increased or decreased, between the Screening/Week -3 (Visit 0) and Baseline (Week 0 [Visit 1]) Any episode of myasthenic crisis (MC) in the 1 month prior to Screening, or (at any time in the past) MC or hospitalization for MG exacerbation associated with a previous CS taper attempt Evidence of malignancy within the past 5 years (non-melanoma skin cancer, carcinoma in situ of cervix is allowed) or thymoma potentially requiring surgical intervention during the course of the trial (intent to perform thymectomy) Thymectomy within the preceding 6 months prior to Screening Rituximab, belimumab, eculizumab or any monoclonal antibody used for immunomodulation within the past 12 months prior to Screening Have received immune globulin treatment given by IV, subcutaneous, or intramuscular route within the last 3 months prior to Screening Received plasma exchange performed within the last 3 months prior to Screening History of anaphylactic reactions or severe reactions to any blood-derived product History of recent (within the last year) myocardial infarction or stroke Uncontrolled congestive heart failure; embolism; or historically documented (within the last year) electrocardiogram changes indicative of myocardial ischemia or atrial fibrillation Current known hyperviscosity or hypercoagulable state Currently receiving anti-coagulation therapy. Oral anti-platelet agents are allowed (e.g., aspirin, clopidogrel, ticlopidine) Females of child-bearing potential who are pregnant, have a positive serum pregnancy test, breastfeeding, or are unwilling to practice a highly effective method of contraception throughout the study. Renal impairment Aspartate aminotransferase or alanine aminotransferase levels exceeding more than 2.5 times the upper limit of normal for the expected normal range for the testing laboratory. Hemoglobin (Hb) levels <9 g/dL
Facility Information:
Facility Name
University of California-Irvine
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Yale University School of Medicine, Department of Neurology
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
University of Florida at Shands Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
University of South Florida
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Georgia Regents University
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Kansas Medical Center Research Institute, Inc.
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Rutgers New Jersey Medical School
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07103
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Ohio State University Wexner Medical Center, Neurology Department
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43220
Country
United States
Facility Name
Thomas Jefferson University Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Houston Methodist Neurological Institute
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Vermont Medical Center
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05405
Country
United States
Facility Name
University of Washington Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
UZ Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
London Health Sciences Centre- University Hospital
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5A5
Country
Canada
Facility Name
University Health Network (UHN) - Toronto General Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2C4
Country
Canada
Facility Name
Fakultni nemocnice Brno, Dept of Neurologicka klinika
City
Brno
ZIP/Postal Code
625 00
Country
Czechia
Facility Name
Fakultni nemocnice Ostrava
City
Ostrava - Poruba
ZIP/Postal Code
708 52
Country
Czechia
Facility Name
Vseobecna fakultni nemocnice v Praze, Dept of Neurologicka klinika
City
Praha 2
ZIP/Postal Code
128 21
Country
Czechia
Facility Name
East Tallinn Central Hospital
City
Tallinn
ZIP/Postal Code
10138
Country
Estonia
Facility Name
CHU Strasbourg - Nouvel Hôpital Civil, Clinique Neurologique
City
Strasbourg cedex
State/Province
Bas Rhin
ZIP/Postal Code
67091
Country
France
Facility Name
CHU de Toulouse - Hôpital Purpan, Service de Neurologie Générale
City
Toulouse cedex 9
State/Province
Haute Garonne
ZIP/Postal Code
31059
Country
France
Facility Name
Universitaetsklinikum Regensburg, Parent
City
Regensburg
State/Province
Bayern
ZIP/Postal Code
93053
Country
Germany
Facility Name
Universitaetsklinikum Giessen und Marburg GmbH Standort Marburg
City
Marburg
State/Province
Hessen
ZIP/Postal Code
35043
Country
Germany
Facility Name
Universitaetsmedizin Goettingen, Parent
City
Göttingen
State/Province
Niedersachsen
ZIP/Postal Code
37075
Country
Germany
Facility Name
Krankenhaus Martha-Maria Halle-Doelau, Klinik fuer Neurologie
City
Halle
State/Province
Sachsen Anhalt
ZIP/Postal Code
6120
Country
Germany
Facility Name
Fachkrankenhaus Hubertusburg gGmbH, Klinik f. Neurologie
City
Wermsdorf
State/Province
Sachsen
ZIP/Postal Code
4779
Country
Germany
Facility Name
Universitaetsklinikum Jena, Klinik fuer Neurologie
City
Jena
State/Province
Thueringen
ZIP/Postal Code
7747
Country
Germany
Facility Name
Charité Universitaetsmedizin Berlin, Klinik für Neurologie
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
Universitaetsklinikum Hamburg-Eppendorf, Klinik und Poliklinik
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Jahn Ferenc Del-pesti Korhaz es Rendelointezet, Neurologiai Osztaly
City
Budapest
ZIP/Postal Code
1204
Country
Hungary
Facility Name
Pest Megyei Flor Ferenc Korhaz, Neurologia es Stroke Osztaly
City
Kistarcsa
ZIP/Postal Code
2143
Country
Hungary
Facility Name
Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
City
Szeged
ZIP/Postal Code
6725
Country
Hungary
Facility Name
Hospital of Lithuanian University of Health Sciences Kaunas Clinics
City
Kaunas
ZIP/Postal Code
50161
Country
Lithuania
Facility Name
Uniwersyteckie Centrum Kliniczne, Dept of Neurology
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej
City
Krakow
ZIP/Postal Code
31-505
Country
Poland
Facility Name
III Szpital Miejski w Lodzi im. Dr K. Jonschera
City
Lodz
ZIP/Postal Code
93-113
Country
Poland
Facility Name
Samodzielny Publiczny Centralny Szpital Kliniczny
City
Warszawa
ZIP/Postal Code
02-097
Country
Poland

12. IPD Sharing Statement

Citations:
PubMed Identifier
36270895
Citation
Bril V, Szczudlik A, Vaitkus A, Rozsa C, Kostera-Pruszczyk A, Hon P, Bednarik J, Tyblova M, Kohler W, Toomsoo T, Nowak RJ, Mozaffar T, Freimer ML, Nicolle MW, Magnus T, Pulley MT, Rivner M, Dimachkie MM, Distad BJ, Pascuzzi RM, Babiar D, Lin J, Querolt Coll M, Griffin R, Mondou E. Randomized Double-Blind Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis. Neurology. 2023 Feb 14;100(7):e671-e682. doi: 10.1212/WNL.0000000000201501. Epub 2022 Oct 21. Erratum In: Neurology. 2023 Sep 12;101(11):501.
Results Reference
derived
PubMed Identifier
35350948
Citation
Dalakas MC, Meisel A. Immunomodulatory effects and clinical benefits of intravenous immunoglobulin in myasthenia gravis. Expert Rev Neurother. 2022 Apr;22(4):313-318. doi: 10.1080/14737175.2022.2057223. Epub 2022 Apr 5.
Results Reference
derived

Learn more about this trial

Efficacy and Safety of IGIV-C in Corticosteroid Dependent Patients With Generalized Myasthenia Gravis

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