Clinical trial NCT02473952
Conditions: Myasthenia Gravis, Generalized
Sponsor: Grifols Therapeutics LLC
Start date: 2015-08-01; Completion date: 2018-01-01
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

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.

Arms: arm 1: 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). arm 2: 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).
Interventions: intervention 1: IGIV-C intervention 2: Placebo
Intervention descriptions: intervention 1: IGIV-C: Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified intervention 2: None

Protocol documents:
Prot_000.pdf: 


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Summary of Changes for Amendment 1
Protocol Version
Date of Approval
2.0
Amendment 1 + Integrated Protocol
15 Jul 2015
1.0
Original
30 Sep 2014
Amendment 1
The protocol for GTI1408 (Version 1.0, dated 30 Sep 2014) has been amended and reissued 
as Protocol Amendment 1, Version 2.0, dated 15 Jul 2015. See Appendix 9 for a summary of 
changes for Amendment 1.


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Investigator Signature Page
The undersigned confirms that he/she agrees to conduct the study under the conditions 
described in this protocol and comply with International Conference on Harmonization 
Good Clinical Practice (ICH GCP) and all applicable regulatory requirements:
___________________________________
______________________
INVESTIGATOR NAME (Please Print)
LOCATION
___________________________________
______________________
INVESTIGATOR SIGNATURE
DATE


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Protocol Synopsis
Title of Study:
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
Study Number
GTI1408
Phase:
2
Number of Subjects Planned:
Approximately 62 adult subjects will be randomized.
Study Centers Planned:
Approximately 40 study centers
Study Objectives:
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.
Target Population:
Eligible participants for this study will include adult subjects with a confirmed diagnosis of 
generalized MG who are receiving standard of care MG treatment, but continue to have 
symptoms of MG as demonstrated by a QMG ≥ 10 points.
Overall Study Description:
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of IGIV-C in subjects with MG who are symptomatic on standard of care 
treatment. Subjects will be randomly allocated in a 1:1 ratio to receive either IGIV-C or 
matched placebo every three weeks in double-blinded fashion. Randomization will be 
stratified by sentinel features of the subject’s Baseline standard of care MG treatment 
regimen at the time randomization: 

Regimen includes ONLY cholinesterase inhibitors

Regimen includes corticosteroid (CS) as the ONLY 
IMMUNOSUPPRESSANT/IMMUNOMODULATOR, alone or in combination 
with other MG medications (e.g., a subject on prednisone plus a cholinesterase 
inhibitor would be in this stratum)


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
Regimen includes ANY NON-CS 
IMMUNOSUPPRESSANT/IMMUNOMODULATOR alone or in combination 
with other MG medications which may include CS (e.g., a subject on azathioprine, 
prednisone, and a cholinesterase inhibitor would be in this stratum)
For those subjects randomized to receive IGIV-C, an initial loading dose of 2 g/kg of body 
weight will be administered after the Baseline assessments are complete 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). The initial loading dose (2 g/kg) will be divided on 2 
consecutive days with extension of up to 4 consecutive days to account for 
tolerability/weight >80 kg. The subsequent 7 maintenance dosages (1 g/kg) will be infused 
on one day with an extension to 2 consecutive days (divided doses) to account for 
tolerability/weight >80 kg. For both loading and maintenance infusions the limit for blinded 
IGIV-C infusion is no more than 80 g/day, corresponding to an 80-kg body weight for a 1 
g/kg per diem dosage.
For those subjects randomized to receive placebo, a sterile 0.9% sodium chloride injection, 
United States Pharmacopeia (USP) or equivalent 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).
The Investigators will hold the subjects’ current background medical regimen constant from 
Screening through the end of the study (Week 24, Visit 9), unless there is a compelling 
emergent medical need to make medication adjustments, the subject discontinues the study 
because criteria for Treatment Failure are met as defined in Section 3.3.3 (after End of Study 
visit assessments are complete), or adverse effects due to other components of the subject’s 
therapy become untenable; in such cases, the Medical Monitor must be contacted.
Week 21 (Visit 8) is the time of the last investigational product (IP) maintenance dosage. 
Week 24 (Visit 9) will constitute the primary endpoint time point for analysis because this 
timing allows an opportunity to assess the effect of the final IP infusion made at Week 21 
(Visit 8). Week 24 (Visit 9) will serve as the final End of Study Visit.
Study Phases:
Screening:
During the three-week Screening Phase, assessments will be performed to determine subject 
eligibility.
Baseline:
Eligible subjects will have the Baseline assessments performed and will be randomized to 
receive either IGIV-C or placebo. After randomization, a loading dose of the blinded IP will 
be administered (Week 0, Visit 1).
IP Maintenance Phase:
Maintenance infusions of blinded IP will be given over 1 day every three weeks at Week 3 


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(Visit 2), Week 6 (Visit 3), Week 9 (Visit 4), Week 12 (Visit 5), Week 15 (Visit 6), Week 18 
(Visit 7), and Week 21 (Visit 8).
End of Study/Early Termination:
Subjects will have an End of Study Visit at Week 24 (Visit 9). 
Key Assessments and Procedures
During the course of the study, subjects will receive scheduled general physical 
examinations, neurological assessments of strength, functional ability and endurance, quality 
of life assessments, and laboratory evaluations.
Duration of Treatment:
Subjects will receive a loading dose of IP at the Baseline Visit (Week 0, Visit 1) in divided 
doses on two days and will then receive IP infusions every 3 weeks on one day from Week 3 
(Visit 2) until Week 21 (Visit 8).
Diagnosis and Main Eligibility Criteria:
Inclusion Criteria
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study:
1. Male or female, ages 18 to 85 years
2. Anti-acetylcholine receptor antibody positive
3. Confirmed diagnosis of generalized MG. Historically, subjects may have previously had 
the Myasthenia Gravis Foundation of America (MGFA) Class II, III, IV, or V.
4. MGFA classification of Class II, III, or IVa inclusive at Screening.
5. QMG score ≥ 10 at Screening. Note: Subjects who only have a history of ocular MG may 
not enroll.
6. 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): 

Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior 
to Screening and no immunosuppressants

Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior 
to Screening and/or only one of the following:
o
Prednisone (up to 60 mg/day or equivalent) for at least two months prior 
to Screening, or
o
Azathioprine for at least 6 months prior to Screening, or
o
Mycophenolate mofetil for at least 6 months prior to Screening, or
o
Methotrexate for at least 6 months prior to Screening, or
o
Cyclosporine or tacrolimus for at least 3 months prior to Screening

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:
o
Azathioprine for at least 6 months prior to Screening, or
o
Mycophenolate mofetil for at least 6 months prior to Screening, or


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o
Methotrexate for at least 6 months prior to Screening, or
o
Cyclosporine or tacrolimus for at least 3 months prior to Screening 
7. Subjects must be willing and able to provide written informed consent. 
8. Subjects must be willing to comply with all aspects of the clinical trial protocol.
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study:
1. Have received cyclophosphamide or any other immunosuppressive agent apart from the 
ones allowed per inclusion criteria within the past 6 months
2. Any change in MG treatment regimen between Screening (Week -3, Visit 0) and Baseline 
(Week 0, Visit 1)
3. Greater than two (>2) point change in QMG score, increased or decreased, between 
Screening (Week -3, Visit 0) and Baseline (Week 0, Visit 1)
4. Any episode of myasthenic crisis (MC) in the one month prior to Screening
5. 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)
6. Thymectomy within the preceding six months
7. Rituximab, belimumab, eculizumab or any monoclonal antibody used for 
immunomodulation within the past 12 months
8. Have received immune globulin (Ig) treatment given by intravenous (IV), subcutaneous, 
or intramuscular route within the last 3 months
9. Current known hyperviscosity or hypercoagulable state
10. 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)
11. Plasma exchange (PLEX) performed within the last 3 months
12. History of non-response to intravenous immunoglobulin (IVIg) when used in 
maintenance therapy of the subject’s MG, as judged by the Investigator
13. Any comorbid condition that in the opinion of the Investigator would put the subject at 
undue safety risk or compromise the ability of the subject to participate in the trial or the 
scientific integrity of the study
14. Inadequate venous access to support repeated IV infusions
15. History of anaphylactic reactions or severe reactions to any blood-derived product
16. History of intolerance to any component of the IP 
17. Documented diagnosis of thrombotic complications to polyclonal IVIg therapy in the past
18. History of recent (within the last year) myocardial infarction or stroke
19. Uncontrolled congestive heart failure; embolism; or historically documented (within the 
last year) electrocardiogram (ECG) changes indicative of myocardial ischemia or atrial 
fibrillation   
20. History of chronic alcoholism or illicit drug abuse (addiction) in the 12 months preceding 
the Screening/Week -3 (Visit 0)
21. Active psychiatric illness that interferes with compliance or communication with health 


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care personnel
22. Females of child-bearing potential who are pregnant or have a positive serum pregnancy 
test (Beta-human chorionic gonadotropin [β-HCG]-based assay)
23. Females who are breastfeeding
24. Females of child-bearing potential who are unwilling to practice a highly effective 
method of contraception (oral, injectable or implanted hormonal methods of 
contraception, placement of an intrauterine device or intrauterine system, condom or 
occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or 
true abstinence*) throughout the study.  
*True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], 
declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.)
25. Currently receiving, or having received within 1 month prior to the Screening/Week -3 
(Visit 0), any investigational medicinal product or device. In the case of an 
investigational medicinal product trial, at least five half-lives (if known) must have 
elapsed prior to Screening.
26. Known Immunoglobulin A (IgA) deficiency and anti-IgA serum antibodies
27. 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)
28. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding 
more than 2.5 times the ULN for the expected normal range for the testing laboratory.
29. Hemoglobin (Hb) levels <9 g/dL
30. Any medical condition which makes the clinical trial participation unadvisable or which 
is likely to interfere with the evaluation of the study treatment and/or the satisfactory 
conduct of the clinical trial according to the Investigator’s judgment. Any factor that in 
the opinion of the Investigator would compromise the ability of the subject to complete 
the trial.
Study Procedures:
Subjects deemed eligible based on Screening evaluations will complete the Baseline 
assessments, thereby initiating double-blind treatment. Subjects will continue with 
assessments for 24 weeks, with scheduled assessments at Week 0 (Visit 1) (Baseline and 
loading infusion divided on 2 consecutive days), followed by assessments and maintenance 
doses every 3 weeks through Week 21 (Visit 8). The time point for assessment of the primary 
endpoint is Week 24 (Visit 9). Visits/procedures and assessments should be scheduled within
± 3 days of the protocol-specified timing. The main protocol text and tabular summary
Schedule of Study Procedures (Appendix 1) provide additional details. Tools for assessing 
MG are provided in Appendix 2 to Appendix 6.
The QMG score and MG Composite will be assessed at every visit. Therefore before each 
visit, subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage 
for 12 hours prior to the visit to assure accurate assessment of the QMG. The MG-Activities 
of Daily Living (MG-ADL) and the 15-item MG Quality-of-Life Instrument (MG-QOL 15) 
are assessed at Baseline, Week 9 (Visit 4), Week 15 (Visit 6), and Week 24 (Visit 9). Safety 
assessments include vital signs performed at each visit, clinical laboratory testing and 
physical examinations performed at Screening, Baseline, Week 9 (Visit 4), Week 15 (Visit 


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6), and Week 24 (Visit 9), assessments of adverse events (AEs) throughout the study, and 
targeted evaluations for potential thromboembolism risk and hemolysis at time points 
designated in Appendix 1 and Section 3.8 of the protocol.  
Investigational Product, Dose, and Mode of Administration:
Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C)
Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified (IGIV-C) is 
the active IP for this study, which is a marketed product. IGIV-C glass vials may be supplied 
in the vial sizes of 10 mL, 25 mL, 50 mL, 100 mL, and 200 mL. The infusion solution will be 
visually masked to maintain the blind.
Administration of IP will be via the IV route, and will be administered in a double-blinded
fashion. The unblinded pharmacist or designee will prepare the IP to maintain the blind for 
all parties during infusions and study assessments. Reference the Pharmacy Manual for 
additional details.
Placebo
Sterile 0.9% sodium chloride injection, USP (0.9% NaCl, USP) or equivalent will be used as 
placebo to maintain the blind. The infusion solution will be at a volume approximate to that 
required for the appropriate weight-based dose of IGIV-C and visually masked to maintain 
the blind.
Method of Assigning Subjects to Treatment Groups
This is a randomized, double-blind, placebo-controlled study. Subjects will be randomized in 
a 1:1 ratio via Interactive Web Response System (IWRS) into IGIV-C treatment group and 
Placebo treatment group to receive either IGIV-C or matching placebo every three weeks in a 
double-blind fashion via IV administration.
Preparation of Investigational Products
The volume (i.e., total infusion dose administered) of IP to be prepared for each IV infusion 
will be individualized for each subject based on body weight, and the protocol specified 
loading dose of 2 g/kg divided over 2 days starting after the randomization at Baseline 
(Week 0), followed by maintenance doses of 1 g/kg administered over 1 day every three 
weeks until Week 21 (Visit 8). The infusion solution will be visually masked to maintain the 
blind.
Note that the loading dosage is divided over 2 days as standard infusion time; however, 
extensions up to 4 days are allowed for tolerability issues or higher weight, i.e., limit for
IGIV-C infusion is no more than 80 g/day (corresponding to 80 kg body weight). Similarly, 
the maintenance dosage is infused on 1 day as standard; however, extension is allowed for 
divided dosage over 2 consecutive days for tolerability issues or higher weight, i.e., limit for 
IGIV-C infusion is no more than 80 g/day (corresponding to 80 kg body weight).
The unblinded pharmacist must inspect IGIV-C visually before preparing for administration 
to subjects. The solution must not be used if turbid or if it contains visible particles. Solution 


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which has been frozen should not be used.
Definition and Management of Treatment Failures Due to MG Worsening:
During the study, MG worsening will be defined as:
•
QMG increase by ≥4 points relative to Baseline/Week 0
All subjects will remain in the study until at least Week 9 (Visit 4) is completed. No 
premature discontinuation of IP administration is to be made for reasons of Treatment Failure 
(QMG increase by ≥4 points relative to Baseline/Week 0) until the subject receives at least a 
total of 3 complete doses of the IP, which includes the initial loading dose and the first two 
maintenance doses irrespective of the QMG scores measured at Week 3 and Week 6 (Visit 2 
and Visit 3) in order to allow time for the investigational medicinal product to potentially 
produce a beneficial effect. 
At Week 9 (Visit 4) through Week 21 (Visit 8), if the subject suffers a worsening of his/her 
MG symptoms defined as a QMG increase ≥ 4 points relative to Baseline (Week 0), and this 
worsening is confirmed at the next scheduled consecutive visit, the subject will discontinue 
from the study. The earliest withdrawal for Treatment Failure will be at Week 9 and would 
occur only if QMG score is increased by 4 points or more (relative to Baseline) at both Week 
6 (Visit 3) and Week 9 (Visit 4).
Safety Evaluation:
Safety will be assessed throughout the clinical trial for all individuals who have received at 
least one infusion of the IP. The following safety variables will be assessed in this study:

Adverse events (AEs), suspected adverse drug reactions (Suspected ADRs), adverse 
reactions (ARs), serious AEs (SAEs), and discontinuations due to AEs and SAEs 
(including myasthenic crisis)

Vital Signs (temperature [T], respiratory rate [RR], heart rate [HR], systolic blood 
pressure [SBP] and diastolic blood pressure [DBP]); during infusions vital signs will be 
carefully monitored.

Physical examinations: physical exams will be recorded as normal or abnormal, 
according to the physician’s judgment criteria, and findings will be recorded.

Blood chemistry and Hematology

Thromboembolic events (TEs) and hemolysis events
Management and Recording of Adverse Events
AEs (includes Suspected ADRs) occurring at any time between signature of the subject’s 
informed consent form (ICF) and the last day of the subject’s participation in the clinical trial 
will be reported and recorded on the appropriate subject’s electronic case report form (eCRF)
entry. 
It is the Investigator’s responsibility to ensure that all AEs are appropriately recorded. 
AEs will be elicited by spontaneous reporting by the study individual or by a non-leading 


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inquiry or direct observation by the study staff.
This study will utilize an Independent Safety Review Committee (ISRC) whose members 
(from Grifols) will be impartial and independent of the clinical trial team. The clinical trial 
team will remain blinded to subject treatment assignment. The ISRC will review relevant 
safety information from the study as outlined in the ISRC Charter. At a minimum, after the 
first 20 subjects are enrolled and have completed half of the treatment period, the ISRC will 
conduct a safety review of the following data at a minimum:

AEs, SAEs, and discontinuations due to AEs and SAEs

Vital signs

Blood chemistry and hematology

Assessing for TEs

Assessing for hemolysis
During the study, the Medical Monitor will review all relevant safety information from the 
study in order to protect subject welfare and preserve study integrity. Data to be reviewed 
include but are not limited to the following: eCRFs, listings from the clinical and safety 
databases, AEs/SAE reports, concomitant medications, laboratory data, vital signs, and 
physical examinations data.
Clinical Outcome Measures:
Primary Efficacy Variable
The primary endpoint is improvement in MG symptoms as measured by the mean change in 
QMG score from Baseline (Week 0) to Week 24 as compared to placebo.
Secondary Efficacy Variables

Percentage of subjects who experience a clinical improvement assessed by QMG score 
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 
3-point decrease in QMG score

Percentage of subjects who experience a clinical improvement assessed by the MG 
Composite from Baseline (Week 0) to Week 24 where clinical improvement is defined as 
at least a 3-point decrease in the MG Composite 

Percentage of subjects who experience a clinical improvement assessed by MG-ADL 
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 
2-point decrease in MG-ADL
Exploratory Variables
The exploratory objectives for this study are to evaluate the effect of IGIV-C on: 

Percentage of subjects who experience a clinical improvement in QMG score (defined 
above) at Weeks 6, 9, 12, 15, 18, and 21 

Time to first clinical improvement in QMG score (at least a 3-point decrease)

Time to Treatment Failure based on QMG definition (Section 3.3.3)


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
Change from Baseline (Week 0) in QMG score to Weeks 6, 9, 12, 15, 18, and 21

Percentage of subjects who experience a clinical improvement in the MG Composite 
(defined above) to Weeks 6, 9, 12, 15, 18, and 21

Change from Baseline (Week 0) in MG Composite to Weeks 6, 9, 12, 15, 18, 21, and 24

Percentage of subjects who experience a clinical improvement in MG-ADL (defined 
above) to Weeks 9 and 15

Change from Baseline (Week 0) in MG-ADL to Weeks 9, 15, and 24

Change from Baseline in MG-QOL 15 to Weeks 9, 15, and 24

MGFA postinterventional change in status at Week 24 relative to Baseline
Statistical and Analytical Methods:
Determination of Sample Size
Assuming that the IGIV treatment group is 50% better than the Placebo group, with 
alpha=0.05 and two-sided test, 28 subjects are needed for each treatment group (total 56 
subjects) to have at least 80% power to detect the treatment difference. Assuming a 10% drop 
out rate, 62 subjects are planned to be randomized.
Subject Populations for Analysis
Intent-To-Treat (ITT) Population
The ITT population consists of all subjects who are randomized. 
Safety Population
The Safety population consists of all subjects who received any amount of IP.  
Per Protocol (PP) Population
The PP population consists of all subjects in ITT population without any major protocol 
deviation which has impact on the primary efficacy data. Any deviations from the protocol 
will be recorded in the protocol deviation list. The validity of a subject for inclusion in the PP 
population will be assessed at a review meeting that will take place before finalizing the 
database. The review meeting will review the protocol deviation list, as well as data listings. 
If protocol deviations are identified which justify removing a subject from the PP population, 
then these decisions will be documented.
Primary Efficacy Analyses
The primary efficacy endpoint is the change in QMG score from Baseline (Week 0) to Week 
24. The treatment comparison will be performed using analysis of covariance (ANCOVA) 
with change in QMG score as dependent variable, treatment and Baseline standard of care 
treatment regimen as fixed factors and Baseline QMG score as a covariate. The null 


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hypothesis (H0) and the alternative hypothesis (Ha) are:  
H0: μ1 = μ2 
Ha: μ1 ≠ μ2
Where μ1 and μ2 represent the population mean in IGIV-C and Placebo group, respectively.
For subjects who discontinued the study early, the last observation carried forward (LOCF) 
method will be used to impute the change in QMG from Baseline to Week 24. A sensitivity 
analysis of completers with non-missing QMG score at Week 24 will be performed. For 
subjects who experience treatment failure (as defined in Section 3.3.3) or myasthenic crisis
(as defined in Section 3.3.4) the value at time of failure will be employed.
For the longitudinal measurements of QMG score at various time points, the treatment effects 
will be explored by using the mixed-effect model repeated measures (MMRM) with change 
from Baseline as dependent variable; treatment, Baseline standard of care treatment regimen, 
protocol-specified visits, treatment by-visit interaction as fixed effects; Baseline QMG value 
as covariates; and measures within-subject at each visit as a repeated measure.
Primary Efficacy analyses will be based on the ITT population. For sensitivity analysis, the 
same analysis will be repeated using the PP population. 
Secondary Efficacy Analyses
Treatment comparison will be performed by Cochran-Mantel-Haenszel (CMH) test adjusted 
for Baseline standard of care treatment regimen. Subjects who discontinued from the study 
early will be considered as not showing clinical improvement. 
Exploratory Efficacy Analyses
For the time to event variables, Kaplan-Meier estimates will be provided and the treatment 
comparison will be performed using log-rank test. For change from Baseline variables, 
ANCOVA and/or MMRM methods similar to the primary efficacy endpoint will be used. For 
percentage variables, the CMH test adjusted for Baseline standard of care treatment regimen
will be used. 
MGFA postinterventional change in status at Week 24 relative to Baseline will be 
summarized by treatment group.
Safety Analyses
The safety analysis will be based on safety population.
The incidence of AEs, SAEs, suspected ADRs, and AEs by severity will be summarized by 
treatment, system organ class and preferred term using descriptive statistics. Subjects with 
deaths, SAEs, and AEs leading to premature discontinuation from the study will be listed.  


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Clinical laboratory results and the change from Baseline values will be summarized by 
treatment group using summary statistics. Shift tables will be provided to summarize values 
that fall outside the normal ranges.
Vital signs will be summarized by treatment using summary statistics at each time point and 
on the change from Baseline.
Physical exam data will be provided in data listings.


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TABLE OF CONTENTS
GLOSSARY AND ABBREVIATIONS..................................................................................20
1
INTRODUCTION ...........................................................................................................23
1.1
Myasthenia Gravis .................................................................................................23
1.2
Treatment of Myasthenia Gravis ...........................................................................24
1.3
Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-
C)............................................................................................................................25
1.4
Study Rationale and Dose Selection......................................................................25
1.4.1
Study Rationale............................................................................................25
1.4.2
Dose Rationale.............................................................................................26
2
STUDY OBJECTIVES....................................................................................................26
2.1
Efficacy Objectives................................................................................................26
2.1.1
Primary Objective........................................................................................26
2.1.2
Secondary Objectives...................................................................................26
2.1.3
Exploratory Objectives ................................................................................27
2.2
Safety Objective.....................................................................................................27
3
INVESTIGATIONAL PLAN..........................................................................................27
3.1
Study Design and Plan...........................................................................................27
3.2
Selection of Study Population................................................................................31
3.2.1
Inclusion Criteria .........................................................................................31
3.2.2
Exclusion Criteria ........................................................................................32
3.3
Study Time Periods and Definitions......................................................................33
3.3.1
Investigational Product Treatment Period ...................................................33
3.3.2
Worsening of MG Symptoms......................................................................33
3.3.3
Definition of Treatment Failure Due to MG Worsening .............................34
3.3.4
Myasthenic Crisis.........................................................................................34
3.4
Treatments..............................................................................................................34
3.4.1
Treatments to Be Administered ...................................................................34
3.4.1.1
Immune Globulin (Human), 10% Caprylate/Chromatography 
Purified (IGIV-C)...............................................................................34
3.4.1.2
Placebo...............................................................................................34
3.4.1.3
Labeling of Investigational Products .................................................35
3.4.1.4
Storage of Investigational Products ...................................................35
3.4.1.5
Preparation of Investigational Products.............................................35
3.4.1.6
Accountability for Investigational Products ......................................36
3.4.2
Rationale for Selection of Doses/Timing of Investigational Product in 
the Study ......................................................................................................36
3.4.2.1
Selection of IGIV-C Dose and Dosing Interval in the Study.............36
3.4.3
Method of Assigning Subjects to Treatment Groups...................................36
3.4.3.1
Subject Numbering ............................................................................37


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3.4.3.2
Blinding..............................................................................................37
3.4.3.3
Administration and Timing of Investigational Products for Each 
Subject................................................................................................37
3.4.3.4
Preparation and Handling of Investigational Products ......................37
3.4.3.5
Treatment Compliance.......................................................................38
3.5
Prior and Concomitant Therapy.............................................................................38
3.5.1
Prohibited Medications Prior to Study Participation ...................................38
3.5.2
Prohibited Concomitant Medications during the Study...............................38
3.5.3
Restricted Concomitant Medications during the Study ...............................39
3.6
Efficacy Study Variables .......................................................................................39
3.6.1
Primary Variable..........................................................................................39
3.6.2
Secondary Variables ....................................................................................39
3.6.3
Exploratory Variables ..................................................................................40
3.6.4
Quantitative Myasthenia Gravis Score (QMG) ...........................................40
3.6.5
MG Composite Scale...................................................................................40
3.6.6
MG-ADL......................................................................................................41
3.6.7
15-item MG Quality-of-Life Instrument (MG-QOL 15).............................41
3.6.8
MGFA Postinterventional Change in Status................................................41
3.7
Safety Study Variables...........................................................................................41
3.7.1
Thromboembolic Events Risk......................................................................41
3.7.2
Hemolysis ....................................................................................................42
3.8
Assessments...........................................................................................................42
3.8.1
Assessment Periods......................................................................................42
3.8.2
Observations and Measurements .................................................................42
3.8.2.1
Overview of Screening, Treatment and Post infusion Follow-up 
Phases.................................................................................................43
3.8.2.2
Screening: Week -3 (Visit 0) .............................................................43
3.8.2.3
Baseline, Randomization, and Loading Dose Infusion: Week 0 
(Visit 1)..............................................................................................44
3.8.2.4
Investigational Product Maintenance Phase: Weeks 3 and 6 
(Visits 2 and 3)...................................................................................45
3.8.2.5
Investigational Product Maintenance Phase: Week 9 (Visit 4) .........46
3.8.2.6
Investigational Product Maintenance Phase: Weeks 12, 18, and 21 
(Visits 5, 7, and 8)..............................................................................47
3.8.2.7
Investigational Product Maintenance Phase: Week 15 (Visit 6) .......48
3.8.2.8
End of Study: Week 24 (Visit 9)........................................................49
3.8.2.9
Early Termination Visit .....................................................................50
3.8.3
Description of Laboratory Tests and Procedures.........................................50
3.8.3.1
Thromboembolic Events Risk Testing...............................................51
3.8.3.2
Hemolysis Testing .............................................................................51
3.8.3.3
Virus Safety Testing ..........................................................................51
3.8.3.4
AChR Antibody Testing ....................................................................51


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3.8.3.5
IgG Concentration Measurements .....................................................52
3.9
Screen Failures.......................................................................................................52
3.10
Removal of Subjects ..............................................................................................52
3.11
Follow-up of Subjects Withdrawn from Study......................................................53
3.12
Premature Termination of Study/Closure of Center..............................................53
4
ADVERSE EVENTS.......................................................................................................53
4.1
Warnings/Precautions ............................................................................................53
4.1.1
Interaction/Overdose....................................................................................53
4.1.2
Live Viral Vaccines .....................................................................................53
4.2
Specification of Safety Parameters ........................................................................54
4.3
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters..............................................................................................................54
4.3.1
Adverse Events ............................................................................................54
4.3.2
Vital Signs....................................................................................................54
4.3.3
Physical Examination...................................................................................55
4.3.4
Blood Chemistry and Hematological Parameters........................................55
4.3.5
Thromboembolic Event Risk.......................................................................55
4.3.6
Hemolysis ....................................................................................................55
4.4
Procedures for Eliciting Reports of and for Recording and Reporting Adverse 
Events and Intercurrent Illnesses ...........................................................................55
4.4.1
Adverse Event..............................................................................................55
4.4.2
Suspected Adverse Drug Reaction (ADR)/Adverse Reaction (AR)............56
4.4.3
Causality of Adverse Event .........................................................................56
4.4.4
Intensity of Adverse Event or Suspected Adverse Drug Reaction ..............57
4.4.5
Expectedness of Adverse Event or Suspected Adverse Drug Reaction ......58
4.4.6
Seriousness of Adverse Event or Suspected Adverse Drug Reaction,  
Serious Adverse Event.................................................................................58
4.4.6.1
Hospitalization or Prolongation of Hospitalization ...........................59
4.4.7
Adverse Events of Special Interest ..............................................................59
4.4.7.1
Thromboembolic Events....................................................................59
4.4.7.2
Hemolysis ..........................................................................................59
4.4.7.3
MG Events That Are Not Considered AEs........................................59
4.4.8
Procedures for Eliciting Reports of and for Recording and Reporting 
Adverse    Events and Suspected Adverse Drug Reactions.........................59
4.4.9
Timelines and Reporting of Serious Adverse Events ..................................60
4.4.10
Type and Duration of the Follow-Up of Subjects after Adverse Event or 
Suspected ADR............................................................................................61
5
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE................61
5.1
Statistical and Analytical Plan ...............................................................................61
5.1.1
Subject Populations for Analysis.................................................................62


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5.1.2
Demographic and Baseline Characteristics .................................................62
5.1.3
Efficacy Analyses ........................................................................................62
5.1.3.1
Primary Efficacy Analyses ................................................................62
5.1.3.2
Secondary Efficacy Analyses ............................................................63
5.1.3.3
Exploratory Efficacy Analyses ..........................................................63
5.1.4
Safety Analyses............................................................................................64
5.2
Determination of Sample Size ...............................................................................65
6
ADMINISTRATIVE .......................................................................................................66
6.1
Investigators, Other Study Personnel and External Committees...........................66
6.1.1
Independent Safety Review Committee.......................................................66
6.2
Data Quality...........................................................................................................66
6.3
Documentation.......................................................................................................66
6.3.1
Record Retention .........................................................................................67
6.3.2
Access to Information for Monitoring.........................................................67
6.3.3
Access to Information for Audits or Inspections.........................................67
7
ETHICAL AND LEGAL ASPECTS...............................................................................68
7.1
Institutional Review Board/Ethics Committee ......................................................68
7.2
Ethical Conduct of the Study.................................................................................68
7.3
Regulatory Authority Approvals/Authorizations...................................................68
7.4
Subject Information and Informed Consent Form.................................................68
7.5
Insurance................................................................................................................69
7.6
Confidentiality .......................................................................................................69
8
USE OF DATA AND PUBLICATION ..........................................................................69
9
REFERENCES ................................................................................................................71
10
APPENDICES .................................................................................................................76
LIST OF FIGURES
Figure 3-1 Overall Study Schema......................................................................................30
LIST OF APPENDICES
Appendix 1
Schedule of Study Procedures ...................................................................77
Appendix 2
MGFA Clinical Classification ...................................................................80
Appendix 3
QMG Test Items ........................................................................................81
Appendix 4
MG Composite Scale.................................................................................82
Appendix 5
MG Activities of Daily Living (MG-ADL) Profile...................................83
Appendix 6
MG-Quality of Life (QOL) 15...................................................................84
Appendix 7
Monitoring of Thromboembolic Events Risk............................................85
Appendix 8
Hemolysis Detection..................................................................................89
Appendix 9
90


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Appendix 10
Summary of Changes for Amendment 1 ...................................................91


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GLOSSARY AND ABBREVIATIONS
AAN
American Academy of Neurology
AChR
Acetylcholine receptor
ADR
Adverse drug reaction
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AR
Adverse reaction
ARC
Absolute reticulocyte count 
AST
Aspartate aminotransferase
β-HCG
Beta-human chorionic gonadotropin
B19V
Parvovirus B19
BUN
Blood urea nitrogen
CBC
Complete blood count
CIDP
Chronic inflammatory demyelinating polyneuropathy
CMH
Cochran-Mantel-Haenszel
CRO
Clinical research organization
CS
Corticosteroid
DAT
Direct antiglobulin test
DBP
Diastolic blood pressure
DNA
Deoxyribonucleic acid
DVT
Deep venous thrombosis
ECG
Electrocardiogram
eCRF
Electronic case report form 
EDC
Electronic data capture
GBS
Guillain-Barré syndrome
H0
Null hypothesis
Ha
Alternative hypothesis
HAV
Hepatitis A virus
Hb
Hemoglobin
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s Brochure


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ICF
Informed consent form
ICH GCP
International Conference on Harmonization Good Clinical Practice
ICU
Intensive Care Unit
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IGIV-C
Immune Globulin (Human), 10% Caprylate/Chromatography Purified
IgM
Immunoglobulin M
IP
Investigational product
IRB/EC
Institutional Review Board/Ethics Committee
ISRC
Independent Safety Review Committee
ITP
Idiopathic thrombocytopenic purpura
ITT
Intent-to-treat
IV
Intravenous
IVIg
Intravenous immunoglobulin
IWRS
Interactive Web Response System 
LDH
Lactate dehydrogenase
LOCF
Last observation carried forward
MC
Myasthenic crisis
MedDRA
Medical Dictionary for Regulatory Activities
MG
Myasthenia gravis
MG-ADL
Myasthenia Gravis-Activities of Daily Living
MGFA
Myasthenia Gravis Foundation of America
MG-QOL 15
15-Item MG Quality-of-Life Instrument
MMRM
mixed-effect model repeated measures
NAT
Nucleic acid amplification technology
NINDS
National Institute of Neurological Disorders and Stroke
PE
Pulmonary embolism
PLEX
Plasma exchange
PP
Per protocol
QMG
Quantitative myasthenia gravis score
RBC
Red blood count
RNA
Ribonucleic acid
RR
Respiratory rate
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
SPC
Summary of product characteristics


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Suspected ADR
Suspected adverse drug reaction
T
Temperature
TBL
Total bilirubin
TE
Thromboembolic event
TEAE
Treatment emergent adverse event
ULN
Upper limit of normal
USP
United States Pharmacopeia


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1
INTRODUCTION
In addition to the information provided below, please also refer to the Immune Globulin 
(Human), 10% Caprylate/Chromatography Purified (IGIV-C) Investigator’s Brochure (IB) 
and any additional data supplied by the Sponsor.
1.1
Myasthenia Gravis 
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction and is 
clinically manifested as variable and fluctuating muscle weakness (1). In most cases, the 
disorder is associated with the production of antibodies against acetylcholine receptors 
(AChR) leading to the destruction of the postsynaptic motor end plate (2). Clinical symptoms 
of MG include muscle fatigue and weakness that can be localized, such as ocular, or 
generalized across multiple muscle groups (systemic). Manifest weakening during continued 
activity, quick restoration of power with rest, and dramatic improvement in strength 
following the administration of drugs inhibiting acetylcholinesterase such as neostigmine and 
pyridostigmine are other notable characteristics (3). The special vulnerability of the 
neuromuscular junctions in certain muscles gives myasthenia a highly characteristic clinical 
presentation. Usually the eyelids and the muscles of eye movement, and somewhat less often 
the face, jaws, throat, and neck are the first to be affected. Exacerbations of disease can lead 
to myasthenic crisis (MC) with severe respiratory weakness requiring intubation.
MG is a relatively rare disorder with an estimated prevalence of 1.7 to 10.4 per million 
depending on the location, and has been reported to be as high as 21 per million in 
Barcelona, Spain (4). While symptoms can be ameliorated with acetylcholinesterase 
inhibitors that prolong native acetylcholine activity, definitive therapy requires attenuation of 
the aberrant immune process. This can be achieved by treating patients with 
immunosuppressive medications, immunomodulation therapies or plasma exchange (5). 
Immunosuppressive medications used in the treatment of MG include corticosteroids, 
azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil. B-cell targeted 
immunotherapies (e.g., rituximab, belimumab), and eculizumab have also been explored as 
investigational treatment modalities. Intravenous immunoglobulin (IVIg) is commonly used 
in the acute setting as an integral part of therapy (4, 6).
While there are a number of studies evaluating IVIg for the treatment of MG worsening or 
exacerbation (7, 8, 9, 10, 11), there are few prospective data from controlled trials in the 
public domain for IVIg treatment of chronic MG (12, 13). The latter 2 studies were in very 
small patient numbers 12 and 15 patients, respectively. The study by Wolfe and colleagues 
was terminated prematurely due to insufficient IVIg inventories, and that by Ronager and 
colleagues was a controlled crossover study wherein IVIg was given for 5 days with 16 
weeks observation followed by plasma exchange every other day (5 interventions) with 16 
weeks observation (or vice versa). Thus, there is a need for definitive, prospective clinical 
studies of IVIg in the chronic/maintenance setting.
Corticosteroids have generally been considered a fairly reliable and appropriate modality for 
immunomodulation of MG, mainly based on clinical experience rather than rigorously 
controlled studies (6). Prednisone (or prednisolone in Europe) is the initial 


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immunosuppressive treatment used in many MG patients, although the optimal dosage and 
schedule of administration have not been precisely defined (14). The long-term use of 
steroids is complicated by severe and often intolerable adverse effects, the cumulative burden 
of steroid side effects is high (15), and therefore there has been much clinical interest in 
approaches to CS dose reduction. The minimum effective CS dose is the clinical target (16). 
1.2
Treatment of Myasthenia Gravis
Therapies for MG are based on two approaches, prolongation of the half-life of the 
neurotransmitter acetylcholine in the synaptic cleft, and reduction in the burden of pathologic 
antibodies inhibiting neuromuscular transmission. 
Acetylcholinesterase inhibitors effectively prolong acetylcholine activity; neostigmine and 
pyridostigmine have been demonstrated to provide symptomatic improvement in muscle 
strength. Common adverse events (AEs) include diarrhea and abdominal cramps, whilst
overdose symptoms show features consistent with acute cholinergic poisoning (4).
Down regulation of the production of antibodies through immune modulation is a 
complementary approach, and corticosteroids, azathioprine, cyclosporine, tacrolimus, and 
cyclophosphamide have been employed. Clinical observation and limited trial data support a 
number of medications using this approach, however all require close monitoring for 
frequent and sometimes serious adverse effects (17, 18, 19, 20, 21). Additionally, onset of 
of action is often reported to be slow with these agents, with the exception of corticosteroids 
(22). Although corticosteroids are the most common first-line immune suppressant employed 
in chronic MG, their adverse effect profile is considerable. Examples of adverse effects of 
systemic CS use include clinical adverse effects (e.g., adipose tissue redistribution, 
hypertension, cardiovascular risk, osteoporosis, peptic ulcer, adrenal insufficiency, 
infections, aseptic necrosis and pancreatitis as well as mood, ophthalmological, menstrual 
and skin disorders) and biological adverse effects (e.g., electrolyte homeostasis 
diabetogenesis, dyslipidemia and pregnancy-related AEs) (23, 24).
Additional therapies include complete thymectomy, an intervention that is the subject of an 
ongoing clinical trial supported by the National Institute of Neurological Disorders and 
Stroke (NINDS) (25) which presents an opportunity to reduce antibody production. Removal 
of an associated thymoma has shown benefit historically. In the setting of MC and 
exacerbations, plasmapheresis has been employed. However, a 2011 American Academy of 
Neurology (AAN) guideline update states that: “There is insufficient evidence to support or 
refute the use of plasmapheresis in myasthenia gravis” (26). Plasmapheresis requires highly 
specialized equipment, significant operator expertise, and often requires large gauge access 
to the central circulation.
IVIg derived from healthy donor plasma appears to mitigate immunologic events related to 
the pathologic antibodies in MG. While there are multiple theoretical mechanisms by which 
exogenous IVIg modulates the immune system, several generally accepted paths include 
competition with anti-idiotype antibodies, anti-complement effects, and Fc receptor 
saturation (27, 28, 29).


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The mechanism by which IVIg exerts its clinical effect in MG remains to be elucidated but it 
is believed to improve symptoms by modulating the pathogenic autoantibody response. Other 
mechanisms of action postulated in other diseases include the Fc receptor blockade of the 
reticuloendothelial system, modulation of the idiotypic-anti-idiotypic network, enhancement 
of regulatory T cells, inhibition of complement deposition, modulation of cytokines, growth 
factors and adhesion molecules, modulation of apoptosis and macrophages, and immune 
regulation of both B-cell and T-cell immune function (30, 31). Improvement in MG 
symptoms typically occurs in about 70% of patients, beginning during treatment or within a 
few days of initiating IVIg treatment and lasting for weeks to months (32).
The Therapeutics and Technology Assessment Subcommittee of AAN recently released 
updated evidence-based guidelines that consider IVIg as an effective therapy for moderate-
to-severe cases of MG, but also acknowledges the need for additional clinical trials (33). 
1.3
Immune Globulin (Human), 10% Caprylate/Chromatography 
Purified (IGIV-C) 
Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) is an 
intravenous (IV) product that is currently available commercially in a number of countries 
for the treatment of primary immunodeficiency, idiopathic thrombocytopenic purpura (ITP), 
and chronic inflammatory demyelinating polyneuropathy (CIDP) as well as other indications 
in some countries. 
In addition to the information provided herein, please refer to the IGIV-C IB and any 
additional data supplied by the Sponsor.
1.4
Study Rationale and Dose Selection
1.4.1
Study Rationale
The general recommendation is that IVIg concentrates are a safe and effective treatment 
option as a short term treatment for acute exacerbation of MG. Moreover, IVIg has 
demonstrated a positive treatment effect in clinical studies of MG worsening or exacerbations 
(7, 9, 11), but further clinical data are needed to confirm the effectiveness of IVIg in the 
treatment of MG as a maintenance therapy (12, 13). In a recent Cochrane review (10) of IVIg 
for MG, controlled trials were generally of limited timeframe underscoring the need for 
longer term evaluation.
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) in symptomatic subjects with generalized MG on standard of care treatment. The 
primary measure of efficacy for this study is the change in score of MG symptoms as 
measured by the Quantitative Myasthenia Gravis (QMG) score from Baseline (Week 0) to 
Week 24.


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1.4.2
Dose Rationale
The optimal dose of IVIg for MG exacerbation is still unclear, but prior reviews reported a 
usual dose of 2 g/kg, which is administered over 3 to 5 days (32, 35). More recent studies in 
MG have evaluated the administration of a total IVIg dose of 2 g/kg over 2 consecutive days 
(1 g/kg daily) with no increase in side effects and a comparable benefit lasting up to 30 to 60 
days post-treatment (7, 9, 11). 
Likewise, in a study of subjects with Guillain-Barré syndrome (GBS), a total IVIg dose of 
2 g/kg administered over 2 consecutive days (1 g/kg daily) was compared to the standard 
regimen of 0.4 g/kg daily for 5 days and there were no significant differences in the primary 
or secondary outcome measures (36).
Based on the above, subjects will receive a loading IGIV-C dose of 2 g/kg of body weight 
administered over two days followed by maintenance infusions at 3-week intervals at a dose 
of 1 g/kg of body weight administered over one day. The loading and maintenance dosage is 
the same as that used for IGIV-C in CIDP which has been well tolerated, and is approved for 
CIDP at this dosage both in North America and Europe.
2
STUDY OBJECTIVES
2.1
Efficacy Objectives
2.1.1
Primary Objective
The primary objective is to evaluate the efficacy of IGIV-C in subjects with generalized MG 
on standard of care treatment at study entry in terms of improvement in MG symptoms as 
measured by the mean change in QMG score from Baseline (Week 0) to Week 24 as 
compared to placebo.
2.1.2
Secondary Objectives
The secondary objectives of this study are to evaluate the efficacy of IGIV-C as compared to 
placebo from Baseline through Week 24 in the following:

Percentage of subjects who experience a clinical improvement assessed by QMG score 
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 
3-point decrease in QMG score

Percentage of subjects who experience a clinical improvement assessed by the MG 
Composite from Baseline (Week 0) to Week 24 where clinical improvement is defined as 
at least a 3-point decrease in the MG Composite 

Percentage of subjects who experience a clinical improvement assessed by MG –
Activities of Daily Living (MG-ADL) from Baseline (Week 0) to Week 24 where clinical 
improvement is defined as at least a 2-point decrease in MG-ADL 


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2.1.3
Exploratory Objectives 
The exploratory objectives for this study are to evaluate the effect of IGIV-C on: 

Percentage of subjects who experience a clinical improvement in QMG score (defined 
above) at Weeks 6, 9, 12, 15, 18, and 21 

Time to first clinical improvement in QMG score (at least a 3-point decrease)

Time to Treatment Failure based on QMG score definition (Section 3.3.3)

Change from Baseline (Week 0) in QMG score to Weeks 6, 9, 12, 15, 18, and 21 

Percentage of subjects who experience a clinical improvement in the MG Composite 
(defined above) to Weeks 6, 9, 12, 15, 18, and 21

Change from Baseline (Week 0) in MG Composite to Weeks 6, 9, 12, 15, 18, 21, and 24

Percentage of subjects who experience a clinical improvement in MG-ADL (defined 
above) to Weeks 9 and 15

Change from Baseline (Week 0) in MG-ADL to Weeks 9, 15, and 24

Change from Baseline in the 15-item MG Quality-of-Life Instrument (MG-QOL 15) to 
Weeks 9, 15, and 24

Myasthenia Gravis Foundation of America (MGFA) postinterventional change in status
at Week 24 relative to Baseline
2.2
Safety Objective
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.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of IGIV-C in subjects with MG who are symptomatic on standard of care 
treatment. Approximately 62 adult subjects will be randomized at approximately 40 global 
study centers.
Subjects who are on standard of care treatment for MG may enroll. Eligibility parameters 
allow monotherapy, dual treatment, or three-drug treatment (i.e., various combinations
consisting of a cholinesterase inhibitor, CS, and an additional immunosuppressant). Subjects 
will be randomly allocated in a 1:1 ratio to receive either IGIV-C or matched placebo every 
three weeks in double-blinded fashion. Randomization will be stratified by sentinel features 
of the subject’s Baseline standard of care MG treatment regimen at the time randomization: 

Regimen includes ONLY cholinesterase inhibitors

Regimen includes CS as the ONLY IMMUNOSUPPRESSANT/
IMMUNOMODULATOR, alone or in combination with other MG medications


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(e.g., a subject on prednisone plus a cholinesterase inhibitor would be in this 
stratum)

Regimen includes ANY NON-CS 
IMMUNOSUPPRESSANT/IMMUNOMODULATOR alone or in combination 
with other MG medications which may include CS (e.g., a subject on 
azathioprine, prednisone, and a cholinesterase inhibitor would be in this stratum)
For those subjects randomized to receive IGIV-C, an initial loading dose of 2 g/kg of body 
weight will be administered after the baseline assessments are complete 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). The initial loading dose (2 g/kg) will be divided on 2 
consecutive days with extension of up to 4 consecutive days to account for
tolerability/weight >80 kg. The subsequent 7 maintenance dosages (1 g/kg) will be infused in 
one day with an extension to 2 consecutive days (divided doses) to account for
tolerability/weight >80 kg. For both loading and maintenance infusions the limit for blinded 
IGIV-C infusion is no more than 80 g/day, corresponding to an 80-kg body weight for a 1 
g/kg per diem dosage.
For those subjects randomized to receive placebo, a sterile 0.9% sodium chloride injection, 
United States Pharmacopeia (USP) or equivalent will be infused at the Baseline/Week 0 Visit 
(Visit1) 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).
The Investigators will hold the subjects’ current background medical regimen constant from 
Screening through the end of the study (Week 24, Visit 9), unless there is a compelling 
emergent medical need to make medication adjustments, the subject discontinues the study 
because criteria for Treatment Failure are met as defined in Section 3.3.3 (after End of Study 
visit assessments are complete), or adverse effects due to other components of the subject’s 
therapy become untenable; in such cases the Medical Monitor must be contacted.
Week 21 (Visit 8) is the time of the last investigational product (IP) maintenance dosage. 
Week 24 (Visit 9) will constitute the primary endpoint time point for analysis because this 
timing allows an opportunity to assess the effect of the final IP infusion made at Week 21 
(Visit 8). Week 24 (Visit 9) will serve as the final End of Study Visit.
A schematic of the overall study design and essential activities is shown in Figure 3-1. The
Schedule of Study Procedures is provided in Appendix 1. Tools for assessing MG are 
provided in Appendix 2 to Appendix 6, and specific safety monitoring in Appendix 7 and
Appendix 8.
Worsening of MG symptoms
The intent is that subjects will receive their original randomized treatment assignment of IP 
through the entire Treatment Period (i.e., through Week 21 [Visit 8]). Subjects will remain on 
IP until at least Week 9 (Visit 4). No premature discontinuations on the basis of the a priori


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defined Treatment Failure (Section 3.3.3) are allowed until the subject receives a minimum 
of 3 complete doses of IP, which includes the initial loading dose and the first two 
maintenance doses irrespective of the QMG scores measured at Week 3 and Week 6 (Visit 2 
and Visit 3), and the subject is assessed at Week 9 (Visit 4) with regard to continuation of 
worsening.
For example, a subject with a QMG increase of 4 points or more at Week 3 (Visit 2) or 
Week 6 (Visit 3) must have confirmation of this QMG increase at the next, subsequent
scheduled visit (i.e., Week 6 [Visit 3] and Week 9 [Visit 4], respectively). However, subjects 
will not be removed from study until at or after Week 9 for reasons of QMG score continuing 
to meet the criteria for Treatment Failure (Section 3.3.3) in order to allow time for the 
investigational medicinal product to potentially produce a beneficial effect.
At Week 9 (Visit 4) through Week 21 (Visit 8), if the subject suffers a worsening of his/her 
MG symptoms with an increase in QMG of 4 points or more, as defined in Section 3.3.3
“Definition of Treatment Failure Due to MG Worsening”, and this worsening (increase 
in QMG of 4 points or more) is confirmed at the next scheduled consecutive visit, the subject 
will be discontinued from the study. 


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Figure 3-1 Overall Study Schema


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3.2
Selection of Study Population
Eligible participants for this study will include adult subjects with a confirmed diagnosis of 
generalized MG who are receiving standard of care MG treatment, but continue to have 
symptoms of MG as demonstrated by a QMG ≥ 10 points. There is a minimum time 
interval prior to Screening during which no change in dosage is allowed for MG 
medications predicated on medication class as delineated below (Inclusion #6). 
Following Screening, the subject’s standard of care background regimen must not 
change in terms of medications used or dosage. The only exception would be an urgent 
medical need.
3.2.1
Inclusion Criteria
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study:
1. Male or female, ages 18 to 85 years
2. Anti-AChR antibody positive
3. Confirmed diagnosis of generalized MG. Historically, subjects may have previously had 
the Myasthenia Gravis Foundation of America (MGFA) Class II, III, IV, or V.
4. MGFA classification of Class II, III, or IVa inclusive at Screening.
5. QMG score ≥ 10 at Screening. Note: Subjects who only have a history of ocular MG may 
not enroll.
6. 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): 

Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior 
to Screening and no immunosuppressants

Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior 
to Screening and/or only one of the following:
o
Prednisone (up to 60 mg/day or equivalent) for at least two months prior to 
Screening, or
o
Azathioprine for at least 6 months prior to Screening, or
o
Mycophenolate mofetil for at least 6 months prior to Screening, or
o
Methotrexate for at least 6 months prior to Screening, or
o
Cyclosporine or tacrolimus for at least 3 months prior to Screening

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:
o
Azathioprine for at least 6 months prior to Screening, or
o
Mycophenolate mofetil for at least 6 months prior to Screening, or
o
Methotrexate for at least 6 months prior to Screening, or
o
Cyclosporine or tacrolimus for at least 3 months prior to Screening
7. Subjects must be willing and able to provide written informed consent. 
8. Subjects must be willing to comply with all aspects of the clinical trial protocol.


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3.2.2
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study:
1. Have received cyclophosphamide or any other immunosuppressive agent apart from the 
ones allowed per inclusion criteria within the past 6 months
2. Any change in MG treatment regimen between Screening (Week -3, Visit 0) and Baseline 
(Week 0, Visit 1)
3. Greater than two (>2) point change in QMG score, increased or decreased, between 
Screening (Week -3, Visit 0) and Baseline (Week 0, Visit 1)
4. Any episode of myasthenic crisis in the one month prior to Screening
5. 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)
6. Thymectomy within the preceding six months
7. Rituximab, belimumab, eculizumab or any monoclonal antibody used for 
immunomodulation within the past 12 months
8. Have received immune globulin (Ig) treatment given by IV, subcutaneous, or 
intramuscular route within the last 3 months
9. Current known hyperviscosity or hypercoagulable state
10. 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)
11. Plasma exchange (PLEX) performed within the last 3 months
12. History of non-response to IVIg when used in maintenance therapy of the subject’s MG, 
as judged by the Investigator
13. Any comorbid condition that in the opinion of the Investigator would put the subject at 
undue safety risk or compromise the ability of the subject to participate in the trial or the 
scientific integrity of the study
14. Inadequate venous access to support repeated intravenous infusions
15. History of anaphylactic reactions or severe reactions to any blood-derived product
16. History of intolerance to any component of the IP 
17. Documented diagnosis of thrombotic complications to polyclonal IVIg therapy in the past
18. History of recent (within the last year) myocardial infarction or stroke
19. Uncontrolled congestive heart failure; embolism; or historically documented (within the 
last year) electrocardiogram (ECG) changes indicative of myocardial ischemia or atrial 
fibrillation   
20. History of chronic alcoholism or illicit drug abuse (addiction) in the 12 months preceding 
the Screening/Week -3 (Visit 0)
21. Active psychiatric illness that interferes with compliance or communication with health 
care personnel
22. Females of child-bearing potential who are pregnant or have a positive serum pregnancy 
test (beta-human chorionic gonadotropin [β-HCG]-based assay)
23. Females who are breastfeeding


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24. Females of child-bearing potential who are unwilling to practice a highly effective 
method of contraception (oral, injectable or implanted hormonal methods of 
contraception, placement of an intrauterine device or intrauterine system, condom or 
occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or 
true abstinence*) throughout the study.
* True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods], declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception.)
25. Currently receiving, or having received within 1 month prior to the Screening/Week -3 
(Visit 0), any investigational medicinal product or device. In the case of an 
investigational medicinal product trial, at least five half-lives (if known) must have 
elapsed prior to Screening.
26. Known Immunoglobulin A (IgA) deficiency and anti-IgA serum antibodies
27. 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)
28. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding 
more than 2.5 times the ULN for the expected normal range for the testing laboratory.
29. Hemoglobin (Hb) levels <9 g/dL
30. Any medical condition which makes the clinical trial participation unadvisable or which 
is likely to interfere with the evaluation of the study treatment and/or the satisfactory 
conduct of the clinical trial according to the Investigator’s judgment. Any factor that in 
the opinion of the Investigator would compromise the ability of the subject to complete 
the trial.
3.3
Study Time Periods and Definitions
3.3.1
Investigational Product Treatment Period
Subjects will receive a total of 8 doses of IP, which includes one initial loading dose at the 
Baseline (Week 0) Visit (after Baseline assessments are complete) and 7 maintenance doses 
at Weeks 3 through 21 (Visits 2 through 8), inclusive.
3.3.2
Worsening of MG Symptoms
All subjects will remain in the study until at least Week 9 (Visit 4) is completed. No 
premature discontinuation of IP administration is to be made for reasons of Treatment Failure 
(defined in Section 3.3.3) until the subject receives at least a total of 3 complete doses of the 
IP, which includes the initial loading dose and the first two maintenance doses irrespective of 
the QMG scores measured at Week 3 and Week 6 (Visit 2 and Visit 3). 
At Week 9 (Visit 4) through Week 21 (Visit 8), if the subject suffers a worsening of his/her 
MG symptoms defined as a QMG increase ≥ 4 points relative to Baseline (Week 0), and this 
worsening (increase in QMG of 4 points or more) is confirmed at the next scheduled 
consecutive visit the subject will discontinue from the study. The earliest withdrawal for 
Treatment Failure will be at Week 9 and would occur only if QMG score is increased by 4 
points or more (relative to Baseline) at both Week 6 (Visit 3) and Week 9 (Visit 4).


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3.3.3
Definition of Treatment Failure Due to MG Worsening
During the study, MG worsening will be defined as:

QMG increase by ≥4 points relative to Baseline/Week 0
If a subject experiences worsening in QMG score fulfilling the criterion above at or after 
Week 9, and this worsening (increase in QMG of 4 points or more) is confirmed at the next 
scheduled consecutive visit, the subject will be considered a Treatment Failure and will be 
discontinued from the study (at completion of the visit where confirmation of worsening is 
demonstrated). 
If a subject experiences worsening in QMG score fulfilling the criterion above at Week 3
(Visit 2) or Week 6 (Visit 3) and the QMG increase by ≥ 4 points relative to Baseline is 
confirmed at the next scheduled visit (i.e., confirmation at Week 6 [Visit 3] or Week 9 
[Visit 4], respectively), and this ≥ 4-point QMG worsening is maintained through Week 9 
(Visit 4) the subject will be considered a Treatment Failure. 
A subject will not be discontinued from the study for reasons of Treatment Failure until the 
Week 9 Visit or later as described in Section 3.3.2.
3.3.4
Myasthenic Crisis
Myasthenic (or MG) crisis will be defined as an episode of worsening (as defined in 
Section 3.3.2) which requires hospitalization. Hospitalizations solely for socioeconomic 
reasons would not fulfill criteria for MG crisis. Also see Early Termination Visit and Section 
3.11.
3.4
Treatments
3.4.1
Treatments to Be Administered
3.4.1.1
Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C)
Immune Globulin Injection (Human), 10%, Caprylate/Chromatography Purified (IGIV-C) is 
the active IP for this study, which is a marketed product. IGIV-C glass vials may be supplied 
in the vial sizes of 10 mL, 25 mL, 50 mL, 100 mL, and 200 mL. Detailed information 
regarding IGIV-C can be found in the IGIV-C Investigator Brochure.
Administration of IP will be via the IV route, and will be administered in a double-blinded 
fashion. The unblinded pharmacist or designee will prepare the IP to maintain the blind for 
all parties during infusions and study assessments. Reference the Pharmacy Manual for 
additional details.
3.4.1.2
Placebo
Sterile 0.9% sodium chloride injection, USP (0.9% NaCl, USP) or equivalent will be used as 
placebo to maintain the blind. 


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3.4.1.3
Labeling of Investigational Products
Labeling will be according to the requirements of local law and legislation. Label text will be 
approved according to Grifols Therapeutics Inc. procedures, and a copy of the labels will be 
made available to the study site upon request.
3.4.1.4
Storage of Investigational Products
IP must be stored in a secure area accessible to the unblinded pharmacist or designee 
responsible for the preparation and dispensing of IP.
Active IP (IGIV-C) must be stored at temperatures of 2°C to 8°C (36°F to 46°F). Do not 
freeze. The unblinded pharmacist or designee is responsible for maintaining storage 
temperature records and for immediately reporting deviations in temperature to the unblinded 
study monitor. Reference the Pharmacy Manual for additional details.
3.4.1.5
Preparation of Investigational Products
The volume (i.e., total infusion dose administered) of IP to be prepared for each IV infusion 
will be individualized for each subject based on body weight, and the protocol specified 
loading dose of 2 g/kg divided on 2 consecutive days starting after the randomization at 
Baseline (Week 0), followed by maintenance doses of 1 g/kg administered over 1 day every 
three weeks until Week 21 (Visit 8). Infusion solution will be visually masked to maintain 
the blind.
Note that the loading dosage is divided over 2 days as standard infusion time; however, 
extensions up to 4 days are allowed for tolerability issues or higher weight, i.e., limit for 
IGIV-C infusion is no more than 80 g/day (corresponding to 80 kg body weight). Similarly, 
the maintenance dosage is infused in 1 day as standard; however, extension is allowed for 
divided dosage over 2 days for tolerability issues or higher weight, i.e., limit for IGIV-C 
infusion is no more than 80 g/day (corresponding to 80 kg body weight).
Subjects randomized to receive placebo will receive 0.9% sodium chloride injection, USP or 
equivalent, visually masked and at a volume approximate to that required for the appropriate 
weight-based dose of IGIV-C in order to maintain blinding of the subject, caregivers, 
Investigator, and assessors. The IP will be prepared by the unblinded study site pharmacist or 
designee.
The unblinded pharmacist must inspect IGIV-C visually before preparing for administration 
to subjects. The solution must not be used if turbid or if it contains visible particles. Solution 
which has been frozen should not be used.
Reference the Pharmacy Manual for detailed IP preparation and administration instructions.


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3.4.1.6
Accountability for Investigational Products
IP is to be used only for the study in accordance with the directions given in this protocol. 
The study pharmacist or designee is responsible for the distribution of the IP in accordance 
with directions given in the protocol and Pharmacy Manual.
The unblinded study pharmacist or designee is responsible for maintaining accurate records 
of the IP for his/her site. IP inventory/dispensing documentation verifying the receipt, 
dispensing, destruction or return must be maintained and kept current by the pharmacist. The 
inventory must be made available for inspection during the study by the unblinded monitor. 
IP supplies must be accounted for by the monitor and inventory/dispensing logs must be 
verified by the monitor prior to IP destruction. Written documentation from Grifols or 
designee of any used and unused inventory is required. At the end of the study, a copy of the 
inventory/dispensing log(s) will be retrieved by the monitor and returned to Grifols 
Therapeutics Inc.
3.4.2
Rationale for Selection of Doses/Timing of Investigational Product in the 
Study
3.4.2.1
Selection of IGIV-C Dose and Dosing Interval in the Study
The optimal dose of IVIg for MG maintenance dosing is still unclear; however, recent studies 
have supported a loading dose of 2 g/kg administered in as little as two consecutive daily 
doses of 1 g/kg each with no increase in side effects as compared to the longer dosing period 
of 3 to 5 days (7, 9, 11, 32, 35). Maintenance dosage of IGIV-C in CIDP has been well 
tolerated at 1 g/kg administered over 1 to 2 days every three weeks and has regulatory 
approval for this indication/dosage in both North America and Europe.
Based on the above, subjects will receive a loading IGIV-C dose of 2 g/kg of body weight 
followed by maintenance dosages at 3-week intervals at a dose of 1 g/kg of body weight. 
3.4.3
Method of Assigning Subjects to Treatment Groups
This is a randomized, double-blind, placebo-controlled study. Subjects will be randomized in 
a 1:1 ratio via Interactive Web Response System (IWRS) into IGIV-C treatment group and 
Placebo treatment group to receive either IGIV-C or matching placebo every three weeks in a 
double-blind fashion via IV administration. Each subject’s IGIV-C dose will be 
individualized based on the subject’s body weight and the protocol specified loading dose of 
2 g/kg over 2 consecutive days and maintenance dosage of 1 g/kg over 1 day every three 
weeks through Week 21 (Visit 8). Therefore, each subject’s infusion volume and duration of 
the infusion will vary from subject to subject, and must be carefully prepared by the 
unblinded pharmacist who will prepare IP consisting of either IGIV-C or an equivalent 
volume of 0.9% sodium chloride injection. Note that for the loading dosage, 2 days is 
standard (2-4 days is allowed as an extension for tolerability issues or higher weight, i.e., 
limit for IGIV-C infusion is no more than 80 g/day [corresponding to 80 kg body weight]). 
Similarly, the maintenance dosage is given over 1 day as the standard time interval (divided 
dosage over 2 days is allowed for tolerability issues or higher weight, i.e., limit for IGIV-C 
infusion is no more than 80 g/day [corresponding to 80 kg body weight]).


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3.4.3.1
Subject Numbering
Within each study site, subjects in the study will receive a consecutive subject number. 
Subject numbers are generated beginning with the study center number (3 digits, assigned by 
the Sponsor) followed consecutively with a unique number for each subject (4 digits, 
including leading zeros). For example, if the Investigator’s center number is 301, subject 
number will be 3010001, 3010002, 3010003, etc., in consecutive order. Subject numbers, 
once assigned, will not be reused at any center.
3.4.3.2
Blinding
This is a double-blind, placebo-controlled study. Placebo infusion will be visually 
indistinguishable from IGIV-C to maintain blinding. The unblinded pharmacist or designee 
will prepare all IP infusion bags with no visual differences between IGIV-C and placebo and 
cover with a non-transparent blinding bag cover. 
Additionally, results of the central laboratory analysis of immunoglobulin G (IgG) levels will 
not be shared with the Investigator, blinded study staff, clinical research organization (CRO) 
or blinded Sponsor personnel involved with study conduct.
3.4.3.3
Administration and Timing of Investigational Products for Each Subject
IGIV-C (or placebo) will be administered as a loading dose of 2 g/kg divided over 2 
consecutive days starting after randomization at Week 0 (Visit 1), followed by maintenance 
doses of 1 g/kg over 1 day every three weeks through Week 21 (Visit 8). Note that for the 
loading dosage, 2 days are standard (2-4 days are allowed as an extension for tolerability 
issues or higher weight, i.e., limit for IGIV-C infusion is no more than 80 g/day 
[corresponding to 80 kg body weight]). Similarly, the maintenance dosage is administered
over 1 day as the standard time interval (divided dosage over 2 days is allowed for 
tolerability issues or higher weight, i.e., limit for IGIV-C infusion is no more than 80 g/day 
[corresponding to 80 kg body weight]). Infusion administration, including infusion rate, is 
provided in the Pharmacy Manual.
In the event that the subject is not able to tolerate the set infusion rate, the rate may be 
decreased for better tolerability. The initial and final infusion rates will be recorded.
3.4.3.4
Preparation and Handling of Investigational Products
Blinded IP (IGIV-C or placebo) should be infused using a separate line by itself, without 
mixing with other IV fluids or medications that the subject might be receiving. The IP 
infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9% sodium chloride 
injection. Do not flush with heparin.


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3.4.3.5
Treatment Compliance
Reasons for any deviation from the administration of less than 100% of the IP dose as 
prepared by the pharmacist or designee must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records.
All IV infusions will be administered at the study site under the supervision of the treating 
Investigator or designee.
3.5
Prior and Concomitant Therapy
Concomitant medications must be recorded in the eCRF, including the trade or generic 
names of the medication, the dose, the route of administration, and the duration of the 
medication (frequency).
Diphenhydramine, acetaminophen/ibuprofen, and non-steroidal anti-inflammatory drugs are 
allowed during the trial as pre-medications for study drug infusions. These and any other 
concomitant medication taken during the study period must be documented in the subject’s 
medical records and the eCRF.
3.5.1
Prohibited Medications Prior to Study Participation
The following medications are prohibited for the specified timeframe prior to study 
participation.

Immune globulin treatment given by IV, subcutaneous or intramuscular route within the 
last 3 months

Rituximab, belimumab, eculizumab, or use of any monoclonal antibody for 
immunomodulation within the past 12 months

Cyclophosphamide or immunosuppressive agents other than those allowed per inclusion 
criteria within the past 6 months

PLEX performed within the last 2 months

Anti-coagulation therapy at the time of Screening (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)

Any investigational drugs within 30 days of Screening (or five half-lives if known) 
3.5.2
Prohibited Concomitant Medications during the Study
Use of the following medications is prohibited during the study or during the specified 
timeframe: 

Any IgG therapy other than IGIV-C provided for this study

Any investigational drugs which are not part of this study

Introduction of new immunosuppressant(s) or other drugs for treatment of MG that the 
subject was not already taking at Screening


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
Rituximab, belimumab, eculizumab, use of any monoclonal antibody for 
immunomodulation or any other investigational agent for treatment of MG

Live viral vaccines (e.g., measles, mumps, rubella)

PLEX
3.5.3
Restricted Concomitant Medications during the Study
This section describes medications that are restricted but not prohibited during the study 
participation:

Any dose change in concomitant immunosuppressant therapy, corticosteroids, or standard 
of care MG treatment medications during the study is not allowed unless there is a real 
medical necessity for safety reasons in the Investigator’s opinion.

Any change in acetylcholinesterase inhibitor (e.g., Mestinon® [pyridostigmine]) dose 
during the study is not allowed unless there is a real medical necessity for safety reasons 
in the Investigator’s opinion. 
In case of a compelling, emergent medical need to make MG medication adjustments during 
study, the Medical Monitor must be contacted.
Use of medications known to potentially worsen MG is discouraged (unless medically 
required) including telithromycin, fluoroquinolones (e.g., Ciprofloxacin and Levofloxacin), 
azithromycin, aminoglycoside antibiotics, botulinum toxin, quinine, quinidine, procainamide, 
D-penicillamine, and β-blockers. For patients entering study already on β-blockers, continued 
use of β-blockers is allowed if medically needed; de novo use (initiation of β-blocker 
treatment for the first time) while on study is discouraged.
3.6
Efficacy Study Variables 
3.6.1
Primary Variable
The primary endpoint is improvement in MG symptoms as measured by the mean change in 
QMG score from Baseline (Week 0) to Week 24 as compared to placebo.
3.6.2
Secondary Variables
Secondary efficacy variables assessed in this study are:

Percentage of subjects who experience a clinical improvement assessed by QMG score 
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 
3-point decrease in QMG score

Percentage of subjects who experience a clinical improvement assessed by the MG 
Composite from Baseline (Week 0) to Week 24 where clinical improvement is defined as 
at least a 3-point decrease in the MG Composite 

Percentage of subjects who experience a clinical improvement assessed by MG-ADL
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 
2-point decrease in MG-ADL


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3.6.3
Exploratory Variables
The exploratory objectives for this study are to evaluate the effect of IGIV-C on: 

Percentage of subjects who experience a clinical improvement in QMG score (defined 
above) at Weeks 6, 9, 12, 15, 18, and 21 

Time to first clinical improvement in QMG score (at least a 3-point decrease)

Time to Treatment Failure based on QMG definition (Section 3.3.3)

Change from Baseline (Week 0) in QMG score to Weeks 6, 9, 12, 15, 18, and 21

Percentage of subjects who experience a clinical improvement in the MG Composite 
(defined above) to Weeks 6, 9, 12, 15, 18, and 21

Change from Baseline (Week 0) in MG Composite to Weeks 6, 9, 12, 15, 18, 21, and 24

Percentage of subjects who experience a clinical improvement in MG-ADL (defined
above) to Weeks 9 and 15

Change from Baseline (Week 0) in MG-ADL to Weeks 9, 15, and 24

Change from Baseline in the MG-QOL 15 to Weeks 9, 15, and 24

MGFA postinterventional change in status at Week 24 relative to Baseline
3.6.4
Quantitative Myasthenia Gravis Score (QMG)
The MGFA, Inc. Task Force on Clinical Research Standards recognizes the utility of the 
QMG score in prospective clinical trials in MG (34) complemented by additional tools such 
as the MG Composite. The QMG is easy to administer by clinical evaluators and/or 
physicians in approximately 30 minutes with minimal equipment to measure spirometry and 
muscle strength testing. An average 3-point improvement in QMG score indicates clinically 
meaningful improvement in terms of minimal clinically important difference and precedent 
set by endpoints in other MG studies (37, 38). Subjects receiving cholinesterase inhibitors 
will be instructed not to take medication 12 hours prior to QMG.
QMG Test Items are listed in Appendix 3.
3.6.5
MG Composite Scale
The MG Composite scale takes less than five minutes to complete, and is made up of three 
ocular, three bulbar, one respiratory, one neck, and two limb items (39, 40).
The task force on MG study design of the medical scientific advisory board of the MGFA 
recommends using the MG Composite as the quantitative measure for determining 
improvement and worsening for subjects with generalized MG disease. A 3-point 
improvement in MG Composite score reliably indicates clinical improvement. A 3-point 
improvement in the MG Composite score also appears to be meaningful to the patient (41).
The MG Composite items are listed in Appendix 4.


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3.6.6
MG-ADL
The MG-ADL is an 8-item, patient reported (or Investigator administered) questionnaire that 
is completed to assess the symptoms and activities in MG (42-44). A 2-point improvement in 
the MG-ADL indicates clinical improvement (42).
The questionnaire and scoring is provided in Appendix 5. 
3.6.7
15-item MG Quality-of-Life Instrument (MG-QOL 15)
MG symptoms significantly impact quality of life (QOL) particularly in aspects of physical 
functioning. The 15 items on the MG-QOL 15 are derived from mobility, symptoms, general 
contentment, and emotional well-being categories assessed by the patient over the past few 
weeks. All individual items related to degree of disease-related impairment are rated on a 
Likert scale ranging from “not at all” (score 0 points) to “very much” (score 4 points) with 
higher scores indicating greater negative impact (worse disease) (45-47).
The MG-QOL 15 and scoring are provided in Appendix 6.
3.6.8
MGFA Postinterventional Change in Status
An MGFA postinterventional change in status relative to Baseline will be evaluated at Week 
24 (Visit 9) wherein the Investigator will classify the patient as: (I) Improved, defined as a 
substantial decrease in pretreatment clinical manifestations of MG, QMG decrease ≥ 3 
points; (U) Unchanged, defined as no substantial change in pretreatment clinical 
manifestations of MG; (W) Worse, defined as a substantial increase in pretreatment clinical 
manifestations of MG, QMG increase ≥ 3 points.
3.7
Safety Study Variables
The following safety variables will be assessed in this study:

Adverse events (AEs), suspected adverse drug reactions (Suspected ADRs), adverse 
reactions (ARs), serious AEs (SAEs), and discontinuations due to AEs and SAEs
(including myasthenic crisis)

Vital Signs (temperature [T], respiratory rate [RR], heart rate [HR], systolic blood 
pressure [SBP] and diastolic blood pressure [DBP]); during infusions vital signs will be 
carefully monitored.

Physical examinations: physical exams will be recorded as normal or abnormal, 
according to the physician’s judgment criteria, and findings will be recorded.

Blood chemistry and Hematology

Thromboembolic events (TEs) and hemolysis events
3.7.1
Thromboembolic Events Risk
During the clinical trial, TE risk will be determined by the Investigator or study staff using 
the measurement of D-dimer blood levels, the Wells clinical prediction rule for both deep 


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venous thrombosis (DVT) and for pulmonary embolism (PE), and evaluation of clinical signs 
and symptoms of TEs (such as pain, dyspnea, discoloration [paleness or redness] in lower 
extremities). Monitoring will be performed at Screening, Baseline/Week 0 (Visit 1) prior to 
infusion, Visit 1 after the first loading infusion, at the time when the last loading infusion is 
complete, and at Week 3 (Visit 2), Week 6 (Visit 3), and Week 15 (Visit 6), after the 
completion of each maintenance dosage.
Procedures for the monitoring of TE risk are provided in Appendix 7.
3.7.2
Hemolysis
Blood assessments including whole blood Hb, serum free Hb, haptoglobin, lactate 
dehydrogenase (LDH), direct antiglobulin test (DAT), absolute reticulocyte count (ARC), red 
blood count (RBC), hematocrit, total (TBL) and indirect bilirubin, and blood smear, and 
urinalysis including urinary sediment and hemoglobinuria will be conducted for hemolysis 
detection at Baseline (Week 0 [Visit1], prior to infusion), Week 0/Visit 1 (after the first 
loading infusion), at the time when the last loading dose infusion is complete, and at Week 3 
(Visit 2), Week 6 (Visit 3), and Week 15 (Visit 6), after the completion of each maintenance 
dosage. In addition, clinical parameters including red/dark urine, jaundice, as well as other 
signs and symptoms of anemia (such as pallor or tachycardia) will be assessed at 
Baseline/Week 0 (Visit 1) and the time points specified above. Hemolysis laboratory 
assessments will also be performed 7 days post loading dose infusion at Baseline (Week 0) 
and 7 days post maintenance infusion at Weeks 3 (Visit 2), 6 (Visit 3), and 15 (Visit 6).
Procedures for hemolysis detection are provided in Appendix 8.
3.8
Assessments
3.8.1
Assessment Periods
The study consists of a three-week Screening period during which assessments are performed 
to determine eligibility. Eligible subjects will have Baseline assessments performed, and be 
randomized at Week 0 (Visit 1). At this time, an initial loading dose of blinded IP will be 
administered at a dose of 2 g/kg divided on 2 consecutive days starting after randomization. 
Maintenance infusions of blinded IP will be given at doses of 1g/kg over 1 day every three 
weeks through Week 21 (Visit 8). Note that the loading dosage is divided over 2 days as 
standard infusion time; however, extensions to 4 days are allowed for tolerability issues or 
higher weight, i.e., limit for IGIV-C infusion is no more than 80 g/day (corresponding to 
80 kg body weight). Similarly the maintenance dosage is infused in 1 day as standard; 
however, extensions for divided dosage over 2 days are allowed for tolerability issues or 
higher weight, i.e., limit for IGIV-C infusion is no more than 80 g/day (corresponding to 
80 kg body weight).
3.8.2
Observations and Measurements
During the course of the study, subjects will receive scheduled general physical 
examinations, neurological assessments of strength and endurance, symptom questionnaires, 
quality of life assessments, and laboratory evaluations.


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The following is a description of the procedures/assessments to take place at each study visit.
Each MG assessment should be performed by the same clinical staff member whenever 
possible. See the Schedule of Study Procedures in Appendix 1 for a summary of study visits 
and the procedures conducted at each visit. 
3.8.2.1
Overview of Screening, Treatment and Post infusion Follow-up Phases
All subjects will start their participation in the study upon the signing of the informed 
consent form (ICF). If applicable, a legally authorized representative may provide informed 
consent on behalf of the subject (see Section 7.4).
Subjects deemed eligible based on screening evaluations will complete the Baseline 
assessments, thereafter initiating treatment. Subjects will continue with assessments for 24
weeks, with scheduled assessments at Week 0 (Visit 1) (Baseline, post-Baseline loading 
infusion over 2 days), followed by assessments and maintenance dosages every 3 weeks 
through Week 24 (Visit 9). Visits/procedures and assessments should be scheduled at the 
protocol specified study day ± 3 days.  
3.8.2.2
Screening: Week -3 (Visit 0)
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 
12 hours prior to the Screening/Week -3 (Visit 0) to assure accurate assessment of the QMG. 
The following procedures and assessments will be conducted during the Screening/Week -3 
(Visit 0) (Note: Screening is considered Visit 0; assessments are to be conducted within 3 
weeks of Baseline/Week 0 [Visit 1]):

Informed consent prior to the initiation of Screening procedures

Inclusion/exclusion criteria review

Medical history including demographics and prior/concomitant diseases

Full physical exam (excluding breast and genitourinary areas)

Height

Weight (Screening will be used to calculate IP infusion dose for Visits 1-3)

Vital signs including temperature (T), respiration rate (RR), heart rate (HR), systolic 
blood pressure (SBP), and diastolic blood pressure (DBP)

Laboratory assessments (see Section 3.8.3) 
-
Blood 
◦
Serum Pregnancy Test (β-HCG) (women of child-bearing potential only; results 
must be negative for the subject to continue in the study)
◦
Chemistry 
◦
Hematology
◦
D-dimer  
◦
AChR antibodies (See Section 3.8.3.4)

QMG score

MG Composite Score

MGFA Clinical Classification

Thromboembolic events risk monitoring assessment 

AEs with onset after informed consent is signed 


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
Prior and concomitant medications 
3.8.2.3
Baseline, Randomization, and Loading Dose Infusion: Week 0 (Visit 1)
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 
12 hours prior to the Baseline/Week 0 (Visit 1) to assure accurate assessment of the QMG.
All Screening laboratory results and assessments must be available and all inclusion and 
exclusion criteria must have been satisfied prior to initiating treatment. For eligible subjects, 
following completion of all Baseline assessments, IGIV-C (or placebo) will be administered 
as a loading dose of 2 g/kg given in divided doses on two consecutive days.
The listed procedures and assessments will be conducted at Baseline/Week 0 (Visit 1). 
Baseline assessments will be immediately followed by randomization and initiation of IP 
loading infusions.
Baseline, Prior to Randomization

Inclusion/Exclusion criteria review

Physical examination (excluding breast and genitourinary areas)

Vital signs including T, RR, HR, SBP, and DBP

Laboratory assessments (see Section 3.8.3):
-
Urine 
◦
Urine sediment and measuring of hemoglobinuria/hematuria  
◦
Urine pregnancy test for women of childbearing potential only (to be eligible 
urine pregnancy test must be negative)
-
Blood 
◦
D-dimer  
◦
Chemistry 
◦
Hematology
◦
Whole blood Hb, RBC, hematocrit (from hematology specimen, see Section 
3.8.3), ARC, blood smear for erythrocyte morphology, serum free Hb, 
haptoglobin, LDH, DAT, TBL (TBL from chemistry specimen, see Section 3.8.3) 
and indirect bilirubin (Hemolysis assessment Appendix 8)
◦
IgG levels
◦
Quantitative/semi-quantitative binding, blocking, and modulating AChR 
antibodies 
◦
Retain samples for virus safety testing as detailed in Section 3.8.3.3 and Table 3-1
(These retention samples will be tested only if the subject exhibits clinical signs 
and symptoms consistent with hepatitis A, hepatitis B, hepatitis C, human 
immunodeficiency virus (HIV), or parvovirus B19 infection while participating in 
the study. These samples will be retained until all analyses in support of the study 
are complete.)

QMG score (to be eligible QMG score must be within ≤ 2 points of Screening value [a 3-
point change is exclusionary])

MG Composite

MG-QOL 15

MG-ADL


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
MGFA Clinical Classification

Thromboembolic events risk monitoring assessment (Appendix 7) (prior to IP infusion)

AEs (includes clinical observation of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia etc]) 

Prior and concomitant medications 
RANDOMIZATION 

Randomization will occur via IWRS once all Baseline assessments are performed and 
eligibility is confirmed. A randomization number will be assigned to each subject based 
on a 1:1 randomization schedule.
POST-BASELINE/POST-RANDOMIZATION LOADING DOSE INFUSION 

Unblinded Pharmacist or designee, to prepare and dispense the IP per randomization 
assignment and the Pharmacy Manual

Administer the loading infusion dosage (blinded active or placebo) of 2 g/kg divided over 
2 days (per Pharmacy Manual). Note that for the loading dosage 2 days is standard (2-4 
days is allowed as an extension for tolerability issues or higher weight, i.e., limit for 
IGIV-C infusion is no more than 80 g/day [corresponding to 80 kg body weight]).

During the infusions, abbreviated vital signs (HR, SBP, and DBP) will be recorded just 
before the start of each infusion (within 15 ± 5 minutes before the beginning of each 
infusion), 30 ± 10 minutes after starting infusion, and immediately after infusion 
completes.

Hemolysis evaluation (laboratory parameters: Hb, hematocrit, RBC, blood smear, serum 
free-Hb, haptoglobin, LDH, DAT, ARC, total and direct/indirect bilirubin; urine for 
urinary sediment and hemoglobinuria/hematuria), and Thromboembolism evaluation 
(Wells score and D-dimer) will be performed at the end of the first infusion of the loading 
dose, and at the time when last loading infusion is complete. Appendix 7 and Appendix 8
provide details.

For each infusion, documentation of total infusion volume prepared (as received from 
pharmacist or designee), total time to infuse, total volume infused, and, if necessary, any 
infusion interruption with explanation

AEs (includes clinical observation of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia etc]) 

Concomitant medications

Additional hemolysis evaluation (laboratory parameters) will be performed 7 days post 
loading dose infusion
3.8.2.4
Investigational Product Maintenance Phase: Weeks 3 and 6 (Visits 2 and 3)
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 
12 hours prior to Weeks 3 and 6 (Visits 2 and 3) to assure accurate assessment of the QMG. 
At Weeks 3 and 6 (Visits 2 and 3), the following will be performed:

QMG score to be assessed pre-infusion


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
MG Composite to be assessed pre-infusion

Vital signs including T, RR, HR, SBP, and DBP (pre-infusion)

Unblinded Pharmacist or designee, to prepare and dispense the IP per randomization 
assignment and Pharmacy Manual
-
Note: Screening subject weight is used for IP dose calculations for Visits 1 to 3.

Administer the maintenance dosage (blinded active or placebo) of 1 g/kg over 1 day (per 
Pharmacy Manual). Note that the maintenance dosage is given over 1 day as the standard 
time interval (divided dosage over 2 days is allowed for tolerability issues or higher 
weight, i.e., limit for IGIV-C infusion is no more than 80 g/day [corresponding to 80 kg 
body weight]).

During the infusions, abbreviated vital signs (HR, SBP, and DBP) will be recorded just 
before the start of each infusion (within 15 ± 5 minutes before the beginning of each 
infusion), 30 ± 10 minutes after starting infusion, and immediately after infusion 
completes.

Hemolysis evaluation (laboratory parameters: Hb, hematocrit, RBC, blood smear, serum 
free-Hb, haptoglobin, LDH, DAT, ARC, total and direct/indirect bilirubin; urine for 
urinary sediment and hemoglobinuria/hematuria), and Thromboembolism evaluation 
(Wells score and D-dimer) will be performed after each maintenance infusion dosage is 
entirely completed. Appendix 7 and Appendix 8 provide details.

For each infusion, documentation of total infusion volume prepared (as received from 
pharmacist or designee), total time to infuse, total volume infused, and, if necessary, any 
infusion interruption with explanation

AEs (includes clinical observation of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia etc])

Concomitant medication

Additional hemolysis evaluation (laboratory parameters) will be performed 7 days post 
maintenance infusion
3.8.2.5
Investigational Product Maintenance Phase: Week 9 (Visit 4)
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 
12 hours prior to Week 9 (Visit 4) to assure accurate assessment of the QMG. At Week 9 
(Visit 4), the following will be performed:
Assessments to be performed pre-infusion:

Full physical examination (excluding breast and genitourinary areas)

Weight (to be used to calculate IP infusion dosage for the scheduled visit and subsequent 
IP infusions until the next scheduled weight measurement)

Note: Subject weight collected at Visit 4 is used for IP dose calculations for 
Visit 4 and Visit 5.

Vital signs including T, RR, HR, SBP, and DBP

Clinical laboratory assessments drawn pre-infusion (see Section 3.8.3)

Hematology

Chemistry


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
Blood for IgG (trough) (data will be assessed centrally and not provided to 
centers/Sponsor until the end of the study due to the potential for unblinding)

Quantitative/semi-quantitative binding, blocking, and modulating AChR antibodies

QMG score to be assessed pre-infusion

MG Composite to be assessed pre-infusion

MG-QOL 15 to be assessed pre-infusion

MG-ADL to be assessed pre-infusion
IP Infusion:

Unblinded Pharmacist or designee, to prepare and dispense the IP per randomization 
assignment and Pharmacy Manual
-
Note: Subject weight this visit is used for IP dose calculation.

Administer the maintenance dosage (blinded active or placebo) of 1 g/kg over 1 day (per 
Pharmacy Manual). Note that the maintenance dosage is given over 1 day as the standard 
time interval (divided dosage over 2 days is allowed for tolerability issues or higher 
weight, i.e., limit for IGIV-C infusion is no more than 80 g/day [corresponding to 80 kg 
body weight]).

During the infusions, abbreviated vital signs (HR, SBP, and DBP) will be recorded just 
before the start of each infusion (within 15 ± 5 minutes before the beginning of each 
infusion), 30 ± 10 minutes after starting infusion, and immediately after infusion 
completes.

For each infusion, documentation of total infusion volume prepared (as received from 
pharmacist or designee), total time to infuse, total volume infused, and, if necessary, any 
infusion interruption with explanation

AEs (includes clinical observation of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia etc])

Concomitant medications
3.8.2.6
Investigational Product Maintenance Phase: Weeks 12, 18, and 21 (Visits 5, 7, 
and 8)
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 
12 hours prior to Week 12, 18, and 21 (Visits 5, 7, and 8) to assure accurate assessment of 
the QMG. At Weeks 12, 18, and 21 (Visits 5, 7, and 8), the following will be performed:

QMG score to be assessed pre-infusion

MG Composite to be assessed pre-infusion

Vital signs including T, RR, HR, SBP, and DBP (pre-infusion)

Unblinded Pharmacist or designee, to prepare and dispense the IP per randomization 
assignment and Pharmacy Manual
-
Note: The subject weight measured at Visit 4 is used for IP dose calculations for Visit 
5, and the weight measured at Visit 6 is used for IP dose calculations for Visits 6-8.

Administer the maintenance dosage (blinded active or placebo) of 1 g/kg over 1 day (per 
Pharmacy Manual). Note that the maintenance dosage is given over 1 day as the standard 
time interval (divided dosage over 2 days is allowed for tolerability issues or higher 


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weight, i.e., limit for IGIV-C infusion is no more than 80 g/day [corresponding to 80 kg 
body weight]).

During the infusions, abbreviated vital signs (HR, SBP, and DBP) will be recorded just 
before the start of each infusion (within 15 ± 5 minutes before the beginning of each 
infusion), 30 ± 10 minutes after starting infusion, and immediately after infusion 
completes.

For each infusion, documentation of total infusion volume prepared (as received from 
pharmacist or designee), total time to infuse, total volume infused, and, if necessary, any 
infusion interruption with explanation

AEs (includes clinical observation of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia etc])

Concomitant medications
3.8.2.7
Investigational Product Maintenance Phase: Week 15 (Visit 6)
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 
12 hours prior to Week 15 (Visit 6) to assure accurate assessment of the QMG. At Week 15
(Visit 6), the following will be performed:
Assessments to be performed pre-infusion (except as specified):

Full physical examination (excluding breast and genitourinary areas)

Weight (to be used to calculate IP infusion dosage for the scheduled visit and subsequent 
IP infusions)

Note: Subject weight collected at Visit 6 is used for IP dose calculations for Visit 7 
and Visit 8.

Full vital signs including T, RR, HR, SBP, and DBP

Clinical laboratory assessments drawn pre-infusion (see Section 3.8.3)

Hematology

Chemistry

Blood for IgG (trough) (data will be assessed centrally and not provided to 
centers/Sponsor until the end of the study due to the potential for unblinding)

Hemolysis evaluation (laboratory parameters: Hb, hematocrit, RBC, blood smear, serum 
free-Hb, haptoglobin, LDH, DAT, ARC, total and direct/indirect bilirubin; urine for 
urinary sediment and hemoglobinuria/hematuria), and Thromboembolism evaluation 
(Wells score and D-dimer) will be performed when last maintenance infusion is 
complete. Appendix 7 and Appendix 8 provide details. 

QMG score to be assessed pre-infusion

MG Composite to be assessed pre-infusion

MG-QOL 15 to be assessed pre-infusion

MG-ADL to be assessed pre-infusion
IP Infusion:

Unblinded Pharmacist or designee, to prepare and dispense the IP per randomization 
assignment and Pharmacy Manual


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-
Note: The subject weight measured at Visit 6 is used for IP dose calculations for Visit
6, Visit 7, and Visit 8.

Administer the maintenance dosage (blinded active or placebo) of 1 g/kg over 1 day (per 
Pharmacy Manual). Note that the maintenance dosage is given over 1 day as the standard 
time interval (divided dosage over 2 days is allowed for tolerability issues or higher 
weight, i.e., limit for IGIV-C infusion is no more than 80 g/day [corresponding to 80 kg 
body weight]).

During the infusions, abbreviated vital signs (HR, SBP, and DBP) will be recorded just 
before the start of each infusion (within 15 ± 5 minutes before the beginning of each 
infusion), 30 ± 10 minutes after starting infusion, and immediately after infusion 
completes.

For each infusion, documentation of total infusion volume prepared (as received from 
pharmacist or designee), total time to infuse, total volume infused, and, if necessary, any 
infusion interruption with explanation

AEs (includes clinical observation of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia etc])

Concomitant medications

Additional hemolysis evaluation (laboratory parameters) will be performed 7 days post 
maintenance infusion
3.8.2.8
End of Study: Week 24 (Visit 9)
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 
12 hours prior to Week 24 (Visit 9) to assure accurate assessment of the QMG. At Week 24 
(Visit 9), the following will be performed:

Full physical examination (excluding breast and genitourinary areas)

Vital signs including T, RR, HR, SBP, and DBP

Laboratory assessments (see Section 3.8.3):
◦
Chemistry 
◦
Hematology
◦
Blood for IgG (trough) (data will be assessed centrally and not provided to 
centers/Sponsor until the end of the study due to the potential for unblinding)
◦
Quantitative/semi-quantitative binding, blocking, and modulating AChR 
antibodies 
◦
Serum Pregnancy Test (qualitative β-HCG) (women of child-bearing potential 
only)

QMG score

MG Composite

MG-QOL 15

MG-ADL

MGFA postinterventional change in status relative to Baseline at Week 24 (Investigator
classification of subject status as improved, unchanged, or worse)

AEs (includes clinical observation of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia etc]) 

Concomitant medications 


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3.8.2.9
Early Termination Visit
The Early Termination visit will consist of the same assessments as Week 24 (Visit 9) except 
for quantitative/semi-quantitative binding, blocking, and modulating AChR antibodies which 
are not required.
If a subject discontinues at any point during the study after receiving IP, the subject will be 
requested to return to the clinic to have the procedures and assessments outlined in Appendix 
1 conducted as soon as practical following the decision to withdraw (at least within 14 days 
after the termination date) if the subject is willing. Subjects must withhold their 
acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 12 hours prior to the Early 
Termination Visit to assure accurate assessment of the QMG.
3.8.3
Description of Laboratory Tests and Procedures
Table 3-1 Name, Description, and Location of Laboratory Tests and Procedures
Test Panel
Description
Location
Hematology a
Hb, hematocrit, platelets, RBC count, including RBC morphology, white 
blood cell count with differential
Central
Chemistry a
Creatinine, blood urea nitrogen (BUN), aspartate transaminase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase (ALP), total 
bilirubin (TBL) 
Central
Hemolysis
Whole blood Hb, RBC, hematocrit, serum free Hb, haptoglobin, LDH, 
DAT, ARC, TBL, and indirect bilirubin, and blood smear 
Central
Urine sediment and measuring of hemoglobinuria 
Thromboembolic 
events risk
D-dimer
Central
AChR a
Acetylcholine Receptor Antibody at Screening (diagnostic - defining 
MG); Baseline, Week 9, and Week 24 quantitative/semi-quantitative 
measurement of binding, blocking, modulating AChR antibody (Please 
see Section 3.8.3.4 for details)
Central
IgG levels
Immunoglobulin G levels 
Central
Serum pregnancy a
Qualitative serum β human chorionic gonadotropin (β-HCG) for females 
of child-bearing potential. Results must be negative to continue in the 
study.
Central
Viral Nucleic Acid 
Amplification 
Technology (NAT)  
Testing
Retains b :
Hepatitis A virus (HAV) ribonucleic acid (RNA), Hepatitis B virus 
(HBV) DNA, Hepatitis C virus (HCV) RNA, Human immunodeficiency 
virus (HIV) RNA, parvovirus B19 (B19V) deoxyribonucleic acid (DNA)
Central
Viral Serology
Testing
Retains b :
HAV antibody differential (Immunoglobulin M [IgM]/IgG), HBV core 
antibody differential (IgM/IgG), HCV antibody, HIV-1/-2 + Group O 
antibody, B19V antibody differential (IgM/IgG)
Central
a
Samples collected for laboratory analyses that are non-analyzable due to any factor (i.e., lost, quantity not 
sufficient, laboratory error) need to be recollected by contacting the subject and arranging for re-sampling.


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b
Blood samples for viral NAT and viral serology testing will be collected at Baseline/Week 0 (Visit 1) prior 
to randomization but will be tested only if the subject exhibits clinical signs and symptoms consistent with 
hepatitis A, hepatitis B, hepatitis C, HIV, or parvovirus B19 infection while participating in the study. 
These samples will be retained until all analyses in support of the study are complete. Additional blood 
samples for viral NAT and viral serology may be collected and tested during the study only if the subject 
exhibits clinical signs and symptoms consistent with hepatitis A, hepatitis B, hepatitis C, HIV or parvovirus 
B19 infection while participating in the study.
3.8.3.1
Thromboembolic Events Risk Testing
Measurement of D-dimer blood levels and thromboembolic events risk testing will be 
performed at Screening, Baseline (Week 0 prior to randomization), at the end of the first 
infusion of the loading dose, at the time when last loading infusion is complete, and at the 
completion of maintenance infusion dosage at Week 3 (Visit 2), Week 6 (Visit 3), and 
Week 15 (Visit 6). Appendix 7 provides details.
3.8.3.2
Hemolysis Testing
Laboratory assessments (urine, whole blood Hb, serum free Hb, haptoglobin, LDH, DAT, 
ARC, RBC, hematocrit, TBL and indirect bilirubin, and blood smear) and urine assessments 
(for urinary sediment and hemoglobinuria, hematuria) will be conducted at Baseline (Week 0 
prior to randomization), at the end of the first infusion of the loading dose, at the time when 
last loading infusion is complete, and at the completion of maintenance infusion dosage at 
Week 3 (Visit 2), Week 6 (Visit 3), and Week 15 (Visit 6). Hemolysis laboratory assessments
will also be performed 7 days post loading dose infusion at Baseline (Week 0) and 7 days 
post maintenance infusion at Weeks 3 (Visit 2), 6 (Visit 3), and 15 (Visit 6). Appendix 8
provides details.
3.8.3.3
Virus Safety Testing
Blood samples for virus safety (viral NAT and viral serology) testing will be collected at 
Baseline/Week 0 (Visit 1) prior to randomization, but will be tested only if the subject 
exhibits clinical signs and symptoms consistent with hepatitis A, hepatitis B, hepatitis C, 
HIV, or parvovirus B19 infection while participating in the study. These samples will be 
retained until all analyses in support of the study are complete. Additional blood samples for 
viral NAT and viral serology may be collected and tested only if the subject exhibits clinical 
signs and symptoms consistent with hepatitis A, hepatitis B, hepatitis C, HIV, or parvovirus 
B19 infection while participating in the study. 
3.8.3.4
AChR Antibody Testing
AChR antibody levels will be measured in all subjects at Screening and must be present for 
the subject to be eligible to participate in the study. Additionally, quantitative/semi-
quantitative binding, blocking, and modulating AChR antibodies will be measured at 
Baseline, Week 9 (Visit 4), and at the End of Study Visit.
Baseline and Week 9 (Visit 4) and End of Study Visit (Week 24) results will not be shared 
during study conduct with the investigator, blinded study staff, CRO, or blinded Sponsor 
personnel involved with study conduct. All measurements will be conducted using qualified 


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assays. Specific details regarding all aspects of sample collection and processing can be
found in the central laboratory Study Reference Manual.
3.8.3.5
IgG Concentration Measurements
Serum total IgG concentrations will be measured in all subjects at specified visits. Results of 
the central laboratory analysis of IgG levels will not be shared with the Investigator, blinded 
study staff, CRO or blinded Sponsor personnel involved with study conduct. All 
measurements will be conducted using qualified assays. Specific details regarding all aspects 
of sample collection and processing can be found in the Study Reference Manual at each site.
3.9
Screen Failures
Screening evaluations will be used to determine the eligibility of each subject for enrollment 
at the Baseline Visit. Subjects who fail to meet eligibility criteria during Screening
evaluations will be considered screen failures. Subjects may re-screen for the study if the 
reason for screen failure is no longer relevant; a new informed consent form must be signed 
for re-screening.
3.10
Removal of Subjects
Removal from Study: Subjects who discontinue the study prematurely will receive an Early 
Termination Visit with same assessments as Week 24 (Visit 9) in Appendix 1 with the 
exception of quantitative/semi-quantitative binding, blocking, and modulating acetylcholine 
receptor antibodies which are not required. 
Subjects may withdraw or be withdrawn from the study for the following reasons:
1. At their own request or at the request of their legally acceptable representative.
2. If, in the Investigator's opinion, continuation in the study would be detrimental to the 
subject's well-being.
3. At the specific request of the Sponsor. 
Also, subjects must be withdrawn for the following reasons: 

Subjects not meeting the inclusion and exclusion criteria prior to the Baseline (Week 0) 
Visit based on laboratory results

Subjects with an occurrence of a concomitant disease or any medical condition which, 
either because of its severity or duration or necessary change in treatment, contravenes 
the condition of the study or puts the patient at unnecessary risk or harm 

Subjects with an occurrence of an AE which in the opinion of the Investigator and/or 
subject requires termination of treatment

QMG increase by ≥ 4 points relative to Baseline (Week 0) occurring at or after Week 9 
(Visit 4) with worsening (increase in QMG of 4 points or more) confirmed at the next 
scheduled consecutive visit indicating worsening MG (Section 3.3.3)

MG crisis (defined in Section 3.3.4)

Subjects who are noncompliant with the protocol per the Investigator’s discretion


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
Pregnancy
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's 
records. 
3.11
Follow-up of Subjects Withdrawn from Study
Subjects who receive any amount of IP and discontinue early from the study will be 
requested to return for the Early Termination Visit procedures (see Section 3.8.2.9) as soon 
as practical following decision to withdraw (at least within 14 days after the termination date) 
if the subject is willing.
3.12
Premature Termination of Study/Closure of Center
The Sponsor, Institutional Review Board/Ethics Committee (IRB/EC), and/or regulatory 
authorities have the right to close this study or a study center, and the Investigator/Sponsor 
has the right to close a center, at any time, although this should occur only after consultation 
between involved parties. The IRB/EC must be informed. Should the study/center be closed 
prematurely, all study materials (except documentation that has to remain stored at site) must 
be returned to the Sponsor. The Investigator will retain all other documents until notification 
given by the Sponsor for destruction.
A study center can be closed for the following reasons:

Lack of enrollment 

Non-compliance with the requirements of the study protocol

Non-compliance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP)
4
ADVERSE EVENTS 
4.1
Warnings/Precautions
For complete IGIV-C safety information, refer to the current IGIV-C IB. It is possible that 
unknown, unforeseen adverse reactions may occur in subjects with MG exacerbations.
4.1.1
Interaction/Overdose
In an overdose situation, cardiovascular overload would be the primary concern and should 
be managed accordingly. Since up to 2 g/kg have been tolerated by many subjects, and the 
maximum g/kg dose allowed at any single infusion day in this study is 1 g/kg, no 
cardiovascular events are expected.
4.1.2
Live Viral Vaccines
Passive transfer of antibodies may transiently interfere with the immune response to live 
virus vaccines such as measles, mumps, rubella and varicella. Inform subjects that blinded 


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IGIV-C/placebo can interfere with their immune response to live viral vaccines. Inform 
subjects to notify their healthcare professional/immunizing physician of recent participation 
in a clinical study including blinded study drug (IGIV-C or placebo). The Investigator must 
consider any potential interaction prior to receiving vaccinations so that appropriate measures 
may be taken.
4.2
Specification of Safety Parameters
Aspects of clinical safety will be evaluated in this clinical trial. 
Safety endpoints will include:

AEs, SAEs and suspected ADRs

Vital signs 

Physical examinations

Blood chemistry and hematology

Thromboembolic events

Hemolysis
4.3
Methods and Timing for Assessing, Recording and Analyzing 
Safety Parameters
Safety will be assessed throughout the clinical trial for all individuals who have received at 
least one infusion of the IP.
4.3.1
Adverse Events
AEs (includes suspected ADRs) occurring at any time between signature of the subject’s ICF 
and the last day of the subject’s participation in the clinical trial will be reported and recorded 
on the appropriate subject’s eCRF entry. 
It is the Investigator’s responsibility to ensure that all AEs are appropriately recorded. 
AEs will be elicited by spontaneous reporting by the study individual or by a non-leading 
inquiry or direct observation by the study staff.
4.3.2
Vital Signs 
During the infusions, abbreviated vital signs (HR, SBP, and DBP) will be recorded just 
before the start of each infusion (within 15 ± 5 minutes before the beginning of each 
infusion), 30 ± 10 minutes after starting infusion, and immediately after infusion completes.
Clinically relevant changes in vital signs during infusions of IP will be reported as AEs 
temporally associated to the infusion. Clinical relevance will be based on the Investigator’s 
criteria. 


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In addition, vital signs will be assessed at scheduled visits. Abnormal vital signs judged as 
clinically relevant by the Investigator in the context of the patient’s medical history will be 
considered AEs.
4.3.3
Physical Examination
Physical exams will be registered as normal or abnormal, according to the physician’s 
judgment or study staff’s criteria and findings will be recorded. Abnormal physical findings 
judged as clinically relevant by the Investigator in the context of the patient’s medical history 
will be considered AEs.
4.3.4
Blood Chemistry and Hematological Parameters
All clinical laboratory data for renal (creatinine, BUN), hepatic (ALT, AST, ALP and TBL) 
and hematological parameters (complete blood count [CBC] including differential leukocyte 
count) will be listed for each clinical trial subject (see Section 3.8.3). Clinical laboratory 
results and the change from Baseline values at Week 24 will be summarized by treatment 
group using summary statistics. Shift tables will be provided to summarize values that fall 
outside the normal ranges.
The Investigator will be required to classify laboratory results out of the normal range 
reported by the laboratory as clinically relevant or not according to his/her criteria in the 
context of the patient’s medical history.
Laboratory results out of the normal range judged by the Investigator as clinically relevant in 
the context of the patient’s medical history/underlying comorbid conditions will be 
considered AEs.
4.3.5
Thromboembolic Event Risk
Procedures for the monitoring of TE risk are provided in Appendix 7. Pulmonary embolism 
and deep venous thrombosis will be considered AEs and/or SAEs if criteria for seriousness 
are met.
4.3.6
Hemolysis
Procedures for hemolysis detection are provided in Appendix 8. In the event that true 
hemolytic anemia develops, it will be considered an AE and/or an SAE depending on 
whether seriousness criteria are met. Hemolytic ARs are defined as temporally associated 
with the study drug within 7 days post infusion.
4.4
Procedures for Eliciting Reports of and for Recording and 
Reporting Adverse Events and Intercurrent Illnesses
4.4.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 


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have a causal relationship with this administration. An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory finding, for example), symptom or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Any AE that occurs at any time between the signature of the ICF and last day of the subject’s 
participation in the clinical trial must be reported and recorded on the AE eCRF entry.
4.4.2
Suspected Adverse Drug Reaction (ADR)/Adverse Reaction (AR)
All noxious and unintended responses to a medicinal product related to any dose should be 
considered suspected ADRs. The phrase “response to a medicinal product” means that a 
causal relationship between a medicinal product and an AE is at least a reasonable 
possibility, that is, the relationship cannot be ruled out. In the framework of this study, a 
suspected ADR with a causal relationship of “definite” will be labeled as an AR; thus, ARs 
are a subset of suspected ADRs.
The Sponsor is responsible for assessing the suspected ADR expectedness during the clinical 
trial.
4.4.3
Causality of Adverse Event
The Investigator is required to provide a causality assessment for each AE reported to the 
Sponsor. The Sponsor will consider the Investigator’s causality assessment. Assessment of 
the causal relationship to the study drug will be made according to the following 
classifications based on Karch FE, et al (48):
Definite: An event that follows a reasonable temporal sequence from administration of the 
treatment or in which the treatment level has been established in body fluids or tissues; that 
follows a known response pattern to the suspected treatment; and that is confirmed by 
improvement on stopping the treatment (dechallenge), and reappearance of the event on 
repeated exposure (rechallenge).
Probable: An event that follows a reasonable temporal sequence from administration of the 
treatment; that follows a known response pattern to the suspected treatment; that is confirmed 
by dechallenge; and that could not be reasonably explained by the known characteristics of 
the patient’s clinical state.
Possible: An event that follows a reasonable temporal sequence from administration of the 
treatment that follows a known response pattern to the suspected treatment but that could 
have been produced by the patient’s clinical state or other modes of therapy administered to 
the patient.
Doubtful/Unlikely: An event that follows a reasonable temporal sequence from 
administration of the treatment; that does not follow a known response pattern to the 
suspected treatment; but that could not be reasonably explained by the known characteristics 
of the patient’s clinical state.


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Unrelated: Any event that does not meet the criteria above.
The operational tool to decide the AE causal relationship is based on algorithms by Karch 
and Lasagna and Naranjo et al (49, 50).
When an AE is classified, assessing causal relationship by the Investigator, as definitive, 
probable, possible or doubtful/unlikely, the event will be defined as a suspected ADR. A 
suspected ADR with a causal relationship of “definite” will be defined as an AR. When the 
causal relationship is labeled “Unrelated”, then it will be considered that the AE is not 
imputable to the study treatment and it is not a suspected ADR.
In addition, when a causal relationship between the study treatment and the AE cannot be 
ruled out by the Investigator and/or Sponsor, it means that the AE cannot be labeled 
“unrelated”.
For any subject, all AEs that occur at any time, between the beginning of the first infusion of 
IGIV-C and the final visit of the clinical trial, will be considered treatment emergent adverse 
events (TEAEs).
AEs occurring during the actual IP infusions (i.e., from the initiation of the IP infusion on the 
first day to the completion of the total dosage of IP on the last day) and within 72 hours 
following the completion of the infusion of the total dosage of IP on the last day, regardless 
of other factors that may impact a possible causal association with product administration, 
will be defined as infusional AEs (i.e., an AE temporally associated with an infusion of the 
IP) and labeled infusional TEAEs (a subset of TEAEs).
For AEs that occur during infusions, the infusion rate in effect at the time of onset of the AE, 
the time of onset of the AE and the time of AE changes materially in intensity and/or 
resolves will be captured.
4.4.4
Intensity of Adverse Event or Suspected Adverse Drug Reaction
AEs and suspected ADRs will be classified depending on their intensity (severity) according 
to the following definitions:
1. Mild: an AE which is well tolerated by the subject, causing minimum degree of malaise 
and without affecting normal activities.
2. Moderate: an AE that interferes with the subject’s normal activities.
3. Severe: an AE that prevents the subject from performing their normal activities.
AE and suspected ADR intensity gradation must be distinguished from AE and suspected 
ADR seriousness gradation, which is defined according to event consequence. For example, 
headache can be mild, moderate or severe but usually is not serious in all these cases.
The Investigator will be responsible for assessing the AE and suspected ADR intensity 
during the clinical trial, taking into account the criteria currently included in this section.


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4.4.5
Expectedness of Adverse Event or Suspected Adverse Drug Reaction
An AE or suspected ADR is considered “unexpected” if the nature, seriousness, severity or 
outcome of the reaction(s) is not consistent with the reference information. The expectedness 
of a suspected ADR shall be determined by the Sponsor according to the reference document 
(IB or Summary of Product Characteristics [SPC] or product label).
Events not listed for the particular drug under investigation in the IB or SPC are considered
“unexpected” and those listed are considered “expected.” When new Serious ADRs (Serious 
potentially-related AEs) are received, it is the Sponsor’s responsibility to determine whether 
the events are “unexpected” for expedited safety reporting purposes.
4.4.6
Seriousness of Adverse Event or Suspected Adverse Drug Reaction, 
Serious Adverse Event
An AE or suspected ADR is considered “serious” if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: 
1. Death
2. Life-threatening AE (life-threatening in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe)
3. In-patient hospitalization or prolongation of existing hospitalization
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
5. A congenital anomaly/birth defect
6. An important medical event (important medical event in the definition of “serious”) 
refers to those events which may not be immediately life-threatening, or result in death, 
or hospitalization, but from medical and scientific judgment may jeopardize the subject 
or/and may require medical or surgical intervention to prevent one of the other outcomes 
listed above
This definition permits either the Sponsor or the Investigator to decide whether an event is 
“serious”. If either the Sponsor or the Investigators believes that the event is serious, the 
event must be considered “serious” and evaluated by the Sponsor for expedited reporting. 
A distinction should be drawn between serious and severe AEs. The term “severe” is used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of 
relative minor medical significance (such as severe headache). This is not the same as 
“serious”, which is defined on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject’s life or functioning. 
According to the medical criteria, an AE or a suspected ADR can be classified as serious, 
although it does not fulfill the conditions fixed in this section, if it is considered important 
from a medical point of view.


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4.4.6.1
Hospitalization or Prolongation of Hospitalization
An AE or suspected ADR is considered “serious” if, in the view of either the Investigator or 
Sponsor, it results in hospitalization or prolongation of hospitalization UNLESS this 
hospitalization or prolongation of hospitalization is part of the clinical practice (according to 
the Investigator’s criteria) for the treatment of the MG.
4.4.7 Adverse Events of Special Interest
4.4.7.1
Thromboembolic Events
Subjects will be monitored for signs and symptoms of arterial and venous thromboses. In 
addition, the Grifols Medical Monitor will routinely review reported AEs for possible 
thromboses. Arterial and venous thromboses will be identified according to definitions in the 
International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). 
Such thrombotic events include, but are not limited to, DVT, PE, myocardial infarction, 
cerebrovascular accident, acute coronary syndrome, limb thrombosis, sagittal sinus 
thrombosis, and portal vein or mesenteric artery thrombosis. All thrombosis will be recorded 
as AEs, reported accordingly, and if serious, may require early discontinuation from study. 
See Appendix 7 for details. 
4.4.7.2
Hemolysis
Subjects will be monitored for signs and symptoms of hemolysis. In addition, the Grifols 
Medical Monitor will routinely review reported AEs for possible hemolysis. Hemolysis will 
be recorded as an AE, reported accordingly, and if resulting in serious hemolytic anemia, 
may require early discontinuation from study. See Appendix 8 for details.
4.4.7.3
MG Events That Are Not Considered AEs
Given that variations in symptoms are an inherent part of the natural history of MG, all 
recorded information regarding severity of MG manifestations will be considered efficacy 
data. 
For the purpose of this study, variation in MG symptoms will not be considered an AE unless 
MC requires hospitalization. If a subject is hospitalized for MG, it will be reported as an 
SAE.
4.4.8 Procedures for Eliciting Reports of and for Recording and Reporting Adverse 
Events and Suspected Adverse Drug Reactions
The occurrence and follow-up details of all AEs experienced by any of the subjects during 
the clinical trial, from signature of the Clinical Trial Written Informed Consent Form to the 
last follow-up visit, will be recorded on the AE eCRF entry and in the subject’s hospital 
record. If no AE has occurred during the study period, this should also be indicated in the 
eCRF.


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At each visit, AEs will be elicited by asking the individual a non-leading question such as 
“Do you feel different in any way since the last visit?” Moreover, AEs will also be collected 
through directly observed events or spontaneously volunteered by the subject. Clearly related 
signs, symptoms and abnormal diagnostic procedures should preferably be grouped together 
and recorded as a single diagnosis or syndrome wherever possible. It is responsibility of the 
Investigator to ensure that AEs are appropriately recorded.
The following variables must be recorded on the AE eCRF entry:
1. the verbatim term (a diagnosis is preferred)
2. date/time of onset
3. date/time of resolution
4. severity (mild, moderate, severe)
5. causality (unrelated, doubtful/unlikely, possible, probable, definite)*
6. seriousness (yes, no)
7. action taken (with regard to IP)
8. other action (to treat the event)
9. outcome and sequel (follow-up on AE)
*AEs occurring before subject's exposure to IP will be always labeled as "unrelated".
For AEs that occur during infusions, the infusion rate in effect at the time of onset of the AE, 
the time of onset of the AE and the time of AE changes materially in intensity and/or 
resolves will be captured the eCRF entry.
In addition to the Investigator’s own description of the AEs, each AE will be encoded by the 
Sponsor or CRO according to the Medical Dictionary for Regulatory Activities (MedDRA®).
For example, a laboratory test abnormality considered clinically relevant, e.g., causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the Investigator, should be reported as an AE. Each 
event must be described in detail along with start and stop dates, severity, relationship to IP, 
action taken and outcome. Each event must be adequately supported by documentation as it 
appears in the subject’s medical or case file.
A pregnancy not verified before the Baseline Visit but occurring during the course of the 
study will be not considered an AE, unless a relation to the study drug is suspected. In any 
case, a Pregnancy Report Form must be completed and sent as soon as possible to the 
Sponsor, and the study treatment must be discontinued. A copy of the form should be filed at 
the study site for follow-up until the end of the pregnancy.
4.4.9
Timelines and Reporting of Serious Adverse Events
Any SAE (see Section 4.4.6) that occurs after signing the ICF through the last day of 
subject´s participation in the clinical trial must be expeditiously reported whether or not 
considered attributable to the study drug. Each SAE must be fully recorded in the subject’s 
eCRF or SAE Report Form.


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SAEs will be reported using the designated SAE Report form. When the Investigator 
becomes aware of an SAE, she/he must submit electronically through the Electronic Data 
Capture (EDC) system or when the EDC system is not available submit a completed, signed 
and dated SAE Report Form (in English) within 24 hours to the Sponsor by email/fax. 
Each SAE must be followed up until resolution or stabilization. After the initial report, all 
relevant information for SAE follow up, and for the outcome, must also be supplied to the 
Sponsor in a timely manner (within 3 days from its identification or within 24 hours for 
relevant new information) by means of the SAE Report Form. In addition, the Sponsor or 
CRO may request additional information and/or reports.
All SAE Report Forms must be reported to Grifols electronically through the EDC system or 
when the EDC system is not available, reported to:
Grifols Global Pharmacovigilance
FAX (back-up only): 
(US/Canada)
and 
(International)
When required, and according to local law and regulations, SAEs must be reported to the 
IRB/EC and regulatory authorities.
4.4.10
Type and Duration of the Follow-Up of Subjects after Adverse Event or 
Suspected ADR
In so far as is possible, all individuals will be followed up until the AE or suspected ADR has 
been resolved. If an AE/suspected ADR/SAE is present when the subject has completed the 
study, the course of the event must be followed until the final outcome is known or the event 
has been stabilized and no further change is expected and the Investigator decides that no 
further follow-up is necessary.
Any pregnancy must be followed by the Investigator until delivery or to the end of 
pregnancy.
5
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE
5.1
Statistical and Analytical Plan
Unless otherwise specified, descriptive statistics will include the number of non-missing 
observations, mean, standard deviation (SD), median, minimum and maximum values for the 
continuous/quantitative data or absolute and relative frequency counts and percentages for 
categorical/qualitative data. All statistical tests will be two-sided at alpha = 0.05.


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Detailed data handling and evaluation procedures will be described in the Statistical Analysis 
Plan.
5.1.1
Subject Populations for Analysis
INTENT-TO-TREAT (ITT) POPULATION
The ITT population consists of all subjects who are randomized. 
SAFETY POPULATION
The Safety population consists of all subjects who received any amount of IP.  
PER PROTOCOL (PP) POPULATION
The PP population consists of all subjects in the ITT population without any major protocol 
deviation which has an impact on the primary efficacy data. Any deviations from the 
protocol will be recorded in the protocol deviation list. The validity of a subject for inclusion 
in the PP population will be assessed at a review meeting that will take place before 
finalizing the database. The review meeting will review the protocol deviation list, as well as 
data listings. If protocol deviations are identified which justify removing a subject from the 
per-protocol population, then these decisions will be documented.
5.1.2
Demographic and Baseline Characteristics
Demographic and Baseline characteristics will be summarized using descriptive statistics.
5.1.3
Efficacy Analyses
5.1.3.1
Primary Efficacy Analyses
The primary efficacy endpoint is the change in QMG score from Baseline (Week 0) to 
Week 24. The treatment comparison will be performed using analysis of covariance 
(ANCOVA) with change in QMG score as dependent variable, treatment and Baseline
standard of care treatment regimen as fixed factors and Baseline QMG score as a covariate. 
The null hypothesis (H0) and the alternative hypothesis (Ha) are:  
H0: μ1 = μ2
                                    Ha: μ1 ≠ μ2
Where μ1 and μ2 represent the population mean in the IGIV-C and Placebo groups, 
respectively.
For subjects who discontinued the study early, the last observation carried forward (LOCF) 
method will be used to impute the change in QMG from Baseline to Week 24. A sensitivity 
analysis of completers with non-missing QMG score at Week 24 will be performed. For 
subjects who experience Treatment Failure (defined in Section 3.3.3) or MG crisis (defined 
in Section 3.3.4) the value at time of failure will be employed.


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For the longitudinal measurements of QMG score at various time points, the treatment effects 
will be explored by using the mixed-effect model repeated measures (MMRM) with change 
from Baseline as dependent variable; treatment, Baseline standard of care treatment regimen, 
protocol-specified visits, treatment-by-visit interaction as fixed effects; Baseline QMG value 
as covariate; and measures within-subject at each visit as a repeated measure.
Primary Efficacy analyses will be based on the ITT population. For sensitivity analysis, the 
same analysis will be repeated using the PP population. 
5.1.3.2
Secondary Efficacy Analyses
Secondary endpoints include the percentage of subjects achieving clinical response as 
measured by QMG, MG Composite, and MG-ADL at Week 24. 
The following secondary efficacy variables will be analyzed using the ITT population: 

Percentage of subjects who experience a clinical improvement assessed by QMG score 
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 
3-point decrease in QMG

Percentage of subjects who experience a clinical improvement assessed by the 
MG Composite from Baseline (Week 0) to Week 24 where clinical improvement is 
defined as at least a 3-point decrease in the MG Composite 

Percentage of subjects who experience a clinical improvement as assessed by MG-ADL 
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 
2-point decrease in MG-ADL
Treatment comparison will be performed by Cochran-Mantel-Haenszel (CMH) test adjusted 
for Baseline standard of care treatment regimen. Subjects who discontinued from the study 
early will be considered as not showing clinical improvement. 
5.1.3.3
Exploratory Efficacy Analyses
Exploratory efficacy analyses will be based on the ITT population. The following 
exploratory efficacy variables will be analyzed:

Percentage of subjects who experience a clinical improvement in QMG score (defined 
above) at Weeks 6, 9, 12, 15, 18, and 21 

Time to first clinical improvement in QMG score (at least a 3-point decrease)

Time to Treatment Failure based on QMG score definition (Section 3.3.3)

Change from Baseline (Week 0) in QMG score to Weeks 6, 9, 12, 15, 18, and 21 

Percentage of subjects who experience a clinical improvement in the MG Composite 
(defined above) to Weeks 6, 9, 12, 15, 18, and 21

Change from Baseline (Week 0) in MG Composite to Weeks 6, 9, 12, 15, 18, 21, and 24

Percentage of subjects who experience a clinical improvement in MG-ADL (defined 
above) to Weeks 9 and 15

Change from Baseline (Week 0) in MG-ADL to Weeks 9, 15, and 24

Change from Baseline in the 15-item MG-QOL 15 to Weeks 9, 15, and 24


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
MGFA postinterventional change in status at Week 24 relative to Baseline
For the time to event variables, Kaplan-Meier estimates will be provided and the treatment 
comparison will be performed using a log-rank test. For change from Baseline variables, 
ANCOVA and/or MMRM methods similar to the primary efficacy endpoint will be used. For 
percentage variables, the CMH test adjusted for Baseline standard of care treatment regimen 
will be used. 
MGFA postinterventional change in status at Week 24 relative to Baseline will be 
summarized by treatment group.
5.1.4
Safety Analyses
The safety analysis will be based on safety population.
The safety analyses will be addressed by listing and tabulation of AEs (including suspected 
ADRs), vital signs, physical examinations and clinical laboratory tests. Data will be 
described using descriptive analyses.
Adverse events:
Safety analysis will be primarily focused on a descriptive analysis of suspected ADRs. Safety 
assessment will be based on the prevalence of suspected ADRs that occurred during the 
clinical trial.
Adverse events will be coded and classified using MedDRA® terms (system organ class and 
preferred terms). 
Adverse events will be classified as TEAEs or non-TEAEs. A TEAE will be defined as an 
AE which occurs between the beginning of the first infusion of IGIV-C and the final visit of 
the clinical trial. A non-TEAE will be defined as an AE which occurs prior to the first dose 
of IP. Non-TEAEs and TEAEs will be summarized separately. 
All AEs will be summarized by presenting subject incidences and percentages, and they will 
also be listed by body systems with subject identification codes.  
In addition, TEAEs, including suspected ADRs, will be summarized by system organ class, 
preferred term, causal-relationship, intensity (severity) and seriousness (serious vs. non-
serious) using descriptive statistics. At each level of summarization, a subject will only be 
counted once per system organ class or preferred term using the most severe or causal 
relationship AE. 
AEs temporally associated with the infusion of the IP (i.e., infusional AEs, including 
infusional suspected ADRs), will be summarized by presenting infusion/subject incidences 
and percentage and listed. In addition, the infusion rate in effect at the time of onset of the 
AE, the time the AE is first reported and the time the AE changes materially in intensity 
and/or resolves will be also reported and listed.


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Subjects with deaths, SAEs, suspected ADRs and AEs leading to premature discontinuation 
from the study will be listed and presented in a narrative form.  
Any AEs for which the Investigator causality assessment is missing or undetermined will be 
individually listed.
Vital signs:
Vital signs (T, RR, HR, SBP and DBP) will be listed for each clinical trial subject and 
summarized by treatment group. In case a subject presents a clinically relevant abnormality 
of vital signs during an infusion, the event will be flagged and reported as an AE temporally 
associated to the infusion. For each subject and for each infusion, every vital sign will be 
considered. Clinical relevance will be based on the Investigator’s criteria. Abnormal vital 
signs judged as clinically relevant by the Investigator in the context of the patient’s medical 
history will be considered AEs. 
Physical examination:
Physical examination findings (normal and abnormal) will be listed for each clinical trial 
subject with the specific findings observed. Abnormal findings judged as clinically relevant 
by the Investigator in the context of the patient’s medical history will be considered AEs.
Blood chemistry and hematology:
All clinical laboratory data for renal (creatinine, BUN), hepatic (ALT, AST, ALP, and TBL) 
and hematological parameters (CBC including differential leukocyte count) will be listed for 
each clinical trial subject and summarized by treatment group. Laboratory results out of the 
normal range judged as clinically relevant by the Investigator in the context of the patient’s 
medical history will be considered AEs.
Lab tests for TEs and hemolysis:
The D-dimer for TE assessment and the laboratory tests for detecting hemolysis (including 
whole blood Hb, serum free Hb, haptoglobin, LDH, DAT, ARC, RBC, hematocrit, TBL and 
indirect bilirubin, and blood smear) will be listed and out of normal range results will be 
flagged. 
5.2
Determination of Sample Size
According to a study by Tackenberg and colleagues in 16 MG subjects with IGIV as 
maintenance therapy, the change from Baseline to endpoint in QMG score averaged 9.81 
with a standard deviation of 4.21 (52). Assuming that the IGIV treatment group is 50% better 
than the Placebo group, with alpha=0.05 and two-sided test, 28 subjects are needed for each 
treatment group (total 56 subjects) to have at least 80% power to detect the treatment 
difference. Assuming a 10% drop out rate, 62 subjects are planned to be randomized.


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6
ADMINISTRATIVE
6.1
Investigators, Other Study Personnel and External Committees
Information regarding additional key personnel involved in the conduct of the study, 
including names and contact details of participating Investigators, monitors, clinical 
laboratories, technical departments and/or institutions, as well as information on members of 
additional study committees, will be found in the study files of the Sponsor and at the 
Investigator sites within the Study Reference Manual/file.
Investigators and staff will receive training via an Investigators meeting, site initiation visit 
or other appropriate individual site training session(s).
6.1.1
Independent Safety Review Committee
This study will utilize an Independent Safety Review Committee (ISRC) whose members 
(from Grifols) will be impartial and independent of the clinical trial team. The clinical trial 
team will remain blinded to subject treatment assignment. The ISRC will review relevant 
safety information from the study as outlined in the ISRC Charter. At a minimum, after the 
first 20 subjects are enrolled and have completed half of the treatment period, the ISRC will 
conduct a safety review of the following data at a minimum:

AEs, SAEs, and discontinuations due to AEs and SAEs

Vital signs

Blood chemistry and hematology

Assessing for TEs

Assessing for hemolysis
During the study, the Medical Monitor will review all relevant safety information from the 
study in order to protect subject welfare and preserve study integrity. Data to be reviewed 
include but are not limited to the following: eCRFs, listings from the clinical and safety 
databases, AEs/SAE reports, concomitant medications, laboratory data, vital signs, and 
physical examinations data.
6.2
Data Quality
Monitoring and auditing procedures defined/agreed by the Sponsor will be followed, in order 
to comply with ICH GCP guidelines. Each center will be visited at regular intervals by a 
monitor to ensure compliance with the study protocol, ICH GCP and legal aspects. The on-
site verification of the eCRF for completeness and clarity will include cross checking with 
source documents and clarification of administrative matters. Query verification of data will 
be described in the Data Management Plan.
6.3
Documentation
The study data will be recorded and kept current in the eCRF by the site study personnel 
directly responsible for the information. Entries made in the eCRF must be verifiable against 


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source documents or have been directly entered into the eCRF, in which case the entry in the 
eCRF will be considered the source data.
The data in the eCRF will be monitored at the site by Grifols Therapeutics Inc. 
representatives at regular intervals and reviewed for completeness and compared with the 
source documents. Examples of source documents include individual subject medical 
records, which are separate from the eCRFs.
All AEs and SAEs must be recorded. All SAEs must be recorded on the SAE form. The SAE 
form must be kept in site records with a copy provided to the designated person as detailed in 
Section 4.4.9.
6.3.1
Record Retention
At study completion, all study data will be transferred to Grifols Therapeutics Inc. according 
to ICH GCP guidelines, local laws, regulations and Grifols Therapeutics Inc. requirements. 
The study file and all source data should be retained until notification is given by the Sponsor 
for destruction.
An Investigator is required by ICH GCP guidelines to retain the study files. If an Investigator 
moves, withdraws from an investigation or retires, the responsibility for maintaining the 
records may be transferred to another person (e.g., other Investigator). Grifols Therapeutics 
Inc. must be notified in writing of the person responsible for record retention and the 
notification will be retained in the Sponsor study file and the Investigator site file.
6.3.2
Access to Information for Monitoring
The data will be recorded and kept current in eCRFs by the study site personnel directly 
responsible for the information and reviewed for completeness by the monitor. Grifols 
Therapeutics Inc. personnel or designee can review the records.
In accordance with ICH GCP guidelines, the monitor must have direct access to the 
Investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency and to verify adherence to the protocol and the completeness, consistency and 
accuracy of data entered. “Source documentation” includes individual subject files, separate 
from the eCRFs, which should be maintained and include visit dates, laboratory results, 
concomitant treatment, vital signs, medical history, examinations, AEs, IP dispensing logs 
and other notes as appropriate. The Investigator agrees to cooperate with the monitor to 
ensure that any problems noted during the course of these monitoring visits are resolved.
6.3.3
Access to Information for Audits or Inspections
Representatives of regulatory authorities or of Grifols Therapeutics Inc. may conduct audits 
or inspections of the Investigator study site. If the Investigator is notified of an audit or 
inspection by a regulatory authority, the Investigator agrees to notify the Grifols Therapeutics 
Inc. Medical Monitor immediately. The Investigator agrees to provide to representatives of a 
Regulatory Agency or Grifols Therapeutics Inc. access to records, facilities and personnel for 
the effective conduct of an audit or inspection.


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7
ETHICAL AND LEGAL ASPECTS
7.1
Institutional Review Board/Ethics Committee  
Documented approval from appropriate IRBs/ECs will be obtained for all participating 
centers/countries prior to study start, according to ICH GCP guidelines, local laws, 
regulations and organizations. When necessary, an extension, amendment or renewal of the 
IRBs/ECs approval must be obtained and also forwarded to the Sponsor. The IRBs/ECs must 
supply to the Sponsor, upon request, a list of the IRBs/ECs members involved in the vote and 
a statement to confirm that the IRB/EC is organized and operates according to ICH GCP 
guidelines and applicable laws and regulations.
7.2
Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation and 
documentation of this study, are designed to ensure that the Sponsor and Investigator abide 
by ICH GCP guidelines. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). This may include an audit by the Sponsor representatives and/or an 
inspection by Regulatory Authority representatives at any time. The Investigator must agree 
to the audit or inspection of study-related records by the Sponsor representatives and/or 
Regulatory Authority representatives and must allow direct access to source documents to the 
Sponsor and/or Regulatory Authority representatives.
Modifications to the study protocol will not be implemented by either the Sponsor or the 
Investigator without agreement by both parties. However, the Investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard(s) to the study 
subjects without prior IRB/EC/Sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IRB/EC/Sponsor. Any deviations from the protocol 
must be fully explained and documented by the Investigator.
7.3
Regulatory Authority Approvals/Authorizations
Regulatory Authority approvals/authorizations/notifications, where required, must be in place 
and fully documented prior to study start. Study information including contact information 
for Investigator sites responsible for conducting the study will be posted on a publicly 
accessible clinical registry(ies) as required by local law.
7.4
Subject Information and Informed Consent Form
Subject information and ICF will be provided to Investigator sites. Prior to the beginning of 
the study, the Investigator must have the IRB/EC written approval/favorable opinion of the 
written ICF and any other written information to be provided to subjects. The written 
approval of the IRB/EC together with the approved subject information/ICF must be filed in 
the study files and a copy of the documents must also be provided to the Sponsor by the 
Investigator site. 


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Written ICF must be obtained before any study specific procedure takes place. If applicable, 
a legally authorized representative may provide informed consent on behalf of the subject. 
Participation in the study and date of ICF given by the subject should be documented 
appropriately in the subject’s files. A signed copy of the subject ICF will be provided to the 
subject or subject’s authorized representative.
7.5
Insurance
Sponsor shall maintain comprehensive general liability insurance or self-insurance in 
amounts adequate to cover any damage, demand, claim, loss or liability caused or incurred 
by Sponsor, or as otherwise required by applicable laws and/or regulations.
7.6
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the Sponsor. Only the subject number will be recorded 
in the eCRF, and if the subject’s name appears on any other document (e.g., pathologist 
report), it must be obliterated before a copy of the document is supplied to the Sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection 
laws. Subjects will be informed in writing that representatives of the Sponsor, IRB/EC or 
Regulatory Authorities may inspect their medical records to verify the information collected 
and that all personal information made available for an audit or inspection will be handled in 
strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects’ records to be identified.
8
USE OF DATA AND PUBLICATION
Institution and the Investigator agree that the first publication shall be made in conjunction 
with the presentation of a joint, multi-center publication of the study results from all 
appropriates sites. If such a multi-center publication is not submitted within twelve (12) 
months after conclusion of the study at all sites or after Grifols confirms there will be no 
joint, multi-center publication, then institution and/or Investigator shall have the right, at 
their discretion, to publish, either in writing or orally, the results of the study performed 
under the protocol, subject to the conditions outlined below:

The results of the study will be reported in the publicly accessible registry(ies).

Institution and/or Investigator shall furnish Grifols with a copy of any proposed 
publication at least thirty (30) days in advance of the date of submission for publication.  

Within said thirty (30) day period, Grifols shall:  
-
Review such proposed publication for Confidential Information (other than Study 
results) and for subject information subject to the Health Insurance Portability and 
Accountability Act of 1996 (“HIPAA”) and other applicable privacy laws;


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-
Review such proposed publication for the unauthorized use of the name, symbols 
and/or trademarks of Grifols;
-
By written notice to the Investigator, identify with specificity the text or graphics in
such proposed publication that Grifols contends contains Confidential Information, 
protected subject information or the unauthorized use of Grifols’ name, symbols 
and/or trademarks so that the proposed publication may be edited appropriately to 
remove such text or graphics before publication; and 
-
By written request, Grifols may delay proposed publications up to sixty (60) days to 
allow Grifols to protect its interests in Grifols Inventions described in such 
publications.  

Institution and/or Investigator shall give Grifols the option of receiving an 
acknowledgment for its sponsorship of the study in all such publications or presentations. 


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9
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54. Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future 
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10
APPENDICES


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Appendix 1
Schedule of Study Procedures
Screening Baseline & 1st
IP Dose
Completion 
of Loading 
IP Dose
Maintenance Infusion Treatment Period
End of Study/
Early Termination n
Visit
0
1 (Day 1)
1 (Day 2)
2
3
4
5
6
7
8
9
Study Week (or days post 
study drug infusion)
-3
0
0
+7 days 
post
3
+7 days 
post
6
+7 days 
post
9
12
15
+7 days 
post
18
21
24
Informed consent
X
Inclusion/Exclusion Criteriaa
X
X
Randomization b
X
Serum Pregnancy Test c
X
X
Urine Pregnancy Test c
X e
Demographics
X
Medical History
X
Physical Exam d
X
X e
X e
X e
X
Height
X
Weight f
X
X e
X e
Vital signs g
X
X
X
X
X
X
X
X
X
X
X
Collection of Virus Safety 
Retain Samples h
X e
Clinical laboratory 
Assessments (Hematology, 
Chemistry)
X
X e
X e
X e
X
QMG score i
X
X e
X e
X e
X e
X e
X e
X e
X e
X
MG Composite 
X
X e
X e
X e
X e
X e
X e
X e
X e
X
MG-QOL 15 
X e
X e
X e
X


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Screening Baseline & 1st
IP Dose
Completion 
of Loading 
IP Dose
Maintenance Infusion Treatment Period
End of Study/
Early Termination n
Visit
0
1 (Day 1)
1 (Day 2)
2
3
4
5
6
7
8
9
Study Week (or days post 
study drug infusion)
-3
0
0
+7 days 
post
3
+7 days 
post
6
+7 days 
post
9
12
15
+7 days 
post
18
21
24
MG-ADL 
X e
X e
X e
X
MGFA Clinical 
Classification
X
X
MGFA Postinterventional 
change in statusj
X
Blood for IgG (trough) 
X e
X e
X e
X
Blood for Anti-AChR 
Antibodies
X
Quantitative/semi-
quantitative binding, 
blocking, and modulating 
AChR antibodies 
X e
X e
X
Hemolysis evaluation 
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Thromboembolism 
evaluation (Wells Score and 
D-Dimers)
X
Xk
Xk
Xk
Xk
Xk
AE Assessment (includes 
clinical observation of signs 
and symptoms suggestive of 
any significant disease or 
condition [e.g., thrombosis, 
anemia, etc.])
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Administration of IP
X l
X l
X m
X m
X m
X m
X m
X m
X m
AChR = acetylcholine receptor, AE = adverse event, IgG = immunoglobulin G, IP = investigational product, MG = myasthenia gravis, MG-ADL = myasthenia 
Gravis-Activities of Daily Living, MGFA = Myasthenia Gravis Foundation of America, MG-QOL = Myasthenia Gravis-Quality of Life, QMG = quantitative 
myasthenia gravis. 
a
Inclusion/exclusion criteria must be satisfied before the subject is randomized and receives the first IP infusion.


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b
A randomization number will be assigned to each subject based on a 1:1 randomization schedule.
c
Potential child-bearing females only; results must be negative at Screening and Baseline for subject to continue in the study.
d
Excludes breast and genitourinary exam.
e
Assessments to be performed prior to IP infusion.
f
Each recorded weight will be used to calculate the IP infusion dose for the scheduled visit and subsequent IP infusions until the next scheduled weight is measured.
g
Full vital signs including temperature, respiratory rate, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) will be recorded at each visit. 
During the infusions, abbreviated vital signs (HR, SBP, and DBP) will be recorded just before the start of each infusion (within 15 ± 5 minutes before the beginning of each 
infusion), 30 ± 10 minutes after starting infusion, and immediately after infusion completes.
h
Collect blood samples at Baseline/Week 0 (Visit 1) prior to randomization but test only if the subject exhibits clinical signs and symptoms consistent with hepatitis A, 
hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or parvovirus B19 infection while participating in the study. See Section 3.8.3.3 and Table 3-1 for details.
i
Subjects must withhold their acetylcholinesterase inhibitor (e.g., pyridostigmine) dosage for 12 hours prior to the visit to assure accurate assessment of the QMG.
j
Modified Myasthenia Gravis Foundation of America (MGFA) postinterventional change in status relative to Baseline will be evaluated at Week 24 (Visit 9) wherein the 
Investigator will classify the patient as: (I) Improved, defined as a substantial decrease in pretreatment clinical manifestations of MG, QMG decrease ≥ 3 points; (U) 
Unchanged, defined as no substantial change in pretreatment clinical manifestations of MG; (W) Worse, defined as a substantial increase in pretreatment clinical 
manifestations of MG, QMG increase ≥ 3 points.
k
Hemolysis evaluation (laboratory parameters) and thromboembolism evaluation will be performed at Baseline prior to start of first IP loading infusion, at the end of the first 
infusion of the loading dose, at the time when last loading infusion is complete, and at the completion of each designated maintenance dosage at Week 3 and Week 6 (Visit 2 
and 3) and at Week 15 (Visit 6). Hemolysis evaluation includes hemoglobin (Hb), hematocrit, red blood cell count (RBC), blood smear, serum free-Hb, haptoglobin, lactate 
dehydrogenase (LDH), direct antiglobulin test (DAT), absolute reticulocyte count (ARC), total and direct/indirect bilirubin, urine for urinary sediment and hemoglobinuria, 
and hematuria. Hemolysis evaluation (laboratory parameters) will also be performed 7 days post loading dose infusion at Baseline (Week 0) and 7 days post study drug
infusion at Weeks 3 (Visit 2), 6 (Visit 3), and 15 (Visit 6).
l
Initiation of induction (loading) dose of IVIG 2 g/kg of body weight begins after all Baseline assessments are complete and patient is randomized. Loading dose is infused 
over 2 days. Note that for the loading dosage 2 days is standard (2 to 4 days is allowed as an extension for tolerability issues or higher weight, i.e., limit for IGIV-C infusion is 
no more than 80g/day [corresponding to 80 kg body weight]).
m
Maintenance doses of 1 g/kg of body weight are administered over 1 day every three weeks through Week 21 (Visit 8). Note that the maintenance dosage is given over 1 day 
as the standard time interval (divided dosage over 2 days is allowed for tolerability issues or higher weight, i.e., limit for IGIV-C infusion is no more than 80g/day 
[corresponding to 80 kg body weight]).
n
The Early Termination visit will consist of the same assessments as Week 24 (Visit 9) except for quantitative/semi-quantitative binding, blocking, and modulating 
acetylcholine receptor (AChR) antibodies which are not required.


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Appendix 2
MGFA Clinical Classification
Classification
Description
Class I
Any ocular muscle weakness; may have weakness of eye closure. All other 
muscle strength is normal
Class II
Mild weakness affecting muscles other than ocular muscles; may also have 
ocular muscle weakness of any severity
IIa
Predominantly affecting limb, axial muscles, or both. May also have lesser 
involvement of oropharyngeal muscles
IIb
Predominantly affecting oropharyngeal, respiratory muscles, or both. May 
also have lesser or equal involvement of limb, axial muscles, or both
Class III
Moderate weakness affecting muscles other than ocular muscles; may also 
have ocular muscle weakness of any severity
IIIa
Predominantly affecting limb, axial muscles, or both. May also have lesser 
involvement of oropharyngeal muscles
IIIb
Predominantly affecting oropharyngeal, respiratory muscles, or both. May 
also have lesser or equal involvement of limb, axial muscles, or both
Class IV
Severe weakness affecting muscles other than ocular muscles; may also 
have ocular muscle weakness of any severity
IVa
Predominantly affecting limb, axial muscles, or both. May also have lesser 
involvement of oropharyngeal muscles
IVb
Predominantly affecting oropharyngeal, respiratory muscles, or both. May 
also have lesser or equal involvement of limb, axial muscles, or both
Class V
Defined as intubation, with or without mechanical ventilation, except when 
employed during routine postoperative management. The use of a feeding 
tube without intubation places the patient in class IVb


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Appendix 3
QMG Test Items
 


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Appendix 4
MG Composite Scale  


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Appendix 5
MG Activities of Daily Living (MG-ADL) Profile


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Appendix 6
MG-Quality of Life (QOL) 15


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Appendix 7
Monitoring of Thromboembolic Events Risk
Subjects will be monitored for signs and symptoms of arterial and venous thromboembolic 
(TE) events. Arterial and venous TE events will be identified according to definitions in the 
International Classification of Diseases (ICD) [51]. Such events include, but are not limited 
to, deep vein thrombosis (DVT), pulmonary embolism (PE), acute myocardial infarction, 
cerebral infarction, acute ischemic heart disease, embolism or thrombosis of arteries of lower 
extremities, sagittal sinus thrombosis, portal vein thrombosis and injury of mesenteric artery.  
All TE events will be recorded as adverse events (AEs) and reported accordingly. Any TE 
event fulfilling any of the criteria for “serious” will be reported as a serious adverse event 
(SAE).
The Sponsor’s Medical Monitor (or designee) will routinely review reported AEs for possible 
TE events.
Thromboembolic events risk will be determined by the Investigator or appropriate study staff 
as indicated by the following schedule (Table 1):
Table 1.
Schedule of Monitoring of Thromboembolic Events Risk
Study visit
Wells score
D-dimer
Signs & symptoms of 
DVT and PE*
Screening
X
X
X
Baseline (Week 0/prior to 
randomization)
X
X
X
End of first IP loading dose 
X
X
X
At the time when last loading 
infusion is complete
X
X
X
Weeks 3, 6, and 15 following 
completion of each 
maintenance infusion dosage
X
X
X
* Evaluation of clinical signs and symptoms of arterial and venous TE as part of AEs assessment.
And using the following assessments: 
The Wells Score [53] will be utilized to assess the clinical characteristics indicative of 
possible DVT or PE (Table 2); 
Measurement of D-dimer blood levels [54]; Evaluation of clinical signs and symptoms of 
arterial and venous TE as part of AEs assessment. 


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Table 2.
Schedule of Monitoring of Thromboembolic Events Risk
DEEP VEIN THROMBOSIS
Clinical Characteristic
Score
Active cancer (treatment ongoing, within previous 6 months or palliative)
  1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
  1
Recently bedridden >3 days or major surgery within previous 12 weeks 
requiring general or regional anesthesia
  1
Previously documented DVT
  1
Localized tenderness along distribution of deep venous system
  1
Entire leg swollen
  1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below 
tibial tuberosity)
  1
Pitting edema confined to the symptomatic leg
  1
Collateral superficial veins (non-varicose)
  1
Alternative diagnosis at least as likely as DVT
-2
Total Score:
PULMONARY EMBOLISM
Clinical Characteristic
Score
Previous DVT or PE 
  1.5
Surgery or bedridden for 3 days during past 4 weeks
  1.5
Active cancer (treatment within 6 months or palliative)
  1
Hemoptysis
  1
Heart rate >100 beats/min
  1.5
Clinical signs of DVT
  3
Alternative diagnosis less likely than PE
  3
Total Score:


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Thromboembolic events risk will be assessed according to the following algorithm adapted 
from Wells [53] (Figure 1 and Figure 2): 
Figure 1. Algorithm to Assess Thromboembolic Events Risk for DVT
•
The Wells Score
•
D-dimer
•
Signs & symptoms of TE
No TE risk
The Wells Score 
(>1 in DVT)
TE risk
The Wells Score 
(≤1 in DVT)
D-dimer (-)
D-dimer (-)
D-dimer (+)
D-dimer (+)
Signs & 
symptoms of 
TE (present)
Signs & 
symptoms of TE 
(not present)
No TE risk
TE risk
TE risk 
Any subject with a total Wells prediction score >1 for DVT assessment should have further 
diagnostic testing per study site standard of care to confirm the occurrence of a TE (Figure 
1). 
Any subject with a total Wells prediction score ≤1 for DVT assessment and a positive D-
dimer value (i.e., above Baseline, out of normal range of the reporting laboratory) in 
combination with clinical signs or symptoms of a TE (as per AEs assessment and such as 
pain, dyspnea, discoloration -paleness or redness- in lower extremities) should have further 
diagnostic testing per study site standard of care to confirm the occurrence of a TE (Figure 
1). 


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Figure 2. Algorithm to Assess Thromboembolic Events Risk for PE
•
The Wells Score
•
D-dimer
•
Signs & symptoms of TE
No TE risk
The Wells Score 
(>4 in PE)
TE risk
The Wells Score 
(≤4 in PE)
D-dimer (negative)
D-dimer (positive)
TE risk
D-dimer (negative)
D-dimer (positive)
TE risk
Any subject with a total Wells prediction score >4 for PE assessment should have further 
diagnostic testing per study site standard of care to confirm the occurrence of a TE (Figure 
2). 
Any subject with a total Wells prediction score ≤4 for PE assessment and a positive D-dimer 
value (i.e., above Baseline, out of normal range of the reporting laboratory) should have 
further diagnostic testing per study site standard of care to confirm the occurrence of a TE 
(Figure 2). 


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Appendix 8
Hemolysis Detection
Schedule of the Procedures:
Study visit
Blood testing
Urine testing
Clinical 
parameters
Baseline (Week 0/prior to randomization)
X
X
X
End of first IP loading dose
X
X
X
At the time when last loading infusion is 
complete a
X
X
X
Weeks 3, 6, and 15 following completion of 
each maintenance infusion dosage a
X
X
X
a
Hemolysis evaluation (laboratory parameters) will also be performed 7 days post loading dose infusion at 
Baseline (Week 0) and 7 days post study drug infusion at Weeks 3 (Visit 2), 6 (Visit 3), and 15 (Visit 6).
Description of the procedures:
For the detection of hemolysis, the following procedure will be carried out to all the study 
population:
1. Blood testing: whole blood Hb, serum free Hb, haptoglobin, LDH, DAT, ARC, RBC, 
hematocrit, TBL and indirect bilirubin, and blood smear.
2. Urine testing: urinary sediment and hemoglobinuria.
3. Clinical parameters including red/dark urine, jaundice, as well as other signs and 
symptoms of anemia (such as pallor or tachycardia).
Definition of hemolysis associated with the use of IGIV-C: 
In this clinical trial, an IVIg-associated hemolytic reaction is one in which there is evidence 
of a new hemolytic process [55]. Consideration of possible hemolysis as defined below 
should only be triggered if other explanatory factors/conditions can be excluded. Subjects 
from this study may be severely ill and may have anemia for a number of reasons. Therefore, 
it is important to exclude the underlying conditions and concomitant medications as a cause 
of anemia. The exclusions are:
-
History or examination consistent with an alternative cause of anemia including blood 
loss (e.g., frequent phlebotomy is highly associated with changes in Hb and hematocrit 
levels for patients admitted to an internal medicine service [56, 57]), iron-deficiency 
anemia, other drug-induced hemolytic anemia, or anemia associated with an underlying 
disease (e.g., autoimmune hemolytic anemia [58, 59]).
-
Negative DAT.
Absence of other inclusion criteria, in particular absence of evidence for hemolysis.


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Potential events would require the following laboratory signs to be present (with the above 
caveats): 
1. Drop in whole blood Hb of ≥10 g/L*
AND
2. Positive DAT
AND
3. At least 2 of:
-
increased ARC*
-
hemoglobinemia
-
increased LDH level*
-
hemoglobinuria 
-
significant spherocytosis
-
low haptoglobin level*
-
unconjugated hyperbilirubinemia
* Abnormal values without other explanation (e.g., LDH elevation due to muscle damage or 
increased reticulocyte count in the setting of hemorrhage) which show a clinically relevant change 
from pre-treatment values.


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Appendix 9
Summary of Changes for Amendment 1
(Note: Administrative changes including minor administrative corrections and the changes in the protocol synopsis are not included in Protocol Summary of 
Changes.)
Sections
Change From:
Change To:
Rationale:
Protocol 
Synopsis
Approximately 30 study centers
Approximately 30 40 study centers
Number of study 
centers increased to 
enhance recruitment
Protocol 
Synopsis
3.2.1
Inclusion Criterion #6
2.
Cholinesterase inhibitor (pyridostigmine or equivalent) for 
at least 2 weeks prior to Screening and/or only one of the 
following:

Prednisone (up to 60 mg/day or equivalent) for at 
least one month prior to Screening, or

Azathioprine for at least 6 months prior to 
Screening, or

Mycophenolate mofetil for at least 6 months prior 
to Screening, or

Cyclosporine or tacrolimus for at least 3 months 
prior to Screening
3.
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:

Azathioprine for at least 6 months prior to 
Screening, or

Mycophenolate mofetil for at least 6 months prior 
to Screening, or

Cyclosporine or tacrolimus for at least 3 months 
prior to Screening 
Inclusion Criterion #6
4.
Cholinesterase inhibitor (pyridostigmine or equivalent) for 
at least 2 weeks prior to Screening and/or only one of the 
following:

Prednisone (up to 60 mg/day or equivalent) for at 
least one two months prior to Screening, or

Azathioprine for at least 6 months prior to 
Screening, or

Mycophenolate mofetil for at least 6 months prior 
to Screening, or

Methotrexate for at least 6 months prior to 
Screening, or

Cyclosporine or tacrolimus for at least 3 months 
prior to Screening
5.
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:

Azathioprine for at least 6 months prior to 
Screening, or

Mycophenolate mofetil for at least 6 months prior 
to Screening, or

Methotrexate for at least 6 months prior to 
Screening, or

Cyclosporine or tacrolimus for at least 3 months 
prior to Screening 
Prednisone 
requirement modified 
from “one month” to 
“two months” for the 
portion of the 
inclusion criterion 
describing 
monotherapies so that 
those subjects on 
prednisone 
monotherapy at study 
entry will establish 2 
months stable dosing 
on monotherapy.
Criterion modified to 
include methotrexate 
to accommodate 
current clinical 
practice patterns for 
myasthenia gravis 
(MG) management


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Sections
Change From:
Change To:
Rationale:
Protocol 
Synopsis
3.2.1
Inclusion Criterion #7
Subjects must be willing and able to provide written informed 
consent (if applicable, a legally authorized representative may 
provide informed consent on behalf of the subject).
Inclusion Criterion #7
Subjects must be willing and able to provide written informed 
consent (if applicable, a legally authorized representative may 
provide informed consent on behalf of the subject).
Intended subjects 
participating in study 
are those who are 
competent and can 
provide their own 
informed consent.
Protocol 
Synopsis
3.2.2
Exclusion Criterion #5
Evidence of malignancy or bulky thymoma potentially 
requiring surgical intervention during the course of the trial
Exclusion Criterion #5
Evidence of malignancy within the past 5 years (non-
melanoma skin cancer, carcinoma in situ of cervix is 
allowed) or bulky thymoma potentially requiring surgical 
intervention during the course of the trial (intent to perform 
thymectomy)
Clarification provided 
regarding malignancy 
exclusion (timeframe 
and exceptions)
Protocol 
Synopsis
3.2.2
Exclusion Criterion #6
Thymectomy within the preceding three months
Exclusion Criterion #6
Thymectomy within the preceding three six months
Longer timeframe post 
thymectomy allowed 
for MG symptom 
stabilization post 
intervention
Protocol 
Synopsis
3.2.2
Exclusion Criterion #11
Plasma exchange (PLEX) performed within the last 2 months
Exclusion Criterion #11
Plasma exchange (PLEX) performed within the last 2 3 months
Timing updated to 
make eligibility 
consistent across MG 
maintenance program


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Sections
Change From:
Change To:
Rationale:
Protocol 
Synopsis 
New text added to Safety Analysis section
This study will utilize an Independent Safety Review 
Committee (ISRC) whose members (from Grifols) will be 
impartial and independent of the clinical trial team. The 
clinical trial team will remain blinded to subject treatment 
assignment. The ISRC will review relevant safety 
information from the study as outlined in the ISRC 
Charter. At a minimum, after the first 20 subjects are 
enrolled and have completed half of the treatment period, 
the ISRC will conduct a safety review of the following data 
at a minimum:
6.
AEs, SAEs, and discontinuations due to AEs and SAEs
7.
Vital signs
8.
Blood chemistry and hematology
9.
Assessing for TEs
10. Assessing for hemolysis
During the study, the Medical Monitor will review all 
relevant safety information from the study in order to 
protect subject welfare and preserve study integrity. Data 
to be reviewed include but are not limited to the following: 
eCRFs, listings from the clinical and safety databases, 
AEs/SAE reports, concomitant medications, laboratory 
data, vital signs, and physical examinations data.
Addition of 
Independent Safety 
Review Committee to 
provide assurance of 
objective, regular and 
comprehensive safety 
data review at defined 
intervals; also 
included is further 
detail regarding 
medical monitoring 
activities.
3.1
Approximately 62 adult subjects will be randomized at 
approximately 30 global study centers.
Approximately 62 adult subjects will be randomized at 
approximately 30 40 global study centers.
Number of study 
centers increased to 
enhance recruitment
3.5
New text added to Prior and Concomitant Therapy
Diphenhydramine, acetaminophen/ibuprofen, and non-
steroidal anti-inflammatory drugs are allowed during the 
trial as pre-medications for study drug infusions. These 
and any other concomitant medication taken during the 
study period must be documented in the subject’s medical 
records and the eCRF.
Clarification that 
discretionary pre-
medication for study 
drug infusion is 
allowed at the 
investigator’s 
discretion.


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Sections
Change From:
Change To:
Rationale:
3.6.4
…An average 3-point improvement in QMG score indicates 
clinically meaningful improvement (37, 38).
…An average 3-point improvement in QMG score indicates 
clinically meaningful improvement in terms of minimal 
clinically important difference and precedent set by 
endpoints in other MG studies (37, 38).
Additional details 
provided and new 
reference added 
pertaining to QMG 
categorical efficacy 
endpoint
3.7.2
….will be assessed at Baseline/Week 0 (Visit 1) and the time 
points specified above.
….will be assessed at Baseline/Week 0 (Visit 1) and the time 
points specified above. Hemolysis laboratory assessments 
will also be performed 7 days post loading dose infusion at 
Baseline (Week 0) and 7 days post maintenance infusion at 
Weeks 3 (Visit 2), 6 (Visit 3), and 15 (Visit 6).
Additional measure of 
laboratory parameters 
to assure 
comprehensive 
potential hemolysis 
surveillance
3.8.2
The following is a description of the procedures/assessments to 
take place at each study visit. See the Schedule of Study 
Procedures in Appendix 1 for a summary of study visits and 
the procedures conducted at each visit.
The following is a description of the procedures/assessments to 
take place at each study visit. Each MG assessment should be 
performed by the same clinical staff member whenever 
possible. See the Schedule of Study Procedures in Appendix 1 
for a summary of study visits and the procedures conducted at 
each visit.
Clarification provided 
to emphasize 
consistency in 
evaluator where 
feasible
3.8.2.3
Post-Baseline/Post-Randomization Loading Dose Infusion –
new assessment added
Post-Baseline/Post-Randomization Loading Dose Infusion
11. Additional hemolysis evaluation (laboratory 
parameters) will be performed 7 days post loading dose 
infusion
Additional measure of 
laboratory parameters 
to assure 
comprehensive 
potential hemolysis 
surveillance
3.8.2.4
New assessment added
12. Additional hemolysis evaluation (laboratory 
parameters) will be performed 7 days post 
maintenance infusion
Additional measure of 
laboratory parameters 
to assure 
comprehensive 
potential hemolysis 
surveillance
3.8.2.7
Assessments to be performed pre-infusion
New Assessment added
Assessments to be performed pre-infusion (except as 
specified):
13. Additional hemolysis evaluation (laboratory
parameters) will be performed 7 days post 
maintenance infusion
Additional measure of 
laboratory parameters 
to assure 
comprehensive 
potential hemolysis 
surveillance


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Sections
Change From:
Change To:
Rationale:
3.8.3
Table 3-1
b.
At time points (Baseline and Week 15) where Chemistry 
and Hematology are coincidentally drawn, whole blood 
Hb, hematocrit, RBC will be obtained from hematology 
specimen; similarly TBL will be from the Chemistry 
sample.
b.
At time points (Baseline and Week 15) where Chemistry 
and Hematology are coincidentally drawn, whole blood 
Hb, hematocrit, RBC will be obtained from hematology 
specimen; similarly TBL will be from the Chemistry 
sample.
Footnote removed 
since timing of these 
parameters is post 
infusion
3.8.3.2
Laboratory assessments (whole blood hemoglobin, serum free 
hemoglobin, haptoglobin, LDH, DAT, ARC, RBC, hematocrit, 
TBL and indirect bilirubin, and blood smear) and urine 
assessments (for urinary sediment and hemoglobinuria, 
hematuria) will be conducted at Baseline (Week 0 prior to 
randomization), at the end of the first infusion of the loading 
dose, at the time when last loading infusion is complete, and at 
the completion of maintenance infusion dosage at Week 3 
(Visit 2), Week 6 (Visit 3), and Week 15 (Visit 6). Appendix 8 
provides details.
Laboratory assessments (whole blood hemoglobinHb, serum 
free hemoglobinHb, haptoglobin, LDH, DAT, ARC, RBC, 
hematocrit, TBL and indirect bilirubin, and blood smear) and 
urine assessments (for urinary sediment and hemoglobinuria, 
hematuria) will be conducted at Baseline (Week 0 prior to 
randomization), at the end of the first infusion of the loading 
dose, at the time when last loading infusion is complete, and at 
the completion of maintenance infusion dosage at Week 3 
(Visit 2), Week 6 (Visit 3), and Week 15 (Visit 6). Hemolysis 
laboratory assessments will also be performed 7 days post 
loading dose infusion at Baseline (Week 0) and 7 days post 
maintenance infusion at Weeks 3 (Visit 2), 6 (Visit 3), and 
15 (Visit 6). Appendix 8 provides details.
Additional measure of 
laboratory parameters 
to assure 
comprehensive 
potential hemolysis 
surveillance
3.8.3.4
[In reference to quantitative/semi-quantitative binding, 
blocking and modulating acetylcholine receptor antibodies]
All measurements will be conducted using qualified assays. 
Specific details regarding all aspects of sample collection and 
processing can be found in the central laboratory Study 
Reference Manual.
[In reference to quantitative/semi-quantitative binding, 
blocking and modulating acetylcholine receptor antibodies]
Baseline and Week 9 (Visit 4) and End of Study Visit 
(Week 24) results will not be shared during study conduct 
with the investigator, blinded study staff, CRO, or blinded 
Sponsor personnel involved with study conduct. All 
measurements will be conducted using qualified assays. 
Specific details regarding all aspects of sample collection and 
processing can be found in the central laboratory Study 
Reference Manual.
Additional language 
added to state 
measures already in 
place to assure that 
quantitative antibody 
measurements could 
not be construed for 
treatment assignment 
inference.
3.9
Subjects may re-screen for the study if the reason for screen 
failure is no longer relevant.
Subjects may re-screen for the study if the reason for screen 
failure is no longer relevant; a new informed consent form 
must be signed for re-screening.
Procedural 
clarification
4.3.6
In the event that true hemolytic anemia develops, it will be 
considered an AE and/or an SAE depending on whether 
seriousness criteria are met.
In the event that true hemolytic anemia develops, it will be 
considered an AE and/or an SAE depending on whether 
seriousness criteria are met. Hemolytic ARs are defined as 
temporally associated with the study drug within 7 days 
post infusion.
Specific definition 
added to be consistent 
with comprehensive 
monitoring for 
potential hemolysis 
effects.


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Sections
Change From:
Change To:
Rationale:
4.4.5
Events not listed for the particular drug under investigation in 
the IB or SPC are considered “unexpected” and those listed are 
considered “expected.” When new AE information is received, 
it is the Sponsor’s responsibility to determine whether the 
event is “unexpected” for Investigational New Drug (IND) 
safety reporting purposes.
Events not listed for the particular drug under investigation in 
the IB or SPC are considered “unexpected” and those listed are 
considered “expected.” When new AE information is Serious 
ADRs (Serious potentially-related AEs) are received, it is 
the Sponsor’s responsibility to determine whether the events is
are “unexpected” for Investigational New Drug (IND)
expedited safety reporting purposes.
Text updated to reflect 
global clinical study
4.4.8
Variable #9
outcome and sequel (follow-up on AE)
*Causality assessment will be only made when the AE occurs 
after the subject has initiated at least one infusion of the IP. 
AEs occurring before subject's exposure to IP will be always 
labeled as "unrelated".
Variable #9
outcome and sequel (follow-up on AE)
*Causality assessment will be only made when the AE occurs 
after the subject has initiated at least one infusion of the IP. 
AEs occurring before subject's exposure to IP will be always 
labeled as "unrelated".
Clarification provided 
to emphasize that 
while pre-IP AEs 
could not reasonably 
be attributed to study 
drug (never received) 
causality is always 
assessed
4.4.9
Grifols Global Drug Safety
Email:
FAX (back-up only): 
Grifols Global Drug Safety Pharmacovigilance
Email: 
FAX (back-up only):
 (US/Canada)
and 
 (International)
Addition of 
international fax 
number


Protocol GTI1408 – Amendment 1   
15 Jul 2015  
CONFIDENTIAL
   Page 97 of 98
Sections
Change From:
Change To:
Rationale:
6
New Section Added – ADMINISTRATIVE
5.3 – Investigators, Other Study Personnel and External 
Committees
New Section Added
6 – ADMINISTRATIVE
5.3 6.1 – Investigators, Other Study Personnel and External 
Committees
1.
6.1.1 - Independent Safety Review Committee
This study will utilize an Independent Safety Review 
Committee (ISRC) whose members (from Grifols) will be 
impartial and independent of the clinical trial team. The 
clinical trial team will remain blinded to subject treatment 
assignment. The ISRC will review relevant safety 
information from the study as outlined in the ISRC 
Charter. At a minimum, after the first 20 subjects are 
enrolled and have completed half of the treatment period, 
the ISRC will conduct a safety review of the following data 
at a minimum:

AEs, SAEs, and discontinuations due to AEs and 
SAEs

Vital signs

Blood chemistry and hematology

Assessing for TEs

Assessing for hemolysis
During the study, the Medical Monitor will review all 
relevant safety information from the study in order to 
protect subject welfare and preserve study integrity. Data 
to be reviewed include but are not limited to the following: 
eCRFs, listings from the clinical and safety databases, 
AEs/SAE reports, concomitant medications, laboratory 
data, vital signs, and physical examinations data.
Addition of 
Independent Safety 
Review Committee to 
provide assurance of 
objective, regular and 
comprehensive safety 
data review at defined 
intervals; also 
included is further 
detail regarding 
medical monitoring 
activities.


Protocol GTI1408 – Amendment 1   
15 Jul 2015  
CONFIDENTIAL
   Page 98 of 98
Sections
Change From:
Change To:
Rationale:
9
Reference #37
Bedlack RS, Simel DL, Bosworth H, Samsa G, Tucker-
Lipscomb B, Sanders DB. Quantitative myasthenia gravis 
score: Assessment of responsiveness and longitudinal validity. 
Neurology 2005; 64: 1968-1970.
Reference #37
Bedlack RS, Simel DL, Bosworth H, Samsa G, Tucker-
Lipscomb B, Sanders DB. Quantitative myasthenia gravis 
score: Assessment of responsiveness and longitudinal validity. 
Neurology 2005; 64: 1968-1970. 
The evaluation of belimumab in myasthenia gravis (MG), 
[Internet], (2015) [updated 2015 Jun 25]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01480596?term=NC
T01480596&rank=1
Reference updates
Appendix 1
Study Week
New assessment added
New row added
k. Hemolysis evaluation (laboratory parameters) and 
thromboembolism evaluation will be performed at Baseline 
prior to start of first IP loading infusion, at the end of the 
first infusion of the loading dose, at the time when last 
loading infusion is complete, and at the completion of each 
designated maintenance dosage at Week 3 and Week 6 
(Visit 2 and 3) and at Week 15 (Visit 6). Hemolysis 
evaluation includes hemoglobin (Hb), hematocrit, red blood 
cell count (RBC), blood smear, serum free-Hb, haptoglobin, 
lactate dehydrogenase (LDH), direct antiglobulin test 
(DAT), absolute reticulocyte count (ARC), total and 
direct/indirect bilirubin, urine for urinary sediment and 
hemoglobinuria, hematuria.
Study Week (or days post study drug infusion)
Additional assessment of +7 days post added to Study Weeks 
0, 3, 6, and 15
k. Hemolysis evaluation (laboratory parameters) and 
thromboembolism evaluation will be performed at Baseline 
prior to start of first IP loading infusion, at the end of the 
first infusion of the loading dose, at the time when last 
loading infusion is complete, and at the completion of each 
designated maintenance dosage at Week 3 and Week 6 
(Visit 2 and 3) and at Week 15 (Visit 6). Hemolysis 
evaluation includes hemoglobin (Hb), hematocrit, red blood 
cell count (RBC), blood smear, serum free-Hb, haptoglobin, 
lactate dehydrogenase (LDH), direct antiglobulin test 
(DAT), absolute reticulocyte count (ARC), total and 
direct/indirect bilirubin, urine for urinary sediment and 
hemoglobinuria, and hematuria. Hemolysis evaluation 
(laboratory parameters) will also be performed 7 days 
post loading dose infusion at Baseline (Week 0) and 7 
days post study drug infusion at Weeks 3 (Visit 2), 6 
(Visit 3), and 15 (Visit 6).
Additional measure of 
laboratory parameters to
assure comprehensive 
potential hemolysis 
surveillance.
Appendix 8
New footnote added
New footnote added: 
a.
Hemolysis evaluation (laboratory parameters) will also 
be performed 7 days post loading dose infusion at 
Baseline (Week 0) and 7 days post study drug infusion 
at Weeks 3 (Visit 2), 6 (Visit 3), and 15 (Visit 6).
Additional measure of 
laboratory parameters to
assure comprehensive 
potential hemolysis 
surveillance.

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STATISTICAL ANALYSIS PLAN 
 
 
GTI1408 
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 
 
 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: FINAL V1.0, 04AUG2017 
 
 




 
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MODIFICATION HISTORY 
 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
0.1 
22NOV2016 
 
Not Applicable – First Version 
0.2 
26JUN2017 
 
Updates from sponsor comments. 
Key changes: 
mITT instead of ITT as primary 
population for efficacy 
Efficacy analyses based on both 
LOCF and OC 
Removal of multiplicity adjustment 
Exposure and Compliance to consider 
dosage across multiple infusion days 
Additional lab test summaries 
Table summary for physical 
examination 
0.3 
24Jul2017 
 
Updates from sponsor comments: 
Key changes: 
Abbreviations 
mITT instead of SAF for medical 
history and medication summaries 
Additional lab test and vital sign 
summaries 
1.0 
04Aug2017 
 
Updates from sponsor comments: 
Key changes: 
Duration of infusion in hours instead 
of minutes 
 
 


 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ..................................................................................................................... 9 
1. INTRODUCTION ............................................................................................................................. 11 
2. STUDY OBJECTIVES ...................................................................................................................... 11 
2.1. 
Primary Objective................................................................................................................................... 11 
2.2. 
Secondary Objectives ............................................................................................................................. 11 
2.3. 
Exploratory Objectives ........................................................................................................................... 11 
2.4. 
Safety Objectives ................................................................................................................................... 12 
3. STUDY DESIGN ............................................................................................................................... 12 
3.1. 
General Description ................................................................................................................................ 12 
3.2. 
Schedule of Events ................................................................................................................................. 14 
3.3. 
Changes to Analysis from Protocol .......................................................................................................... 14 
4. PLANNED ANALYSES .................................................................................................................... 14 
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................ 15 
4.2. 
Interim Analysis ..................................................................................................................................... 15 
4.3. 
Final Analysis ......................................................................................................................................... 15 
5. ANALYSIS SETS .............................................................................................................................. 15 
5.1. 
All Subjects Screened Population ............................................................................................................ 15 
5.2. 
Intent-To-Treat Population [ITT] ............................................................................................................. 15 
5.3. 
Modified Intent-To-Treat Population [mITT] ........................................................................................... 16 


 
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5.4. 
Per Protocol Population [PP] .................................................................................................................. 16 
5.5. 
Safety Population [SAF] .......................................................................................................................... 16 
6. GENERAL CONSIDERATIONS ..................................................................................................... 16 
6.1. 
Reference Start Date and Study Day ....................................................................................................... 16 
6.2. 
Baseline ................................................................................................................................................. 17 
6.3. 
Derived Timepoints ................................................................................................................................ 17 
6.4. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 17 
6.5. 
Windowing Conventions ........................................................................................................................ 18 
6.6. 
Statistical Tests ...................................................................................................................................... 18 
6.7. 
Common Calculations ............................................................................................................................. 18 
6.8. 
Software Version .................................................................................................................................... 18 
7. STATISTICAL CONSIDERATIONS ............................................................................................. 18 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ......................................................... 18 
7.2. 
Multicenter Studies ................................................................................................................................ 19 
7.3. 
Missing data ........................................................................................................................................... 19 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................ 19 
7.5. 
Examination of Subgroups ...................................................................................................................... 19 
8. OUTPUT PRESENTATIONS ......................................................................................................... 20 
9. DISPOSITION AND WITHDRAWALS ....................................................................................... 20 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 21 
10.1. 
Derivations ......................................................................................................................................... 21 


 
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11. 
MEDICAL HISTORY ................................................................................................................... 22 
12. 
CONCOMITANT ILLNESSES ..................................................................................................... 22 
13. 
MEDICATIONS ............................................................................................................................ 22 
14. 
STUDY MEDICATION EXPOSURE .......................................................................................... 22 
14.1. 
Derivations ......................................................................................................................................... 23 
15. 
STUDY MEDICATION COMPLIANCE ..................................................................................... 23 
15.1. 
Derivations ......................................................................................................................................... 24 
16. 
EFFICACY OUTCOMES .............................................................................................................. 25 
16.1. 
Primary Efficacy .................................................................................................................................. 25 
16.1.1. 
Primary Efficacy Variable & Derivation .....................................................................................................25 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable ...............................................................................25 
16.1.3. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................25 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................26 
16.2. 
Secondary Efficacy .............................................................................................................................. 26 
16.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................26 
16.2.1.1. 
Percentage of Subjects with a Clinical Improvement Assessed by QMG Total Score at Week 24 ...26 
16.2.1.2. 
Percentage of Subjects with a Clinical Improvement Assessed by MG Composite at Week 24 .......27 
16.2.1.3. 
Percentage of Subjects with a Clinical Improvement Assessed by MG-ADL at Week 24 .................27 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .......................................................................27 
16.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................27 
16.2.3.1. 
Analysis of Clinical Improvement ......................................................................................................27 
16.3. 
Exploratory Efficacy ............................................................................................................................ 28 
16.3.1. 
Exploratory Efficacy Variables & Derivations............................................................................................28 
16.3.1.1. 
Percentage of Subjects with a Clinical Improvement Assessed by QMG Total Score at Weeks 6, 9, 
12, 15, 18, and 21 .................................................................................................................................................28 
16.3.1.2. 
Time to First Clinical Improvement in QMG Total Score ..................................................................28 
16.3.1.3. 
Time to Treatment Failure Based on QMG Total Score ....................................................................28 
16.3.1.4. 
CFB in QMG Total Score at Weeks 6, 9, 12, 15, 18, and 21 ..............................................................28 
16.3.1.5. 
Percentage of Subjects with a Clinical Improvement Assessed by MG Composite Score at Weeks 6, 
9, 12, 15, 18, and 21 .............................................................................................................................................28 
16.3.1.6. 
CFB in MG Composite at Weeks 6, 9, 12, 15, 18, 21, and 24 ............................................................28 
16.3.1.7. 
Percentage of Subjects with a Clinical Improvement Assessed by MG-ADL Score at Weeks 9 and 15
 
29 


 
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16.3.1.8. 
CFB in MG-ADL at Weeks 9, 15, and 24 ............................................................................................29 
16.3.1.9. 
CFB in the 15-item MG-QOL 15 at Weeks 9, 15, and 24 ...................................................................29 
16.3.1.10. MGFA Post-interventional Change in Status at Week 24 Relative to Baseline .................................29 
16.3.1.11. Subgroup Analysis of Primary Efficacy Variable ................................................................................29 
16.3.2. 
Missing Data Methods for Exploratory Efficacy Variables ........................................................................29 
16.3.2.1. 
Analyses of Clinical Improvement .....................................................................................................29 
16.3.2.2. 
Time to Clinical Improvement and Time to Treatment Failure ........................................................30 
16.3.2.3. 
CFB in QMG, MG Composite, MG-ADL, or MG-QOL 15 ....................................................................30 
16.3.2.4. 
MGFA Post-interventional Change in Status ....................................................................................30 
16.3.2.5. 
Subgroup Analysis of Primary Efficacy Variable ................................................................................30 
16.3.3. 
Analysis of Exploratory Efficacy Variables ................................................................................................30 
16.3.3.1. 
Analyses of Clinical Improvement .....................................................................................................30 
16.3.3.2. 
Time to Clinical Improvement and Time to Treatment Failure ........................................................30 
16.3.3.3. 
CFB in QMG, MG Composite, MG-ADL, or MG-QOL 15 The same ANCOVA method described in 
Section 16.1.3 will be used. The MMRM method described in section 16.1.4 will also be used to assess 
longitudinal measurements for the other parameters.........................................................................................30 
16.3.3.4. 
MGFA Post-interventional Change in Status ....................................................................................30 
16.3.3.5. 
Subgroup Analysis of Primary Efficacy Variable ................................................................................31 
17. 
SAFETY OUTCOMES .................................................................................................................. 31 
17.1. 
Adverse Events ................................................................................................................................... 31 
17.1.1. 
All TEAEs ...................................................................................................................................................31 
17.1.1.1. 
Intensity ............................................................................................................................................32 
17.1.1.2. 
Causal-Relationship to Study Medication .........................................................................................32 
17.1.2. 
TEAEs Leading to Discontinuation From the Study ...................................................................................32 
17.1.3. 
Serious Adverse Events .............................................................................................................................32 
17.1.4. 
Adverse Events Leading to Death .............................................................................................................32 
17.1.5. 
Infusional Adverse Events .........................................................................................................................32 
17.1.6. 
Adverse Events Of Special Interest ...........................................................................................................33 
17.2. 
Laboratory Evaluations ....................................................................................................................... 33 
17.2.1. 
Chemistry, Hematology, Hemolysis, Acetylcholine Receptor Antibody (AChR), and Immunoglobulin G 
(IgG) 
33 
17.2.2. 
D-dimer and Wells Score ..........................................................................................................................34 
17.2.3. 
Virus Safety Testing ..................................................................................................................................34 
17.2.4. 
Laboratory Reference Ranges ...................................................................................................................34 
17.3. 
Vital Signs ........................................................................................................................................... 35 
17.4. 
Physical Examination .......................................................................................................................... 35 
18. 
REFERENCES ............................................................................................................................... 36 


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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ............................................... 37 
Quintiles Output Conventions ........................................................................................................................... 37 
Dates & Times ................................................................................................................................................... 42 
Spelling Format ................................................................................................................................................. 42 
Presentation of Treatment Groups .................................................................................................................... 42 
Presentation of Visits ........................................................................................................................................ 42 
Listings .............................................................................................................................................................. 43 
APPENDIX 2. PARTIAL DATE CONVENTIONS .............................................................................. 44 
Algorithm for Treatment Emergence of Adverse Events: .................................................................................... 44 
Algorithm for Prior / Concomitant Medications: ................................................................................................ 45 
APPENDIX 3. QMG TEST ITEMS ........................................................................................................ 48 
APPENDIX 4. MG COMPOSITE SCALE .............................................................................................. 49 
APPENDIX 5. MG-ADL PROFILE ........................................................................................................ 50 
APPENDIX 6. MG-QOL 15 .................................................................................................................... 51 
 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AChR 
Acetylcholine Receptor Antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AR 
Adverse Reaction 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CFB 
Change From Baseline 
CS 
Corticosteroid 
DAT 
Direct Antiglobulin 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
HIV 
Human Immunodeficiency Virus 
IgG 
Immunoglobulin G 
IGIV-C 
Immune Globulin (Human), 10% Caprylate/Chromatography Purified 
IP 
Investigational Product 
ISRC 
Independent Safety Review Committee 
ITT 
Intent-to-Treat 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
Myasthenia Gravis 
MG-ADL 
Myasthenia Gravis – Activities of Daily Living 
MGFA 
Myasthenia Gravis Foundation of America 
MG-QOL 15 
Myasthenia Gravis Quality-of-Life Instrument 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model for Repeated Measures 
NAT 
Nucleic Acid Amplification Technology 
OC 
Observed Case 
PP 
Per Protocol 
PT 
Preferred Term 
QMG 
Quantitative Myasthenia Gravis 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis Software 
SD 
Standard Deviation 
SI 
Standard International 
SOC 
System Organ Class 
TE 
Treatment-Emergent 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 


 
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Abbreviation 
Term 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for Protocol GTI1408. It describes the data to be summarized and analyzed, 
including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 2.0, dated 15 July 2015. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
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 the Quantitative Myasthenia Gravis (QMG) score from Baseline 
(Week 0) to Week 24 as compared to placebo. 
2.2. SECONDARY OBJECTIVES 
The secondary objectives are to evaluate the efficacy of IGIV-C as compared to placebo from Baseline 
through Week 24 in the following: 
• 
Percentage of subjects who experience a clinical improvement assessed by QMG total score from 
Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 3-point 
decrease in QMG total score 
• 
Percentage of subjects who experience a clinical improvement assessed by the MG Composite 
from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 3-point 
decrease in the MG Composite 
• 
Percentage of subjects who experience a clinical improvement assessed by MG – Activities of 
Daily Living (MG-ADL) from Baseline (Week 0) to Week 24 where clinical improvement is defined 
as at least a 2-point decrease in MG-ADL 
2.3. 
 EXPLORATORY OBJECTIVES 
The exploratory objectives are to evaluate the effect of IGIV-C on: 
• 
Percentage of subjects who experience a clinical improvement in QMG total score (at least a 3-
point decrease) at Weeks 6, 9, 12, 15, 18, and 21 
• 
Time to first clinical improvement in QMG total score (at least a 3-point decrease) 


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• 
Time to Treatment Failure based on QMG total score definition (see Section 3.1 of this analysis 
plan and protocol Section 3.3.3) 
• 
Change from Baseline (CFB) (Week 0) in QMG total score to Weeks 6, 9, 12, 15, 18, and 21 
• 
Percentage of subjects who experience a clinical improvement in the MG Composite (at least a 3-
point decrease) to Weeks 6, 9, 12, 15, 18, and 21 
• 
CFB in MG Composite to Weeks 6, 9, 12, 15, 18, 21, and 24 
• 
Percentage of subjects who experience a clinical improvement in MG-ADL (at least a 2-point 
decrease) to Weeks 9 and 15 
• 
CFB in MG-ADL to Weeks 9, 15, and 24 
• 
CFB in the 15-item MG Quality-of-Life Instrument (MG-QOL 15) to Weeks 9, 15, and 24 
• 
Myasthenia Gravis Foundation of America (MGFA) post-interventional change in status at Week 
24 relative to Baseline 
2.4. SAFETY OBJECTIVES 
The safety objective 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.  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of IGIV-C in subjects with MG who are symptomatic on standard of care treatment. Approximately 
62 adult subjects will be randomized at approximately 40 global study centers. 
 
Subjects who are on standard of care treatment for MG may enroll. Eligibility parameters allow 
monotherapy, dual treatment, or three-drug treatment (i.e., various combinations consisting of a 
cholinesterase inhibitor, corticosteroid (CS), and an additional immunosuppressant). Subjects will be 
randomly allocated in a 1:1 ratio to receive either IGIV-C or matched placebo every three weeks in 
double-blinded fashion. Randomization will be stratified by sentinel features of the subject’s Baseline 
standard of care MG treatment regimen at the time randomization: 
 
• 
Regimen includes ONLY cholinesterase inhibitors 


 
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• 
Regimen includes CS as the ONLY IMMUNOSUPPRESSANT/IMMUNOMODULATOR, alone or 
in combination with other MG medications (e.g., a subject on prednisone plus a cholinesterase 
inhibitor would be in this stratum) 
• 
Regimen includes ANY NON-CS IMMUNOSUPPRESSANT/IMMUNOMODULATOR alone or in 
combination with other MG medications which may include CS (e.g., a subject on azathioprine, 
prednisone, and a cholinesterase inhibitor would be in this stratum) 
 
For those subjects randomized to receive IGIV-C, an initial loading dose of 2 g/kg of body weight will be 
administered after the baseline assessments are complete 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). The 
initial loading dose (2 g/kg) will be divided on 2 consecutive days with extension of up to 4 consecutive 
days to account for tolerability/weight >80 kg. The subsequent 7 maintenance dosages (1 g/kg) will be 
infused in one day with an extension to 2 consecutive days (divided doses) to account for 
tolerability/weight >80 kg. For both loading and maintenance infusions the limit for blinded IGIV-C infusion 
is no more than 80 g/day, corresponding to an 80-kg body weight for a 1 g/kg per diem dosage. 
 
For those subjects randomized to receive placebo, a sterile 0.9% sodium chloride injection, United States 
Pharmacopeia (USP) or equivalent 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). 
 
The investigators will hold the subjects’ current background medical regimen constant from Screening 
through the end of the study (Week 24, Visit 9), unless there is a compelling emergent medical need to 
make medication adjustments, the subject discontinues the study because criteria for treatment failure are 
met as defined below (after End of Study visit assessments are complete), or adverse effects due to other 
components of the subject’s therapy become untenable. 
 
MG worsening is defined as a QMG increase by ≥4 points relative to Baseline/Week 0. If a subject 
experiences worsening in QMG total score fulfilling the criterion at or after Week 9, and this worsening 
(increase in QMG of 4 points or more) is confirmed at the next scheduled consecutive visit, the subject will 
be considered a treatment failure and will be discontinued from the study (at completion of the visit where 
confirmation of worsening is demonstrated). If a subject experiences worsening in QMG total score 
fulfilling the criterion above at Week 3 (Visit 2) or Week 6 (Visit 3) and the QMG increase by ≥ 4 points 
relative to Baseline is confirmed at the next scheduled visit (i.e., confirmation at Week 6 [Visit 3] or Week 
9 [Visit 4], respectively), and this ≥ 4-point QMG worsening is maintained through Week 9 (Visit 4), the 
subject will be considered a treatment failure. A subject will not be discontinued from the study for reasons 
of treatment failure until the Week 9 Visit or later. 
 
Week 21 (Visit 8) is the time of the last investigational product (IP) maintenance dosage. Week 24 (Visit 9) 
will constitute the primary endpoint time point for analysis because this timing allows an opportunity to 
assess the effect of the final IP infusion made at Week 21 (Visit 8). Week 24 (Visit 9) will serve as the final 
End of Study Visit. 
 
A schematic of the overall study design and essential activities is shown in Figure A.  


 
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Figure A: Overall Study Schema 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Appendix 1 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
In the protocol, efficacy analyses were to be based on the intent-to-treat (ITT) population, consisting of 
all subjects who were randomized. In this analysis plan, the primary efficacy analysis population has 
been changed to the modified intent-to-treat (mITT) population, consisting of all subjects who were 
randomized and received at least one dose of study medication. 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Final Analysis  


 
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4.1. DATA MONITORING COMMITTEE (DMC)  
There was no DMC for this study. The study did utilize an Independent Safety Review Committee 
(ISRC) whose members (from Grifols) reviewed relevant safety information. The ISRC did not evaluate 
any efficacy data, nor were efficacy analyses performed. Review by ISRC was limited to listings of 
safety parameters (adverse events [AEs], serious adverse events [SAEs], discontinuations due to AEs, 
and laboratory data) evaluated in a blinded fashion unless unblinding became necessary for an 
individual subject (urgently) for critical medical interpretation. Throughout study conduct, the clinical trial 
team members remained blinded to any knowledge of subject treatment assignment stemming from 
ISRC activities. 
4.2. INTERIM ANALYSIS  
No interim analysis for this study was planned. 
4.3. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by Quintiles Biostatistics following 
Sponsor Authorization of this SAP, Database Lock, Sponsor Authorization of Analysis Sets and 
Unblinding of Treatment. 
5. ANALYSIS SETS 
Agreement and authorization of subjects included/ excluded from each population will be conducted 
prior to the unblinding of the study.  
5.1. ALL SUBJECTS SCREENED POPULATION  
The all subjects screened population will contain all subjects who provide informed consent for this 
study. 
5.2. INTENT-TO-TREAT POPULATION [ITT] 
The intent-to-treat population (ITT) will contain all subjects who were randomized to study medication. 
Subjects will be classified according to randomized treatment. 


 
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5.3. MODIFIED INTENT-TO-TREAT POPULATION [MITT] 
The modified intent-to-treat population (mITT) will include all subjects who were randomized and 
received at least one dose of study medication. This is the primary population for efficacy analysis. 
Subjects will be classified according to randomized treatment. 
5.4. PER PROTOCOL POPULATION [PP] 
The Per Protocol population (PP) will contain all subjects in the mITT population who did not experience 
any major protocol violations impacting the primary efficacy data. 
Any deviations from the protocol will be recorded in the protocol deviation list. The validity of a subject 
for inclusion in the PP population will be assessed at a blinded review meeting that will take place 
before unblinding/finalizing the database. The review meeting will review the protocol deviation list, as 
well as data listings. If protocol deviations are identified which justify removing a subject from the PP 
population, then these decisions will be documented. 
5.5. SAFETY POPULATION [SAF] 
The safety population (SAF) will contain all randomized subjects who receive any amount of study 
medication. Subjects will be classified according to treatment received.  
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of 
assessments and events.  
Reference start date is defined as the day of the first dose of study medication, (Day 1 is the day of the 
first dose of study medication), and will appear in every listing where an assessment date or event date 
appears.  
• 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
• 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, the date will appear as the available values in 


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the listings, and any values for study day or corresponding durations will be missing. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to the 
date/time of the first dose of study medication (including unscheduled assessments). In the case where 
the last non-missing measurement and the reference start date coincide, that measurement will be 
considered pre-baseline, unless a particular assessment (such as abbreviated vital signs) or specific 
laboratory draws (e.g., end of infusion laboratory draws) are designated as post baseline. Medications 
commencing on the reference start date will be considered either pre-baseline or post-baseline 
depending on start date and specific start time in relation to the date/time of IP infusion.  
For subjects randomized but not treated, baseline is defined as the last non-missing measurement 
taken on or before the baseline (Visit 1) visit date. 
6.3. DERIVED TIMEPOINTS  
Imputation for missing values will be applied to continuous efficacy endpoints using the last observation 
carried forward (LOCF) method. For subjects who experience treatment failure (defined in protocol 
Section 3.3.3) or MG crisis (defined in protocol Section 3.3.4), the value at time of confirmation of failure 
or at time of MG crisis will be carried forward to impute values for all remaining visits. For subjects who 
discontinued the study early due to any other reasons, the last non-missing on-treatment value 
(including scheduled, unscheduled, and early termination) will be carried forward. In addition, any 
intermittent missing values up to the last visit will be imputed by the closest previous non-missing value. 
Note that if a subject has missing values immediately after baseline, the baseline observation will not be 
carried forward and these values will be left as missing. 
For the same efficacy endpoints above that utilize the LOCF algorithm, separate analyses will also be 
performed using observed data only without imputing any missing data. This non-imputation method will 
be referred to as the observed case (OC). 
Missing values for the binary endpoints (e.g., whether or not the subject experienced clinical 
improvement) will be handled similarly as for the continuous endpoints. First, the LOCF algorithm above 
will be used to impute the (continuous) missing values. The imputed values will then be used to derive 
the binary endpoints. The binary endpoints will also be analyzed with the OC approach. 
Efficacy analyses will be performed on the mITT population using both the LOCF and OC approaches 
with regards to the missing data, which should allow for more robust assessments of efficacy. See 
Section 16 for the set of analyses using each of the two approaches. The LOCF endpoint row in by-visit 
listings will indicate the value that was used in the LOCF efficacy analysis. 
6.4. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit summaries, but will contribute to the best/worst case value 
where required (e.g. shift table). Unscheduled visits may also contribute to QMG at time of treatment 


 
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failure or MG crisis in terms of both LOCF and time to treatment failure analyses. It is also possible that 
unscheduled visits may be used for time to first clinical improvement if the visit timing is appropriate for 
earliest change. 
In the case of a retest (same visit number assigned), the latest available measurement for that visit will 
be used for by-visit summaries.  
Early termination data will not be mapped to the next available visit number for by-visit summaries; 
instead, they will be summarized under a separate “Early Termination” visit. By-visit summaries will only 
present those visits where an assessment is scheduled to be collected. Early termination data will be 
eligible for the LOCF endpoint but will not be mapped for OC analysis. 
6.5. WINDOWING CONVENTIONS  
No visit windowing will be performed for this study. Summaries and statistical analyses will be based on 
scheduled (i.e., nominal visit) data.  Listings will include scheduled, unscheduled, retest and early 
termination data. 
6.6. STATISTICAL TESTS 
Unless otherwise noted, all statistical inference will be tested as 2-sided with α=0.05. 
6.7. COMMON CALCULATIONS 
For quantitative measurements, CFB will be calculated as: 
 
• 
Test Value at Visit X – Baseline Value 
6.8. SOFTWARE VERSION 
All analyses will be conducted using Statistical Analysis Software (SAS) version 9.4 or higher. The 
actual SAS version used to perform the analyses will be documented in the Clinical Study Report. 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the 
models, see the specific analysis section. 


 
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• 
Baseline value 
• 
Treatment group (IGIV-C, Placebo) 
• 
Standard of Care Treatment Regimen at the time of randomization (only cholinesterase inhibitors, 
CS as the only immunosuppressant/immunomodulator, any non-CS 
immunosuppressant/immunomodulator) 
• 
Protocol specified visits (Week 3, Week 6, Week 9, Week 12, Week 15, Week 18, Week 21, Week 
24) 
• 
Treatment-by-visit interaction 
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers internationally. Randomization 
to treatment arms is not stratified by country or center. The number of subjects per center is expected to 
be small. Data from this study will be summarized for all centers combined. No center effect will be 
considered in the statistical models. 
7.3. MISSING DATA 
Refer to Section 6.3 of this analysis plan on detailed approaches for missing data handling. Sensitivity 
analyses for missing data are described in section 16.1.4 of this analysis plan. 
In the calculation of total scores, if one or more items are missing at a given assessment, the total score 
will be set to missing. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
There will be no adjustment for multiple comparisons/multiplicity in this Phase 2 proof of concept study. 
All secondary and exploratory endpoints will be evaluated statistically and will have the corresponding 
results presented with 95% confidence intervals and nominal p-values.  
7.5. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in the exploratory analysis sections. It should be noted 
that the study was not designed to detect treatment differences with high statistical power within 
subgroups. 
The following subgroups will be assessed and described within the exploratory analysis sections:  


 
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• 
Stratification categories in terms of Baseline standard of care MG treatment regimen at the time of 
randomization: 
o 
Only cholinesterase inhibitors 
o 
CS as the only immunosuppressant/immunomodulator 
o 
Any non-CS immunosuppressant/immunomodulator 
• 
Baseline QMG categories in relation to the median Baseline QMG across all subjects: 
o 
< median 
o 
≥ median 
• 
Sex:  
o 
Female 
o 
Male 
• 
Age (years): 
o 
<65 
o 
≥65  
• 
Geographic Region: 
o 
North America (United States, Canada) 
o 
Europe (Czech Republic, France, Germany, Hungary, Estonia, Lithuania, Poland, Belgium) 
• 
MGFA classification at randomization 
o 
Class IIa 
o 
Class IIb 
o 
Class IIIa 
o 
Class IIIb 
o 
Class IVa 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format 
and content of the summary tables, figures and listings to be provided by Quintiles Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study.  
Subject disposition and reasons for discontinuation will be provided for the All Subjects Screened 
population. The list of protocol deviations (as defined in section 5.3), including inclusion and exclusion 


 
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criteria, will be presented for the All Subjects Screened population. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the mITT population. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
• 
Age (years) - calculated relative to date of consent 
• 
Sex 
• 
Race  
• 
Ethnicity 
• 
Geographic Region 
• 
Screening Weight (kg) 
• 
Height (cm) 
• 
Screening Body Mass Index (BMI) (kg/m2) 
• 
Time since diagnosis (years) - calculated relative to date of consent 
• 
Tests performed to confirm MG 
• 
MGFA classification at time of diagnosis 
• 
MGFA classification at screening 
• 
MGFA classification at randomization 
• 
MG treatment used during last six months 
• 
Thymectomy history (yes/no) 
• 
Standard of Care Treatment Regimen at randomization 
10.1. DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 


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11. MEDICAL HISTORY 
Medical History information will be presented for the mITT population.  
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 17.1, 
and presented by System Organ Class (SOC) and Preferred Term (PT). 
12. CONCOMITANT ILLNESSES 
All Concomitant Illnesses will be reported as medical history or as adverse events, as appropriate, and 
will contribute to the corresponding summaries. 
13. MEDICATIONS 
Medications will be presented for the mITT population and coded using World Health Organization 
(WHO) Drug Dictionary Enhanced 01MAR2015. Medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) Class Level 2 and Medication Sub-Class ATC Level 4. If the ATC Level 2 
or 4 term is missing, the higher level term will be used in the medication summary tables and data 
listing. 
See Appendix 2 for handling of partial dates and times for medications. In the case where it is not 
possible to define a medication as prior or concomitant, the medication will be classified by the worst 
case; i.e. concomitant.  
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of study 
medication.  
• 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the first dose of study medication,  
o 
AND ended on or after the date and time of first dose of study medication or were ongoing 
at the end of the study. 
14. STUDY MEDICATION EXPOSURE 
Exposure to study medication in weeks will be presented for the Safety population. 
The date of first study medication administration will be taken as the earliest start date of infusion from 
the electronic Case Report Form (eCRF) Study Drug Infusion form. The date of last study medication 
will be taken as the latest stop date from the eCRF Study Drug Infusion form. 
Interruptions, compliance, and dose changes are not taken into account for duration of exposure.  
The total number of dosages, the total number of days of infusions, and the total volume infused (in mL) 
will be summarized on a per-subject basis. Note that subjects can have more than one infusion day per 
treatment visit. The initial loading dosage (2 g/kg) will be divided on 2 consecutive days with extension 


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of up to 4 consecutive days to account for tolerability and/or weight >80 kg. The subsequent 7 
maintenance dosages (1 g/kg) will be infused in one day with an extension to 2 consecutive days 
(divided dosages) to account for tolerability and/or weight >80 kg. For both loading and maintenance 
dosages the limit for blinded IGIV-C infusion is no more than 80 g/day, corresponding to an 80-kg body 
weight for a 1 g/kg per diem dosage. 
In addition, the following variables will be derived and summarized separately for the loading dosage 
and the maintenance dosages: 
On a per-subject basis: 
• 
Number of dosage(s) received 
On a per-dosage basis: 
• 
Dosage in grams 
• 
Dosage in g/kg 
• 
Number of infusion days 
On a per-infusion basis: 
• 
Duration of infusion in hours 
14.1. DERIVATIONS 
Duration of exposure (weeks) = (date of last study medication administration – date of first study 
medication administration + 21)/7. The addition of 21 days is to take into account total exposure time to 
the study medication since the dosages are administrated every 3 weeks. Based on this derivation, the 
minimum exposure for any treated subject is 21 days. 
In the below derivations, a dosage includes all infusion days within a given treatment visit. 
Number of dosage(s) received will be determined directly from entries in the eCRF Study Drug Infusion 
form. 
Dosage (g) = Total volume infused for the indicated dosage (mL) x Concentration of 0.1 (g/mL). 
Dosage (g/kg) = Dosage (g) / Weight (kg), using the most recently available weight for the indicated 
treatment visit. 
Number of infusion days will be determined directly from entries in the eCRF Study Drug Infusion form. 
Duration of infusion in minutes will be calculated for each infusion day as: Stop time of infusion – Start 
time of infusion. Duration of infusion in hours will be calculated as: Duration of infusion in minutes / 60. If 
the time portion of either start or stop date/time is missing, then the duration will be missing for that 
infusion. 
15. STUDY MEDICATION COMPLIANCE  
Compliance to study medication, displayed as treatment compliance, infusion compliance, and overall 
compliance, will be presented for the Safety population. 


 
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15.1. DERIVATIONS 
Treatment compliance will be calculated as the total volume infused divided by the total volume 
prepared, expressed as a percentage. The total volume prepared and dispensed by the pharmacist is 
the intended dose volume a subject should be given based on the body weight. This total volume 
prepared is recorded on the eCRF Study Drug Infusion form. 
Infusion compliance will be calculated as the actual number of infusions received divided by the 
expected number of infusions, expressed as a percentage. Note that the number of days of infusions is 
a function of investigator choice based on both tolerability and weight. Subjects weighing > 80 kg will 
need to have infusions divided over more than 1 day as the limit for blinded study drug administration is 
80 g/day. However, should a subject weigh more than 80 kg, the investigator may choose to divide the 
loading dose (2 g/kg) over 3 or 4 days as 3 or 4 daily infusions. For maintenance doses (1 g/kg) every 3 
weeks, the choice is 1 or 2 days based on either tolerability or weight, given the mandatory dose limit of 
no more than 80 g/day. For the purpose of infusion compliance calculation, each loading or 
maintenance dose is counted as a single infusion (i.e., a single dosage). The expected number of 
infusions during the study is equal to 8 for subjects who complete the study. The total number of 
expected infusions for those who discontinue early is equal to the number of dosing visits, including 
completion of loading dose, up to the time of discontinuation. (For example, if a subject discontinues 
between weeks 6 and 9, the number of expected infusions is 3: one loading dose at Baseline, one 
maintenance dose at Week 3, and one maintenance dose at Week 6.) 
 
Overall compliance will be calculated as treatment compliance multiplied by infusion compliance. 
See calculations below.  
• 
Treatment Compliance (%) to study medication will be calculated as follows: 
[୘୭୲ୟ୪ ୅ୡ୲୳ୟ୪ ୚୭୪୳୫ୣ ୍୬୤୳ୱୣୢ ୟ୲ ଵୱ୲ ୍୔ ୢ୭ୱୣ]ା⋯ା[୘୭୲ୟ୪ ୅ୡ୲୳ୟ୪ ୚୭୪୳୫ୣ ୍୬୤୳ୱୣୢ ୟ୲ ୪ୟୱ୲ ୍୔ ୢ୭ୱୣ]
[୘୭୲ୟ୪ ୚୭୪୳୫ୣ ୔୰ୣ୮ୟ୰ୣୢ ୤୭୰ ୍୬୤୳ୱ୧୭୬ ୟ୲ ଵୱ୲ ୍୔ ୢ୭ୱୣ]ା⋯ା[୘୭୲ୟ୪ ୚୭୪୳୫ୣ ୔୰ୣ୮ୟ୰ୣୢ ୤୭୰ ୍୬୤୳ୱ୧୭୬ ୟ୲ ୪ୟୱ୲ ୍୔ ୢ୭ୱୣ] x 100 
• 
Infusion Compliance (%) to study medication will be calculated as follows: 
 
[୘୭୲ୟ୪ ୒୳୫ୠୣ୰ ୭୤ ୈ୭ୱୟ୥ୣୱ ୖୣୡୣ୧୴ୣୢ ୈ୳୰୧୬୥ ୲୦ୣ ୗ୲୳ୢ୷]
[୘୭୲ୟ୪ ୒୳୫ୠୣ୰ ୭୤ ୉୶୮ୣୡ୲ୣୢ ୈ୭ୱୟ୥ୣୱ ୈ୳୰୧୬୥ ୲୦ୣ ୗ୲୳ୢ୷]  
x 100 
• 
Overall Compliance (%) to study medication will be calculated as follows: 


 
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(Treatment Compliance x Infusion Compliance) / 100 
16. EFFICACY OUTCOMES  
16.1. PRIMARY EFFICACY 
16.1.1. PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is the mean change in QMG total score from Baseline (Week 0) to Week 
24. 
The QMG total score consists of 13 individual items. Each item is scored from 0 (none) to 3 (severe). 
The results of the QMG test items are entered on the eCRF. The QMG Test Items are listed in Appendix 
3. 
The QMG total score is the sum of all 13 items and ranges from 0 to 39. If one or more individual items 
are missing, the QMG total score will be set to missing. Note that total scores are reported on the eCRF 
and in general will not be recalculated. The CFB for the QMG total score and for each individual item 
will be calculated and summarized. No statistical analysis will be performed on the individual items. 
The CFB is calculated as indicated in section 6.7. 
16.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
For subjects who do not have QMG total score at Week 24, the LOCF will be used to impute the CFB to 
Week 24. For subjects who experience treatment failure (defined in protocol Section 3.3.3) or MG crisis 
(defined in protocol Section 3.3.4) the value at time of confirmation of failure or at time of MG crisis will 
be carried forward to impute values for all remaining visits. For subjects who discontinue the study early 
due to any other reasons, the last non-missing on-treatment value (including scheduled, unscheduled, 
and early termination) will be carried forward. 
Subjects with no post-baseline QMG total score available will be excluded from analysis. 
Refer to section 16.1.4 for analyses on sensitivity to missing data. 
16.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary objective of this study is to test the null hypothesis that the mean change in QMG total 
score from Baseline to Week 24 (mean CFB) in the IGIV-C group is equal to the mean CFB in the 
Placebo group (µ1=µ2). The alternative hypothesis (Ha) is that the mean CFB in the IGIV-C group is not 
equal to the mean CFB in the Placebo group (µ1≠µ2). 
The primary efficacy analysis will be performed for the mITT population. 
The primary efficacy variable will be analyzed using analysis of covariance (ANCOVA). The ANCOVA 
model will include CFB in QMG total score as the dependent variable, with treatment and Baseline 


 
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standard of care treatment regimen as fixed factors and Baseline QMG total score as a covariate 
(Dobson, 2002). Refer to section 7.1 for categorical levels of the fixed factors. 
16.1.4. SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
Sensitivity analyses will be performed to assess the robustness of the primary analysis. 
Sensitivity to population: 
• 
The primary analysis described in section 16.1.3 will be repeated for the PP population. 
Sensitivity to missing data assumptions: 
• 
An analysis of subjects with non-missing QMG total score at Week 24 will be performed. 
Subjects with missing values will be excluded from this sensitivity analysis and the analysis will 
be performed on the mITT population using OC data only. The same ANCOVA model described 
in section 16.1.3 will be used. 
• 
To assess the longitudinal measurements of QMG total score at various time points, the 
treatment effects will be explored by using the mixed-effect model repeated measures (MMRM.) 
The MMRM model will include CFB as the repeated dependent variable, with treatment, 
Baseline standard of care treatment regimen, protocol-specified visits, and treatment-by-visit 
interaction as fixed effects, with Baseline QMG value as a covariate, and with measures within-
subject at each visit as a repeated measure (McCulloch, 2001). An unstructured covariance 
matrix will be used to model the within-subject error. If the fit of the unstructured covariance 
structure fails to converge, a compound symmetry covariance structure will be used. 
Parameters will be estimated using restricted maximum likelihood with the Kenward-Roger 
method for calculating the denominator degrees of freedom. For the MMRM, all available data 
will be utilized and no missing data will be imputed. Data collected starting at the Week 3 visit 
and up to the Week 24 visit is included in this analysis. 
• 
Sensitivity analyses will be performed for the mITT population and repeated for the PP 
population. 
16.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the mITT population using both the LOCF and 
OC approaches for missing data handling. 
16.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. 
Percentage of Subjects with a Clinical Improvement Assessed by QMG Total Score at 
Week 24 
The QMG total score is calculated as described in section 16.1.1. 
Clinical improvement is defined as at least a 3-point decrease in QMG total score from Baseline to 
Week 24. 


 
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16.2.1.2. 
Percentage of Subjects with a Clinical Improvement Assessed by MG Composite at Week 
24 
The MG Composite scale consists of 10 individual items. The results of the MG Composite items are 
entered on the eCRF. The MG Composite scale is shown in Appendix 4. 
The MG Composite total score is the sum of all 10 items and ranges from 0 to 50. Higher item values 
represent greater severity of illness. If one or more individual items are missing, the MG Composite total 
score will be set to missing. Note that total scores are reported on the eCRF and in general will not be 
recalculated. 
Clinical improvement is defined as at least a 3-point decrease in the MG Composite total score from 
Baseline to Week 24. 
16.2.1.3. 
Percentage of Subjects with a Clinical Improvement Assessed by MG-ADL at Week 24 
The MG-ADL is an 8-item questionnaire. Each item grade ranges from 0 to 3. The results of the MG-
ADL items are entered on the eCRF. The MG-ADL profile is shown in Appendix 5. 
The MG-ADL total score is the sum of all 8 items. Higher item values represent greater severity of 
illness. If one or more individual items are missing, the MG-ADL total score will be set to missing. 
Clinical improvement is defined as at least a 2-point decrease in MG-ADL total score from Baseline to 
Week 24. Note that total scores are reported on the eCRF and in general will not be recalculated. 
16.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
Missing values for the secondary binary endpoints will be handled similarly as for the continuous 
endpoints. First, the LOCF algorithm will be used to impute the (continuous) missing values. The 
imputed values will then be used to derive the binary endpoints.  
The binary endpoints will also be analyzed with the OC approach, i.e., missing data will not be imputed. 
16.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLES 
16.2.3.1. 
Analysis of Clinical Improvement 
All three clinical improvement variables will be analyzed using the same method. The effect of treatment 
on the percentage of subjects with clinical improvement will be tested using the Cochran-Mantel-
Haenszel method (Mantel, 1963), adjusted for Baseline standard of care treatment regimen. The 
hypothesis test will be based on the General Association statistic. 


 
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16.3. EXPLORATORY EFFICACY  
16.3.1. EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
16.3.1.1. 
Percentage of Subjects with a Clinical Improvement Assessed by QMG Total Score at 
Weeks 6, 9, 12, 15, 18, and 21 
Clinical Improvement as assessed by QMG total score is defined in the same way as in Section 
16.2.1.1.  
16.3.1.2. 
Time to First Clinical Improvement in QMG Total Score 
Clinical Improvement as assessed by QMG total score is defined in the same way as in Section 
16.2.1.1. Time to first clinical improvement is calculated as the date of first assessment with clinical 
improvement – date of Baseline visit + 1. The date of first assessment with clinical improvement will be 
used regardless of whether subsequent visits also demonstrate improvement. Subjects who never 
experience clinical improvement will be censored at the date of their last non-missing QMG total score 
assessment. 
16.3.1.3. 
Time to Treatment Failure Based on QMG Total Score 
Treatment failure due to MG worsening is defined as at least a 4-point increase in QMG total score from 
Baseline at two consecutive visits after Week 9. To qualify, the 4-point increase in QMG total score 
must be confirmed at next consecutive visit. Time to treatment failure is calculated as the date of the 
first of the two consecutive assessments meeting MG worsening – date of Baseline visit + 1. Subjects 
who never experience treatment failure will be censored at the date of their last non-missing QMG total 
score assessment. 
16.3.1.4. 
CFB in QMG Total Score at Weeks 6, 9, 12, 15, 18, and 21 
The CFB in QMG total score is defined in the same way as defined in section 16.1.1. 
16.3.1.5. 
Percentage of Subjects with a Clinical Improvement Assessed by MG Composite Score at 
Weeks 6, 9, 12, 15, 18, and 21 
Clinical Improvement as assessed by MG Composite score is defined in the same way as in Section 
16.2.1.2.  
16.3.1.6. 
CFB in MG Composite at Weeks 6, 9, 12, 15, 18, 21, and 24 
MG Composite total score is defined in the same way as defined in section 16.2.1.2. The CFB is 
calculated as indicated in section 6.7. 


 
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16.3.1.7. 
Percentage of Subjects with a Clinical Improvement Assessed by MG-ADL Score at Weeks 
9 and 15 
Clinical Improvement as assessed by MG-ADL score is defined in the same way as in Section 16.2.1.3.  
16.3.1.8. 
CFB in MG-ADL at Weeks 9, 15, and 24 
MG-ADL total score is defined in the same way as in section 16.2.1.3. The CFB is calculated as 
indicated in section 6.7. 
16.3.1.9. 
CFB in the 15-item MG-QOL 15 at Weeks 9, 15, and 24 
The MG-QOL 15 is made up of 15-items. All individual items related to degree of disease-related 
impairment are rated on a Likert scale ranging from “not at all” (score 0 points) to “very much” (score 4 
points), with higher scores indicating worse disease. The results of the MG-QOL 15 items are entered 
on the eCRF. The MG-QOL 15 is shown in Appendix 6. 
The MG-QOL 15 total score is the sum of all 15 items. If one or more individual items are missing, the 
MG-QOL 15 total score will be set to missing. Note that total scores are reported on the eCRF and in 
general will not be recalculated. 
The CFB is calculated as indicated in section 6.7. 
16.3.1.10. 
MGFA Post-interventional Change in Status at Week 24 Relative to Baseline 
An MGFA post-interventional change in status relative to Baseline will be evaluated at Week 24. The 
Investigator will classify the subject as: (I) Improved, defined as a substantial decrease in pre-treatment 
clinical manifestations of MG, QMG decrease ≥ 3 points; (U) Unchanged, defined as no substantial 
change in pre-treatment clinical manifestations of MG; (W) Worse, defined as a substantial increase in 
pre-treatment clinical manifestations of MG, QMG increase ≥ 3 points. The status value provided by the 
investigator will be used as the variable for analysis. 
16.3.1.11. 
Subgroup Analysis of Primary Efficacy Variable 
The primary efficacy variable defined in Section 16.1.1 will be analysed for the subgroups mentioned in 
Section 7.5. 
16.3.2. MISSING DATA METHODS FOR EXPLORATORY EFFICACY VARIABLES 
16.3.2.1. 
Analyses of Clinical Improvement 
Missing values for the exploratory binary endpoints will be handled using both the LOCF and the OC 
approaches. With the LOCF approach, first the missing total scores at the weeks indicated will be 
imputed using the LOCF approach for continuous endpoints as detailed in Section 6.3. The imputed 
scores will then be used to derive whether subjects met the clinical improvement criteria. With the OC 
approach, the analysis will be based on observed non-missing data only and subjects with missing total 
scores at the indicated visits will be excluded from the analysis. 


 
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16.3.2.2. 
Time to Clinical Improvement and Time to Treatment Failure 
Subjects with no post-baseline data will be censored at Day 1. Subjects with missing data for at least 
one but not all scheduled visits will be censored at the last visit with non-missing data, unless they 
experience the event based on the assessments available. Both scheduled and unscheduled visits are 
considered in identifying the last visit with non-missing data. 
16.3.2.3. 
CFB in QMG, MG Composite, MG-ADL, or MG-QOL 15 
For subjects who do not have a total score at the week indicated, the same method as in section 16.1.2 
will be used. As additional sensitivity analyses, the OC approach for handling missing data will also be 
used. 
16.3.2.4. 
MGFA Post-interventional Change in Status 
Subjects with missing results will be excluded from analysis. 
16.3.2.5. 
Subgroup Analysis of Primary Efficacy Variable 
For subjects who do not have a total score at Week 24, the same method as in section 16.1.2 will be 
used. As additional sensitivity analyses, the OC approach for handling missing data will also be used. 
16.3.3. ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
Exploratory efficacy analyses will be based on the mITT population. Both the LOCF and the OC 
approaches for handling missing data will be used. P-values presented for exploratory analyses are for 
information purposes only. 
16.3.3.1. 
Analyses of Clinical Improvement 
The same method described in section 16.2.3.1 will be used. 
16.3.3.2. 
Time to Clinical Improvement and Time to Treatment Failure 
For the time to event variables, Kaplan-Meier estimates (Kaplan, 1958) will be provided and the 
treatment comparison will be performed using a log-rank test, stratified by Baseline standard of care 
treatment regimen. 
16.3.3.3. 
CFB in QMG, MG Composite, MG-ADL, or MG-QOL 15 
The same ANCOVA method described in Section 16.1.3 will be used. The MMRM method described in 
section 16.1.4 will also be used to assess longitudinal measurements for the other parameters. 
16.3.3.4. 
MGFA Post-interventional Change in Status 
MGFA post-interventional change in status at Week 24 relative to Baseline will be summarized by 


 
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treatment group. 
16.3.3.5. 
Subgroup Analysis of Primary Efficacy Variable 
The observed and CFB values will be presented for each visit, including week 24, as well as for the 
LOCF endpoint used in the primary analysis, as described in section 16.1. Presentation by subgroups 
will not include any statistical testing. 
17. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety population.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified within the relevant section.  
17.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 17.1. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started on or after the beginning 
of the first infusion of study medication and prior to the final study visit.  
See Appendix 2 for handling of partial or missing dates/times for AEs. In the case where it is not 
possible to define an AE as treatment emergent or not, the AE will be classified by the worst case; i.e. 
treatment emergent.  
Listings will include TEAEs and Non-TEAEs. Subjects with deaths, serious adverse events (SAEs), 
suspected adverse drug reactions (ADRs) and AEs leading to premature discontinuation from the study 
will be listed. 
An overall summary of number of subjects and number of events within categories of interest will be 
provided as specified in the templates.  
17.1.1. ALL TEAES  
Incidence of TEAEs and of suspected ADRs will be presented by SOC and PT and also broken down 
further by intensity and causal-relationship to study medication. Non-TEAEs will be summarized 
separately from TEAEs. 
Summaries presented by PT will also be provided for the total number of events, the rate per dosage, 
and the rate per exposure week. The rate per dosage, where a dosage includes all infusion days within 
a given treatment visit, will be calculated as: 
Total number of events / Total number of dosages received 
The rate per exposure week will be calculated as: 
Total number of events / Total duration of exposure in weeks 


 
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17.1.1.1. 
Intensity 
Intensity (severity) is classed as mild/ moderate/ severe (increasing severity).  The subject incidence of 
TEAEs by intensity and the subject incidence of TEAEs and suspected ADRs by maximum intensity will 
be summarized.  The incidence of TEAEs and suspected ADRs will also be presented by SOC/PT; if a 
subject reports a TEAE more than once within that SOC/PT, the AE with the worst case severity will be 
included for the relevant SOC/PT. 
17.1.1.2. 
Causal-Relationship to Study Medication 
Causality to study drug, as indicated by the Investigator, is classed as “unrelated”, “doubtful/unlikely”, 
“possible”, “probable”, or “definite” (increasing level of relationship). The subject incidence of TEAEs 
and ADRs by relationship will be summarized.  The incidence of TEAEs will also be summarized by 
relationship; if a subject reports the same AE more than once within that SOC/PT, the AE with the worst 
case relationship to study medication will be used in the corresponding relationship summaries. AEs 
classified as “definite”, “probable”, “possible” or “doubtful/unlikely” will be defined as suspected ADRs. 
ADRs will be presented by SOC and PT. A suspected ADR with a causal relationship of “definite” will be 
defined as an adverse reaction (AR). 
17.1.2. TEAES LEADING TO DISCONTINUATION FROM THE STUDY 
TEAEs leading to permanent discontinuation of study medication will be identified based on the eCRF 
response to the question ‘Did subject withdraw from the study as a result of this event?’ TEAEs leading 
to discontinuation will be presented in a listing. 
17.1.3. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of 
the eCRF. A summary of serious TEAEs by SOC and PT will be prepared. A listing will also be 
presented. 
17.1.4. ADVERSE EVENTS LEADING TO DEATH 
AEs leading to Death are those events which are recorded as “Fatal” on the Adverse Events page of the 
eCRF. AEs leading to death will be presented in a listing. 
17.1.5. INFUSIONAL ADVERSE EVENTS 
Infusional AEs, including infusional suspected ADRs, are those temporally associated with the infusion 
of the IP and are defined as TEAEs that occur from the initiation of the IP infusion and within 72 hours 
following the completion of the infusion of the total dosage of IP. These will be summarized by 
presenting infusional events and subject incidences and percentage. A corresponding listing will also be 
presented. In addition, the infusion rate in effect at the time of onset of the AE, the time the AE is first 
reported, and the time the AE changes materially in intensity and/or resolves will be also reported and 
listed. 


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17.1.6. ADVERSE EVENTS OF SPECIAL INTEREST 
Summaries of Thromboembolic or Hemolysis events will be presented by SOC and PT. 
Thromboembolic and Hemolysis Events are indicated on the eCRF. 
17.2. LABORATORY EVALUATIONS 
17.2.1. CHEMISTRY, HEMATOLOGY, HEMOLYSIS, ACETYLCHOLINE RECEPTOR ANTIBODY (ACHR), AND 
IMMUNOGLOBULIN G (IGG)  
Results from the central laboratory will be included in the reporting of this study for clinical laboratory 
assessments (chemistry and hematology) parameters.  
Presentations will use SI Units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification, or 
“> X”, i.e. above the upper limit of quantification, will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
The following summaries will be provided for laboratory data: 
• 
Actual and CFB by visit (for quantitative measurements) 
• 
Shift from baseline according to normal range criteria (for quantitative measurements and 
categorical measurements with normal ranges) 
Results out of normal range will be flagged in the listings. 
For selected analytes, tabular summaries and listings will be provided for treatment-emergent laboratory 
abnormalities, utilizing the following thresholds of interest. Note that thresholds are in some cases 
relative to the established reference range (multiples of lower limit of normal [LLN] or upper limit of 
normal [ULN]) and in other cases are relative to an absolute value threshold: 
• 
Hemoglobin: treatment-emergent (TE) value 8.9 g/dL or less AND a decrease of 1 g/dL from 
Baseline 
• 
Absolute Neutrophils will have two thresholds: 
o 
TE Neutrophils <750/mm3 
o 
TE Neutrophils < 500/mm3 
• 
Creatinine: TE > 2.5 x ULN (reference range specific to gender/age) 
• 
Alanine aminotransferase [ALT]: TE > 3 x ULN (reference range specific to gender/age) 
• 
Total bilirubin: TE > 3 x ULN (reference range specific to gender/age) 
• 
Haptoglobin: < LLN 
Quantitative/semiquantitative binding, blocking, and modulating Acetylcholine Receptor Antibody 
(AChR) antibodies, hemolysis labs, and trough Immunoglobulin G (IgG) level results from the central 


 
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 Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
laboratory will also be analyzed with methods similar to routine chemistry and hematology labs.  
A listing of subjects with positive direct antiglobulin (DAT) test results will be provided. Subjects with 
positive DAT results are defined as those having a positive result for at least one of IgG and C3 from 
Screening through end of study. The listing will include all DAT results for any subject with at least one 
positive DAT value and will also include all hemoglobin, absolute reticulocyte count, serum free 
hemoglobin, haptoglobin, lactate dehydrogenase, and total and indirect bilirubin values at corresponding 
time points. Blood smear results (specifically “RBC morphology” whether there is presence of 
spherocytosis) and “urine blood” with any corresponding entries for “urine RBC/HPF” on urinalysis will 
also be included. 
17.2.2. D-DIMER AND WELLS SCORE 
D-dimer and Wells Score are collected for thromboembolism evaluation. D-dimer results are included in 
the laboratory data. The Wells Score data is collected on the eCRF. D-dimer and total scores of the 
Wells Score for Deep Vein Thrombosis and Pulmonary Embolism will be summarized with number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum values.  Summaries will be 
presented for actual and CFB by treatment and visit. All D-dimer and Wells Score data will also be 
presented in data listings. 
17.2.3. VIRUS SAFETY TESTING 
Blood samples for virus safety (viral nucleic acid amplification technology [NAT] and viral serology) 
testing will be collected at Baseline/Week 0 (Visit 1) prior to randomization, but will be tested only if the 
subject exhibits clinical signs and symptoms consistent with hepatitis A, hepatitis B, hepatitis C, human 
immunodeficiency virus (HIV), or parvovirus B19 infection while participating in the study. These 
samples will be retained until all analyses in support of the study are complete. Additional blood 
samples for viral NAT and viral serology may be collected and tested only if the subject exhibits clinical 
signs and symptoms consistent with hepatitis A, hepatitis B, hepatitis C, HIV, or parvovirus B19 infection 
while participating in the study. 
If any virus safety testing was conducted, all available results will be listed. 
17.2.4. LABORATORY REFERENCE RANGES 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in 
standard international (SI) units and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 


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17.3. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Heart Rate (beats/min) 
• 
Respiratory Rate (breaths/min) 
• 
Temperature (⁰C) 
Weight (kg) will be presented in listings and summarized with other vital signs. 
The following summaries will be provided for vital signs data: 
• 
Actual and CFB by visit 
17.4. PHYSICAL EXAMINATION  
Full physical assessment findings will be summarized with numbers and percentages by body system. 
Entries for 'Other' body systems will be grouped together; a subject with 2 or more 'Other' entries will be 
counted only once. Physical assessment change findings will be summarized with numbers and 
percentages per category of the change findings. Physical examination findings (normal and abnormal) 
with specific findings observed will be listed for each subject. 


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18. REFERENCES  
Dobson, Annette J. An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC, 2002. 
Kaplan EL, Meier P. "Nonparametric estimation from incomplete observations." Journal of the American Statistical 
Association 53 (1958): 457-481. 
Mantel, N. "Chi-square tests with one degree of freedom; extensions of the Mantel Haenszel procedure." Journal 
ofthe American Statistical Association 58 (1963): 690-700. 
McCulloch CE, Searle SR. Generalized, Linear, and Mixed Models. New York: John Wiley and Sons, 2001. 
 
 
 
 
 
 
 


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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
QUINTILES OUTPUT CONVENTIONS 
Outputs will be presented according to the following output conventions. 
  
1. 
ABBREVIATIONS 
ASCII  American standard code for information interchange file format 
CGM  Computer graphics metafile 
ODS  
Output Delivery System 
RTF  
Rich text file format 
PDF 
Portable Document Format 
 
2. 
INTRODUCTION 
This document applies to standards used for outputting tables, listings and figures. It is intended to 
provide specifications to guide the statistician or statistical programmer in setting up specifications for 
programming tables, listings and figures. 
 
3. 
OUTPUT FILE NAMING CONVENTIONS 
File names should only consist of uppercase letters, lowercase letters, digits (0 to 9) and underscores. A 
period should only be used to indicate a separator between the file name and the extension. No spaces, 
other special characters or punctuation marks are permitted. 
As far as possible, output files should be in RTF format, although .DOC files are also permitted. 
The program, program log and output file name should reflect the type and number of the statistical 
output. If this is not possible, then the output name should be at least as descriptive as possible. A 
prefix can be used to distinguish between a Table, Listing and Figure document (‘T’ for table, ‘L’ for 
listing and ‘F’ for figure). If there is only 1 digit in the number of the table, listing or figure in the place 
where 2 digits are possible, a leading zero should be added in the file name to make sorting consistent 
with the sequence (eg T14_3_01_1_disp.RTF) 
 
4. 
PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter for the United States. 
The page orientation should be landscape. 
Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless 
of the paper size. 


 
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The number of columns per page (linesize) should be 145 for A4 and 134 for Letter. 
The number of rows per page (pagesize) should be 49 for A4 and 51 for Letter. 
 
 
5. 
FONTS 
 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8. The 
font color should be black. No bolding, underlining, italics or subscripting should be permitted. Super-
scripts will be avoided. Single spacing should be used for all text. 
 
6. 
HEADER INFORMATION 
Headers should be defined as follows: 
• The header should be placed at the top of the page (same place on each page) regardless of the size 
or orientation of the table or listing 
• The protocol number and treatment should appear in row 1, left-aligned, and the page number (in the 
format of Page X of Y) should appear as right-aligned 
• The indication should appear in row 2, left-aligned, and the customer name should be right-aligned 
• Row 3 should be blank 
• The output identification number should appear in row 4, centered 
• The output title should start in row 5, centered 
• The output population should appear in row 6, centered. The population should be spelled out in full, 
e.g. Intention-to-Treat in preference to ITT. 
• Row 7 should be a continuous row of underscores (‘_’) (the number of underscores should equal the 
linesize) 
• Row 8 should be a blank line 
• Mixed case should be used for titles 
• The output titles should be designed so that they are arranged consistently through all outputs. For 
example, content (eg Vital Signs) followed by metric (eg CFB) e.g. Vital Signs – CFB. 
• Titles should not contain quotation marks or footnote references 
• The column headings should be underlined with a row of underscores (‘_’) 
• Column headings spanning more than one column should be underlined and have underscores on 
either side of the title and should be centered 
• Column headings containing numbers should be centered 
• Column headings should be in sentence case 
• In general, the population count should appear in the column header in the form “(N=XXX)” 


 
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• “Statistic” should be the column header over n, Mean, SE, n (%) etc. 
• As a rule, all columns should have column headings. 
 
7. 
TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
• The first row in the body of the table or listing should be blank 
• The left hand column should start in column 1. No indenting or centering of the output should occur. 
• Rounding should be done with the SAS function ROUND. 
• Numbers in tables should be rounded, not truncated. 
• Alphanumeric output should be left aligned. 
• Numbers should be decimal point aligned. 
• Whole numbers should be right aligned. 
• Text values should be left aligned. 
• The first letter of a text entry should be capitalized 
• Listings of adverse events, concomitant medications, medical histories etc. should be sorted in 
chronological order within subject, with earliest adverse event, medication or history coming first. 
• The study drug should appear first in tables with treatments as columns 
• In general, only present totals (across treatment groups) at baseline/randomization, and do not present 
them post randomization. 
• If possible, include 100% frequencies in the table shell, so that it is clear what the denominator is for 
percentage calculations. 
• All listing outputs should be sorted (preferably by Treatment, Site Number and Subject Number). 
• Do not use superscripts and subscripts 
• All variables that are output in the eCRF (which have data present) should appear in the listings 
• The width of the entire output should match the linesize 
 
Univariate Statistics: 
• Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, Minimum, 
Maximum) 
• Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points 
should line up.  
• If the original data has N decimal places, then the summary statistics should have the following 
decimal places: 
Minimum and maximum: N 


 
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Mean and median: N + 1 
SD and CV: N + 2 
CV%: N, but with a maximum number of 1 decimal place 
The maximum number of decimal places should be 4 for statistics other than CV%. 
  
Frequencies and percentages (n and %): 
• Percent values should be reported inside parentheses, with one space between the count and the left 
parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 as a 
value and padded with blank space if the percent is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
 
Confidence Intervals: 
• As a rule confidence intervals are output to one place more than the raw data.  Standard errors are 
output to two places more than the raw data. 
• Boundary values of confidence intervals should be separated by a comma. 
• Boundary values should be padded as necessary to accept negative values and to allow alignment of 
the decimal place. 
• Boundary value of -0.00 should be presented as 0.00. 
• An example is given below: 
(-0.12, -0.10) 
( 9.54, 12.91) 
 
P-values: 
• P-values should be reported to three decimal places, except values <1.000 but >0.999 will be 
presented as ‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as 
‘<0.001’ (e.g., 0.0009 is presented as <0.001). Rounding will be applied after the <0.001 and >0.999 
rule 
 
Ratios: 
• Ratios should be reported to one more decimal place than the original data. 
 
Spacing: 
• There must be a minimum of 1 blank space between columns (preferably 2) 


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Denominators: 
• If a different count other than the population count is used for a denominator (within the table) to 
calculate percentages, there should be a row in the table that identifies that number “n”. 
• Alternatively, a footnote should be included in each table with percentages to indicate the denominator 
for percentages. 
 
Missing values 
• A “0” should be used to indicate a zero frequency. 
• A blank will be used to indicate missing data in an end-of-text table or subject listing. 
 
8. 
FOOTNOTE INFORMATION 
Footers should be defined as follows: 
• A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any footnotes at 
the bottom of the page 
• Table footnotes should be defined using compute statements in the proc report, and should appear 
directly after the body of the table 
• The program path and name should appear as footnote 1 at the bottom of the page, followed on the 
same line by the date/time stamp 
• Footnotes should be left-aligned. 
• Footnotes should be in sentence case. 
• Only “typewriter” symbols are permitted – eg “*”, “$”, “#”, “@”, “&” and “+”. 
• The choice of footnote symbols should be consistent. E.g. if you have the footnote “# indicates last 
observation carried forward” for one table, the same symbol and footnote should indicate LOCF for all 
tables. 
• If text wraps across more than one line (for a note), the first letter for all lines of text after the first one 
will be indented to align beneath the first letter of the text in the first line. 
 
Ordering of footnotes should be as follows: 
1.) Abbreviations and definitions 
2.) Formulae 
3.) Symbols 
4.) Specific notes 
• Common notes from table to table should appear in the same order. 
• The symbols should appear in the same order as what they are defined in the table or listing, from left 


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to right. 
 
10. 
PROGRAMMING INSTRUCTIONS 
Programming instructions, if required, must appear in blue font at the end of each table or listing shell. 
Programming instructions, where necessary, should follow the table or listing shells in blue font, 
beginning with the words “Programming Note” followed by a colon. These include notes on the output, 
reminders of how to handle missing values, repeat shells for similar tables etc. 
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYYY/HH:MM. 
SPELLING FORMAT 
English US 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables, Listings and Graphs 
Immune Globulin (Human), 10% 
Caprylate/Chromatography Purified (IGIV-C) loading 
dose of 2 g/kg followed by 7 maintenance dosages of 
1 g/kg every 3 weeks 
IGIV-C 
Matched Placebo 
Placebo 
Total 
Total 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order. Where necessary to uniquely identify 
data records, additional time points will be included in the outputs. 
Long Name (default) 
Short Name  
Screening  
 
Scr  
Baseline  
BL 


 
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Long Name (default) 
Short Name  
Week 3 
WK3 
Week 6 
WK6 
Week 9 
WK9 
Week 12 
WK12 
Week 15 
WK15 
Week 21 
WK21 
Week 24 
WK24 
Early Termination 
ET 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
randomized treatment group (or treatment received if it’s a safety output), first by active and then placebo  
• 
center-subject ID,  
• 
date (where applicable), 
• 
For listings where non-randomized subjects are included, these will appear in a category after the 
randomized treatment groups labeled ‘Not Randomized’. 
 
 


 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
AE START 
DATE TIME 
STUDY 
MEDICATION 
START DATE 
TIME 
ACTION 
Known 
Known 
If start date/time < study med start date/time, then not TEAE 
If start date/time >= study med start date/time, then TEAE 
Partial or 
Missing 
Known 
If start date < study med start date, then not TEAE 
If start date > study med start date, then TEAE 
If start date = study med start date, then impute AE start time to 
the latest possible time (i.e. 23:59 if hours and minutes are 
missing, or 59 minutes past the hour if only minutes are 
missing). If this imputed date/time is after AE stop date/time, 
then use AE stop date/time as the imputed AE start date/time. 
Then: 
If imputed start date/time < study med start date/time, then not 
TEAE 
If imputed start date/time >= study med start date/time, then 
TEAE 
Known 
Partial or 
Missing 
If start date < study med start date, then not TEAE 
If start date > study med start date, then TEAE 
If start date = study med start date, then impute study med start 
time as the earliest possible time (i.e. 00:00 if hours and 
minutes are missing, or 00 minutes past the hour if only 
minutes are missing). Then: 
If start date/time < imputed study med start date/time, then not 
TEAE 
If start date/time >= imputed study med start date/time, then 
TEAE 


 
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AE START 
DATE TIME 
STUDY 
MEDICATION 
START DATE 
TIME 
ACTION 
Partial or 
Missing 
Partial or 
Missing 
If start date < study med start date, then not TEAE 
If start date > study med start date, then TEAE 
If start date = study med start date then impute AE start time to 
the latest possible time (i.e. 23:59 if hours and minutes are 
missing, or 59 minutes past the hour if only minutes are 
missing). If this imputed date/time is after AE stop date/time, 
then use AE stop date/time as the imputed AE start date/time. 
Also impute study med start time as the earliest possible time 
(i.e. 00:00 if hours and minutes are missing, or 00 minutes past 
the hour if only minutes are missing). Then: 
If imputed start date/time < imputed study med start date/time, 
then not TEAE 
If imputed start date/time >= imputed study med start date/time, 
then TEAE 
(e.g. cases of fully missing times on the same date will be 
assumed TEAE) 
 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
Any imputed concomitant medication stop date/time will only be used to determine whether a 
medication is prior or concomitant.  The start and stop dates/times reported on the eCRF will be 
presented in the listings. 
NON-
STUDY 
MED 
STOP 
DATE 
TIME 
STUDY MED 
START DATE 
TIME 
ACTION 
Known 
Known 
If stop date/time < study med start date/time, assign as prior  
If stop date/time >= study med start date/time, assign as concomitant  
 


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NON-
STUDY 
MED 
STOP 
DATE 
TIME 
STUDY MED 
START DATE 
TIME 
ACTION 
Partial 
Known 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown) with latest 
possible time (i.e. 23:59 if hours and minutes are missing, or 59 
minutes past the hour if only minutes are missing), then: 
If stop date/time < study med start date/time, assign as prior 
If stop date/time >= study med start date/time, assign as concomitant 
 
Missing 
Known or Partial 
Year can only be missing in stop date for ongoing medication. 
If entire stop date including year is missing, assign as concomitant. 
 
Known 
Partial or Missing 
Time 
If stop date < study med start date, assign as prior 
If stop date > study med start date, assign as concomitant 
If start date = study med start date, then impute study med start 
time as the earliest possible time (i.e. 00:00 if hours and 
minutes are missing, or 00 minutes past the hour if only 
minutes are missing). Then: 
If stop date/time < imputed study med start date/time, assign as 
prior 
If stop date/time >= imputed study med start date/time, assign 
as concomitant 
 


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NON-
STUDY 
MED 
STOP 
DATE 
TIME 
STUDY MED 
START DATE 
TIME 
ACTION 
Partial 
Partial or Missing 
Time 
If stop date < study med start date, assign as prior 
If stop date > study med start date, assign as concomitant 
If start date = study med start date, impute stop date as latest 
possible date (i.e. last day of month if day unknown, or 31st 
December if day and month are unknown) with latest possible 
time (i.e. 23:59 if hours and minutes are missing, or 59 minutes 
past the hour if only minutes are missing).  Also impute study 
med start time as the earliest possible time (i.e. 00:00 if hours 
and minutes are missing, or 00 minutes past the hour if only 
minutes are missing). Then: 
If imputed start date/time < imputed study med start date/time, 
assign as prior 
If imputed start date/time >= imputed study med start date/time, 
assign as concomitant 
 
 
 


 
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APPENDIX 3. QMG TEST ITEMS 
 
 
 


 
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APPENDIX 4. MG COMPOSITE SCALE 
 
 


 
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  Revision 4 
Reference:
 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 
. All rights reserved. 
The contents of this document are confidential and proprietary to 
 Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
APPENDIX 5. MG-ADL PROFILE 
 
 


 
Analysis Plan 
Grifols Therapeutics Inc.
PROTOCOL GTI1408 
Page 51 of 51
 
Document: 
S:\SAS\Grifols\IGIV_C\HXAA3789\Biostatistics\Documentation\SAP\GTI1408_SAP 
Author: 
 
Version Number: 
Final 1.0 
 
 
Version Date: 
04Aug2017 
Template No:
  Revision 4 
Reference:  
 
Effective Date: 01Apr2016 
 
Copyright © 2009, 2010, 2012, 2016 
 All rights reserved. 
The contents of this document are confidential and proprietary to 
. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
APPENDIX 6. MG-QOL 15