A Study to Evaluate the Efficacy and Safety of IGIV-C in Symptomatic Subjects With Generalized Myasthenia Gravis

• Sponsor: Grifols Therapeutics LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02473952
• Collaborator: (none)
• Enrollment: 62
• Locations: 40
• Arms: 2
• Actual Duration (Months): 29
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective is to evaluate whether IGIV-C improves MG symptoms as compared to placebo in subjects with MG.

Condition or Disease	Intervention/Treatment	Phase
Myasthenia Gravis, Generalized	Drug: IGIV-C; Drug: Placebo	Phase 2

Detailed Description

The primary objective is to evaluate the efficacy of IGIV-C in subjects with generalized myasthenia gravis (MG) on standard of care treatment at study entry in terms of improvement in MG symptoms as measured by the mean change in Quantitative Myasthenia Gravis (QMG) score from Baseline (Week 0) to Week 24 as compared to placebo.

The safety objective of this study is to evaluate the safety and tolerability of IGIV-C loading dose of 2 g/kg followed by 7 maintenance dosages of 1 g/kg every 3 weeks through Week 21 in subjects with MG.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) in Symptomatic Subjects With Generalized Myasthenia Gravis
• Actual Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Jan 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IGIV-C IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified. An initial loading dose of 2 g/kg of body weight will be administered at Baseline (Week 0, Visit 1) followed by maintenance doses of 1 g/kg of body weight administered every third week through Week 21 (Visit 8).	Drug: IGIV-C; IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified
Placebo Comparator: Placebo Placebo: Sterile 0.9% sodium chloride injection or equivalent. Placebo will be infused at the Baseline/Week 0 Visit (Visit 1) using the same volume as would be required for the IGIV-C loading dose. Subsequent placebo maintenance doses will be matched in volume to the IGIV-C maintenance doses and administered every third week until Week 21 (Visit 8).	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Improvement in Myasthenia Gravis (MG) Symptoms as Measured by the Mean Change in Quantitative Myasthenia Gravis (QMG) Total Score. [Baseline (Week 0) to Week 24]

   To measure improvement in MG symptoms by the mean change in QMG total score from Baseline (Week 0) to Week 24 as compared to placebo. Evaluators score 13 individual items (range from 0=best to 3=worst) and the individual scores are added together for the total score (range 0-39). An average 3-point improvement in QMG score indicates clinically meaningful improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Anti-acetylcholine receptor (AChR) antibody positive

• Confirmed diagnosis of generalized myasthenia gravis (MG).

• Myasthenia Gravis Foundation of America (MGFA) classification of Class II, III, or IVa inclusive at Screening.

• QMG >= 10 at Screening. Note: Subjects who only have a history of ocular MG may not enroll.

• Receiving standard of care MG treatment at a stable dose consisting of any one of the following for the time intervals delineated below (time intervals apply to medications and maintenance of stable dose level):

1. Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to Screening and no immunosuppressants

2. Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to Screening AND/OR only one of the following:

3. Prednisone (up to 60 mg/day or equivalent) for at least 2 months prior to Screening, OR

4. Azathioprine for at least 6 months prior to Screening, OR

5. Mycophenolate mofetil for at least 6 months prior to Screening, OR

6. Methotrexate for at least 6 months prior to Screening, OR

7. Cyclosporine or tacrolimus for at least 3 months prior to Screening

8. Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to Screening AND/OR prednisone (up to 60 mg/day or equivalent) for at least one month prior to Screening and only one of the following:

9. Azathioprine for at least 6 months prior to Screening, OR

10. Mycophenolate mofetil for at least 6 months prior to Screening, OR

11. Methotrexate for at least 6 months prior to Screening, OR

12. Cyclosporine or tacrolimus for at least 3 months prior to Screening

Exclusion Criteria:

• Have received cyclophosphamide or any other immunosuppressive agent apart from the ones allowed per inclusion criteria within the past 6 months

• Any change in MG treatment regimen between Screening (Week -3, Visit 0) and Baseline (Week 0, Visit 1)

• Greater than two point change in QMG score, increased or decreased, between Screening (Week -3, Visit 0) and Baseline (Week 0, Visit 1)

• Any episode of myasthenic crisis in the one month prior to Screening

• 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

• Rituximab, belimumab, eculizumab or any monoclonal antibody used for immunomodulation within the past 12 months

• Have received immune globulin (Ig) treatment given by intravenous (IV), subcutaneous, or intramuscular route within the last 3 months

• Current known hyperviscosity or hypercoagulable state

• Currently receiving anti-coagulation therapy (vitamin K antagonists, nonvitamin K antagonist oral anticoagulants [e.g., dabigatran etexilate, rivaroxaban, edoxaban, and apixaban], parenteral anticoagulants [e.g., fondaparinux]). Note that oral anti-platelet agents are allowed (e.g., aspirin, clopidogrel, ticlodipine)

• Documented diagnosis of thrombotic complications to polyclonal intravenous immunoglobulin (IVIg) therapy in the past

• History of recent (within the last year) myocardial infarction or stroke

• Uncontrolled congestive heart failure; embolism; or historically documented (within the last year) electrocardiogram (ECG) changes indicative of myocardial ischemia or atrial fibrillation

• History of chronic alcoholism or illicit drug abuse (addiction) in the 12 months preceding the Screening/Week -3 (Visit 0)

• Plasma exchange (PLEX) performed within the last 3 months

• Renal impairment (i.e., serum creatinine exceeds more than 1.5 times the upper limit of normal [ULN] for the expected normal range for the testing laboratory).

• Hemoglobin levels less than 9 g per dL

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Neurological Associates, Ltd.	Phoenix	Arizona	United States	85018
2	University of California-Irvine	Orange	California	United States	92868
3	Yale University School of Medicine	New Haven	Connecticut	United States	06510
4	University of Florida Health Science Center	Jacksonville	Florida	United States	32209
5	University of South Florida	Tampa	Florida	United States	33612
6	Georgia Regents University	Augusta	Georgia	United States	30912
7	Indiana University	Indianapolis	Indiana	United States	46202
8	University of Kansas Medical Center Research Institute, Inc.	Kansas City	Kansas	United States	66160
9	Rutgers New Jersey Medical School	Newark	New Jersey	United States	07103
10	Columbia University Medical Center	New York	New York	United States	10032
11	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43220
12	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
13	Houston Methodist Neurological Institute	Houston	Texas	United States	77030
14	University of Vermont Medical Center	Burlington	Vermont	United States	05405
15	University of Washington Medical Center	Seattle	Washington	United States	98195
16	UZ Leuven	Leuven		Belgium	3000
17	London Health Sciences Centre - University Hospital	London	Ontario	Canada	N6A 5A5
18	University Health Network (UHN) - Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
19	Fakultni nemocnice Brno, Dept of Neurologicka klinika	Brno		Czechia	625 00
20	Fakultni nemocnice Ostrava	Ostrava - Poruba		Czechia	708 52
21	East Tallinn Central Hospital	Tallinn		Estonia	10138
22	CHU Nice - Hôpital de l'Archet 1, Ctre de Réf Maladies Neuromusculaires et SLA	Nice cedex 3	Alpes Maritimes	France	6202
23	CHU Strasbourg - Nouvel Hôpital Civil, Clinique Neurologique	Strasbourg cedex	Bas Rhin	France	67091
24	CHU de Toulouse - Hôpital Purpan, Service de Neurologie Générale	Toulouse cedex 9	Haute Garonne	France	31059
25	Hopital Neurologique Pierre Wertheimer, Neuro-musculaire - Electromyographie	Bron cedex	Rhone	France	69677
26	Universitaetsklinikum Regensburg, Parent	Regensburg	Bayern	Germany	93053
27	Universitaetsmedizin Göttingen, Parent	Göttingen	Niedersachsen	Germany	37075
28	Universitaetsklinikum Koeln, Neurologie und Psychiatrie	Koeln	Nordrhein Westfalen	Germany	50937
29	Krankenhaus Martha-Maria Halle-Doelau, Klinik fuer Neurologie	Halle	Sachsen Anhalt	Germany	6120
30	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden	Sachsen	Germany	1307
31	Universitaetsklinikum Jena, Klinik fuer Neurologie	Jena	Thueringen	Germany	7747
32	Universitaetsklinikum Hamburg-Eppendorf, Klinik und Poliklinik fuer Neurologie	Hamburg		Germany	20246
33	Jahn Ferenc Del-pesti Korhaz es Rendelointezet, Neurologiai Osztaly	Budapest		Hungary	1204
34	Pest Megyei Flor Ferenc Korhaz, Neurologia es Stroke Osztaly	Kistarcsa		Hungary	2143
35	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged		Hungary	6725
36	Hospital of Lithuanian University of Health Sciences Kaunas Clinics	Kaunas		Lithuania	50009
37	Uniwersyteckie Centrum Kliniczne, Dept of Neurology	Gdansk		Poland	80-952
38	Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej	Krakow		Poland	31-505
39	III Szpital Miejski w Lodzi im. Dr K. Jonschera	Lodz		Poland	93-113
40	Samodzielny Publiczny Centralny Szpital Kliniczny, Dept of Neurology	Warszawa		Poland	02-097

Sponsors and Collaborators

• Grifols Therapeutics LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 15, 2015
• Statistical Analysis Plan - Aug 4, 2017

More Information

Publications

None provided.

• Responsible Party: Grifols Therapeutics LLC
• ClinicalTrials.gov Identifier: NCT02473952
• Other Study ID Numbers: GTI1408
• First Posted: Jun 17, 2015
• Last Update Posted: Mar 5, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Myasthenia Gravis; Muscle Weakness

Study Results

Participant Flow

Arm/Group Title	IGIV-C	Placebo
Arm/Group Description	IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified. An initial loading dose of 2 g/kg of body weight will be administered at Baseline (Week 0, Visit 1) followed by maintenance doses of 1 g/kg of body weight administered every third week through Week 21 (Visit 8). IGIV-C: IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified	Placebo: Sterile 0.9% sodium chloride injection or equivalent. Placebo will be infused at the Baseline/Week 0 Visit (Visit 1) using the same volume as would be required for the IGIV-C loading dose. Subsequent placebo maintenance doses will be matched in volume to the IGIV-C maintenance doses and administered every third week until Week 21 (Visit 8). Placebo
Period Title: Overall Study
STARTED	30	32
COMPLETED	28	24
NOT COMPLETED	2	8

Baseline Characteristics

Arm/Group Title	IGIV-C	Placebo	Total
Arm/Group Description	IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified. An initial loading dose of 2 g/kg of body weight will be administered at Baseline (Week 0, Visit 1) followed by maintenance doses of 1 g/kg of body weight administered every third week through Week 21 (Visit 8). IGIV-C: IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified	Placebo: Sterile 0.9% sodium chloride injection or equivalent. Placebo will be infused at the Baseline/Week 0 Visit (Visit 1) using the same volume as would be required for the IGIV-C loading dose. Subsequent placebo maintenance doses will be matched in volume to the IGIV-C maintenance doses and administered every third week until Week 21 (Visit 8). Placebo	Total of all reporting groups
Overall Participants	30	32	62
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.6 (17.06)	48.0 (13.66)	51.2 (15.63)
Age, Customized (Count of Participants)
<65 years	20 66.7%	29 90.6%	49 79%
>=65	10 33.3%	3 9.4%	13 21%
Sex: Female, Male (Count of Participants)
Female	14 46.7%	19 59.4%	33 53.2%
Male	16 53.3%	13 40.6%	29 46.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.7%	3 9.4%	5 8.1%
Not Hispanic or Latino	28 93.3%	29 90.6%	57 91.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 3.1%	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	1 3.1%	1 1.6%
Black or African American	1 3.3%	0 0%	1 1.6%
White	29 96.7%	30 93.8%	59 95.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
North America	11 36.7%	12 37.5%	23 37.1%
Europe	19 63.3%	20 62.5%	39 62.9%

Outcome Measures

1. Primary Outcome

Title	Improvement in Myasthenia Gravis (MG) Symptoms as Measured by the Mean Change in Quantitative Myasthenia Gravis (QMG) Total Score.
Description	To measure improvement in MG symptoms by the mean change in QMG total score from Baseline (Week 0) to Week 24 as compared to placebo. Evaluators score 13 individual items (range from 0=best to 3=worst) and the individual scores are added together for the total score (range 0-39). An average 3-point improvement in QMG score indicates clinically meaningful improvement.
Time Frame	Baseline (Week 0) to Week 24

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population consisting of all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	IGIV-C	Placebo
Arm/Group Description	IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified. An initial loading dose of 2 g/kg of body weight will be administered at Baseline (Week 0, Visit 1) followed by maintenance doses of 1 g/kg of body weight administered every third week through Week 21 (Visit 8). IGIV-C: IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified	Placebo: Sterile 0.9% sodium chloride injection or equivalent. Placebo will be infused at the Baseline/Week 0 Visit (Visit 1) using the same volume as would be required for the IGIV-C loading dose. Subsequent placebo maintenance doses will be matched in volume to the IGIV-C maintenance doses and administered every third week until Week 21 (Visit 8). Placebo
Measure Participants	30	32
Mean (Standard Deviation) [units on a scale]	-4.6 (5.11)	-2.7 (6.23)

Adverse Events

Time Frame	Adverse event data were collected from screening through Week 24.
Arm/Group Title	IGIV-C		Placebo
Arm/Group Description	IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified. An initial loading dose of 2 g/kg of body weight will be administered at Baseline (Week 0, Visit 1) followed by maintenance doses of 1 g/kg of body weight administered every third week through Week 21 (Visit 8). IGIV-C: IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified		Placebo: Sterile 0.9% sodium chloride injection or equivalent. Placebo will be infused at the Baseline/Week 0 Visit (Visit 1) using the same volume as would be required for the IGIV-C loading dose. Subsequent placebo maintenance doses will be matched in volume to the IGIV-C maintenance doses and administered every third week until Week 21 (Visit 8). Placebo
All Cause Mortality
	IGIV-C		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		0/32 (0%)
Serious Adverse Events
	IGIV-C		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/30 (16.7%)		4/32 (12.5%)
Cardiac disorders
Atrial fibrillation	1/30 (3.3%)	1	0/32 (0%)	0
Cardiopulmonary failure	1/30 (3.3%)	1	0/32 (0%)	0
Gastrointestinal disorders
Haemorrhoids thrombosed	1/30 (3.3%)	1	0/32 (0%)	0
Infections and infestations
Pneumonia	1/30 (3.3%)	1	0/32 (0%)	0
Septic shock	1/30 (3.3%)	1	0/32 (0%)	0
Injury, poisoning and procedural complications
Lower limb fracture	0/30 (0%)	0	1/32 (3.1%)	1
Wrist fracture	0/30 (0%)	0	1/32 (3.1%)	1
Nervous system disorders
Myasthenia gravis	3/30 (10%)	3	1/32 (3.1%)	1
Ischaemic stroke	0/30 (0%)	0	1/32 (3.1%)	1
Cerebral haemorrhage	0/30 (0%)	0	1/32 (3.1%)	1
Psychiatric disorders
Panic attack	1/30 (3.3%)	1	0/32 (0%)	0
Other (Not Including Serious) Adverse Events
	IGIV-C		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/30 (73.3%)		21/32 (65.6%)
Gastrointestinal disorders
Diarrhoea	3/30 (10%)	4	2/32 (6.3%)	2
Nausea	3/30 (10%)	13	1/32 (3.1%)	1
General disorders
Chills	2/30 (6.7%)	2	0/32 (0%)	0
Fatigue	2/30 (6.7%)	3	0/32 (0%)	0
Infections and infestations
Nasopharyngitis	3/30 (10%)	3	4/32 (12.5%)	4
Upper respiratory tract infection	0/30 (0%)	0	3/32 (9.4%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	2/30 (6.7%)	2	0/32 (0%)	0
Back pain	2/30 (6.7%)	3	1/32 (3.1%)	1
Neck pain	2/30 (6.7%)	2	0/32 (0%)	0
Pain in extremity	1/30 (3.3%)	1	2/32 (6.3%)	2
Nervous system disorders
Dizziness	2/30 (6.7%)	2	1/32 (3.1%)	1
Headache	9/30 (30%)	22	4/32 (12.5%)	6
Myasthenia gravis	0/30 (0%)	0	2/32 (6.3%)	2
Respiratory, thoracic and mediastinal disorders
Catarrh	2/30 (6.7%)	3	0/32 (0%)	0
Cough	3/30 (10%)	4	0/32 (0%)	0
Dyspnoea	2/30 (6.7%)	2	0/32 (0%)	0
Skin and subcutaneous tissue disorders
Rash	2/30 (6.7%)	2	1/32 (3.1%)	1
Vascular disorders
Hypertension	3/30 (10%)	5	2/32 (6.3%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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