Clinical trial NCT02100969
Conditions: Myasthenia Gravis
Keywords: MG Hizentra autoimmune neuromuscular disorder
Sponsor: Mazen Dimachkie, MD
Start date: 2015-05-01; Completion date: 2018-01-01
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether Hizentra is a safe and effective treatment for people with myasthenia gravis (MG).

Detailed description:
Myasthenia gravis (MG) is a rare autoimmune disorder which causes the muscles to become weak because the immune system attacks the connection between the nerves and the muscles.

Hizentra is a subcutaneous (under the skin) immunoglobin (SCIg). An immunoglobin is a blood protein. Hizentra is being studied for the treatment of patients with MG. Hizentra is administered by an injection into the skin through a portable infusion pump, which may be easier for patients to administer than the current treatments.

Participants will be asked to complete 9 clinic visits and 3 telephone calls. It could take up to 30 weeks to complete all study visits.

Arms: arm 1: Hizentra is a subcutaneous (under the skin) immunoglobin (SCIg). Participants will receive Hizentra in a minimum of one infusion per week and a maximum of 4 infusions per week. Dose and rate depend on the visit and how each participant tolerates the drug. Max cc per site is 50 cc per site per hour.
Interventions: intervention 1: HIZENTRA ®
Intervention descriptions: intervention 1: Patients must fulfill inclusion criteria and remain stable at week 0, which means QMG does not increase by 3 points, will enter receive Hizentra for 12 weeks.

Protocol documents:
Prot_001.pdf: 
Version Date: 22 August 2016 
Open Label study of subcutaneous immunoglobulin (SCIg) in myasthenia gravis 
IND #: 15927 
Version 3.6 
Mazen M. Dimachkie, MD 
Principal Investigator 
Professor, Department of Neurology 
Director, Neuromuscular Section 
Department of Neurology 
University of Kansas Medical Center 
3901 Rainbow Blvd., Mail Stop 2012 
Kansas City, KS  66160 
Phone: 913-588-6094 
Fax: 913-588-0609 
Email: mdimachkie@kumc.edu 
NCT02100969


 
 
Version Date: 22-Aug-2016 
 
2 
 
 
 
 
Key Personnel: 
 
University of Kansas Medical Center: 
Principal Investigator: Mazen M. Dimachkie, MD 
Co-Investigators: 
Richard J. Barohn, MD 
Omar Jawdat, MD 
Mamatha Pasnoor, MD 
 
 
 
Jeffrey Statland, MD 
 
 
 
 
 
 
Project Manager: 
 
Primary: Kiley Sims 
Back-up: Laura Herbelin, BSc 
 
 
 
Data Safety Monitoring Committee: 
Chair: John Kissel, MD 
Member: Gary Cutter, PhD 
 
 
 
Member: Jonathan Goldstein, MD  
Member: Jonathan Katz, MD  
 
 
 
 
 
 
Member: Maryam TahmasbiSohi, MD 
 
 
 
Medical Monitor: 
Melanie Glenn, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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3 
 
 
TABLE OF CONTENTS 
 
Face Page 
 
 
 
 
 
 
 
 
 
1 
Table of Contents 
 
 
 
 
 
 
 
 
3 
Research Plan 
 
 
 
 
 
 
 
 
4 
 
Specific Aims  
 
 
 
 
 
 
 
4 
 
Background, Prevalence and Significance 
 
 
 
 
4 
 
 
Prevalence 
 
 
 
 
 
 
 
4 
 
 
Background and Significance  
 
 
 
 
5 
 
Preliminary Studies 
 
 
 
 
 
 
 
7 
 
 
Previous Clinical Trial Experience 
 
 
 
 
7 
Methods, Expected Results, Data Analysis,  
                   Interpretations, and Significance      
 
 
 
8 
 
 
Study Design  
 
 
 
 
 
 
8 
 
 
Screening Phase on IVIg 
 
 
 
 
 
8 
 
 
Hizentra Administration 
 
 
 
 
 
9 
Baseline 
 
 
 
 
 
 
 
14 
 
 
3-month treatment phase on SCIg 
 
 
 
 
14 
 
 
Timeline 
 
 
 
 
 
 
 
14 
 
 
Study Eligibility 
 
 
 
 
 
 
14 
Study Procedures 
 
 
 
 
 
 
16 
  
Screening & Informed Consent 
 
 
 
17 
  
Screening Phase Infusion visits 
 
 
 
17 
  
Baseline 
 
 
 
 
 
 
17 
  
 Week 1 
 
 
 
 
 
            17 
  
 Week 2 & 3 
 
 
 
 
 
 
18 
  
Follow up visits 
 
 
 
 
 
18 
  
 Week 6 
 
 
 
 
 
 
18 
 
 
 
Unscheduled Visits 
 
 
 
 
 
18 
End of Study Visits Follow Up Calls  
 
 
19 
Concomitant Medication 
 
 
 
 
19 
  
Medication Reconciliation 
 
 
 
 
19 
  
Adverse Events 
 
 
 
 
 
19 
  
Hemolysis Risk 
 
 
 
 
 
21 
  
Thrombosis Risk 
 
 
 
 
 
21 
  
Renal Failure Risk 
 
 
 
 
 
23 
Laboratory Monitoring 
 
 
 
 
23 
  
Treatment Failures 
 
 
 
 
 
24 
  
Subject Deterioration and Rescue Medication 
 
24 
Study Timeline 
 
 
 
 
 
 
26 
Data Analysis Plan and Statistical Considerations  
 
26 
Safety Monitoring 
 
 
 
 
 
 
30 
Annual Site Monitoring 
 
 
 
 
 
30 
Stopping Rule  
 
 
 
 
 
 
30 
Literature Cited 
 
 
 
 
 
 
30 
Table 1 – Schedule of Visits  
 
 
 
 
 
 
34 
Appendix 1 
 
 
 
 
 
 
                                   35 
Appendix 2 
                                                                                                          36 
Appendix 3  
 
 
 
 
 
                                               37 


 
 
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4 
 
 
 
3.1. Summary of Specific Aims 
Little is known about subcutaneous immunoglobulin (SCIg) in myasthenia gravis (MG). A 
Pubmed search using the search terms myasthenia and subcutaneous immunoglobulin 
yields no relevant study. A prior controlled study found that intravenous immunoglobulin 
(IVIg) -treated (2 g/kg of IVIg) MG patients with progressive symptoms experienced a 
clinically meaningful improvement in the quantitative myasthenia gravis (QMG) score at day 
14 which persisted at day 28.1 More recently, IVIg was found to have comparable efficacy to 
plasma exchange (PLEX) in the treatment of patients with moderate to severe MG defined as 
QMG > 10.5.2 As part of routine clinical care, we have treated MG cases with chronic 
outpatient IVIg. In those patients, SCIg would be easier to administer and foster more patient 
independence. We propose the hypothesis that SCIg is as effective as IVIg in controlling MG 
in patients transitioning from intravenous (IV) to subcutaneous (SC) mode of administration. 
We also hypothesize that the SCIg is safe and well tolerated in MG cases. There is some 
data from SCIg in other neuromuscular disorders the SCIg may be better tolerated than IVIg. 
 
The primary objective is to measure the efficacy of SCIg in the 12-week experimental 
treatment phase (Week 0 to Week 12) of MG subjects who are stable after completing the 
IVIg screening phase (Week minus 9 [-9] to Week 0). Disease stability in the screening 
phase is considered a change of no more than 3 points increase in the QMG score at Week 
0 as compared to Week -9. The primary outcome is after the screening phase and is the 
percent of subjects enrolled in the experimental treatment phase of SCIg experiencing an 
increase of no more than 3 points in the QMG score from baseline (Week 0) to Week 12 
visits of SCIg open label therapy.  
 
The secondary objectives are: 
1) To further assess the efficacy of SCIg in MG 
2) To assess the safety and tolerability of SCIg in subjects with MG 
3) To evaluate whether SCIg can result in stable IgG antibody levels 
 
The secondary outcome measures include the change:  
1. from baseline (Week 0) to Week 12 in myasthenia activities of daily living (MG-ADL), 
myasthenia gravis 15 item quality of life survey (MG QOL-15), MG composite score, 
and treatment satisfaction questionnaire for medication (TSQM) in completers of the 
experimental treatment phase  
2. from week -10 to week 12 in the safety profile between intravenous screening phase 
and subcutaneous experimental treatment phase as measured by abnormalities on 
routine safety laboratory parameters (CBC, differential and comprehensive chemistry 
profile) and overall rate, severity and treatment–relatedness of any adverse event. 
3. from week -10 to week 12, IgG level between intravenous screening phase and 
subcutaneous experimental treatment study phase 
 
 
3.2. Background, Prevalence and Significance: 
 
Prevalence: 
Myasthenia gravis (MG) is a rare neuromuscular disorder. The estimated prevalence is 
20/100,000.3 Using this prevalence, we estimate the MG population in US to be 60,000 
based on a US population of 300,000,000. A wide range of incidence is reported with an 
estimate of about 2.0 to 10.4/million/year in Virginia4 to 21.27/million/year in Barcelona, 


 
 
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5 
Spain.5 In patients younger than 40, women predominate with a ratio of 7:3. In the fifth 
decade, new cases of MG are evenly distributed between men and women. After age 50, 
new cases of MG are slightly more common in men with a ratio of 3:2.6-7 
 
Background and Significance: 
Myasthenia gravis is characterized by weakness and fatigability of ocular, bulbar, and 
extremity musculature.8-12 The “fatigue” of MG can be analyzed electrophysiologically by 
demonstrating a decremental response of the compound motor action potential to repetitive 
nerve stimulation.13 The improvement of strength with reversible anti-acetylcholinesterase 
drugs such as edrophonium, physostigmine, and pyridostigmine was the first evidence 
implicating the neuromuscular junction in the pathogenesis of MG.14  
 
The autoimmune nature of MG was established by producing experimental allergic MG 
(EAMG) through the immunization of animals with purified acetylcholine receptor (AChR) in 
addition to exhibiting clinical and electrophysiological similarities with human MG. 
Subsequently, circulating AChR antibodies (Abs) were found to be present in the serum of 
patients with MG15 and passive transfer of human serum to healthy rodents produced clinical 
evidence of MG in animals.16  
 
Therapeutic initiatives in MG have focused on ways of either increasing the amount of 
acetylcholine in the synaptic cleft or suppressing the aberrant immune response.12,17-18 The 
first effective treatment of MG involved the administration of an acetylcholinesterase inhibitor 
to increase the amount of acetylcholine available for binding in the neuromuscular junction14. 
This approach, while effective in mild cases of MG, is directed only toward the control of 
symptoms and does nothing to alter the pathophysiology of the disease.12,17-18 
 
A number of attempts have been made to suppress the immune system and the associated 
antibody response. Thymectomy was first performed more than a half-century ago and was 
the earliest form of immune-directed therapy in MG.19 While there is evidence for involvement 
of the thymus in the autoimmune response in MG, less than one-third of patients who have 
undergone thymectomy enter remission.20-21 
 
The introduction of corticosteroids in the therapy of MG was a major clinical advance. 
Prednisone is the most commonly used corticosteroid22 and has been associated with an 
improvement in half23 and a clinical remission in more than a quarter of patients. As a result, 
steroids are often considered the immunotherapeutic of choice in patients who remain 
symptomatic on pyridostigmine. Many patients, however, can never be weaned completely 
from steroid therapy.23 Corticosteroids exert a variety of effects on the immune system, but 
the exact mechanism of action in MG has yet to be defined. However, corticosteroids have 
dose-limiting side effects such as generalized immunosuppression, hyperglycemia, 
hypertension, myopathy, weight gain, cataracts, and osteoporosis.  
 
Other approaches to immunosuppression have come into clinical use in recent years. Drugs 
such as azathioprine,24-25 cyclophosphamide,26 cyclosporine,27-28 mycophenolate mofetil,29-32 
and intravenous immunoglobulin (IVIg)1-33 have been studied with varying degrees of 
success. 
We 
are 
completing 
a 
study 
of 
methotrexate 
in 
MG34 
http://clinicaltrials.gov/ct2/show/NCT00814138. 
 
 
IVIg is an approved treatment for several immunodeficiency syndromes35-38 and more 
recently has been approved for the management of two other autoimmune neuromuscular 


 
 
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6 
disorders, chronic inflammatory demyelinating polyneuropathy (CIDP)39 and multifocal motor 
neuropathy.40 Intravenous immunoglobulin (IVIg), a pooled gammaglobulin product from 
several thousand blood donors, has a complex immunomodulatory mechanism of action. It is 
thought to involve pathogenic autoantibody production modulation and binding inhibition, pro-
inflammatory cytokinesuppression, Fc receptor blockade, macrophage colony stimulating 
factor and monocyte chemotactant protein-1 increase, alteration in T cell function, decrease 
in circulating CD54 lymphocytes, and inhibition of cell transmigration into the muscle.41 More 
recently, investigators from the Rockefeller found that Fc core polysaccharide 2,6-sialylation 
mediates the anti-inflammatory properties of IVIg.42 
 
IVIg is administered as an induction dose of 2 gm/kg over 2 to 5 days, followed by monthly 
maintenance doses of 0.4- 2.0 gm/kg given every 2 to 4 weeks. While it is generally infused 
no faster than 150 to 200 cc/h, a recent report described infusion rates of up to 800 cc/h in 
50 patients, which was reasonably well tolerated.43 Lee and colleagues treated two CIDP 
patients with subcutaneous infusion of immunoglobulins (SCIg) after IVIg therapy was shown 
to be effective.44 Application of SCIg was well tolerated and led to stabilization of 
the disease course.44 A study of SCIg IgPro20 in CIDP is currently ongoing 
http://clinicaltrials.gov/ct2/show/NCT01545076. 
 
 
IgPro20 (Hizentra®) is a ready-to-use formulation of human IgG with ≥98% purity for 
subcutaneous (SC) administration. It is approved in the United States of America (US), in the 
EU, in Switzerland, and in Canada under the brand name Hizentra® for SC application in 
primary immune deficiency (PID) syndromes and is manufactured at CSL Behring’s (CSLB’s) 
facility in Berne, Switzerland. It is a 20% liquid formulation (200 mg/mL) of human normal 
immunoglobulin for subcutaneous use administered SC weekly or biweekly (ie-using 2x the 
weekly dose). Bioavailability and pharmacokinetics of SCIg and intravenous IgG (IVIg) differ 
in patients with primary immunodeficiencies. Based on area under the curve (AUC) of serum 
IgG versus time and trough level ratios (TLRs) on SCIg/IVIg, the mean dose adjustments 
required for non-inferior AUCs with multiple different SCIg preparations were 142% (± 11, 
with no real difference between different preparations.45 However, there were wide variations 
between adjustments required by different subjects. Combined data from multiple studies 
allow estimation of the ratio of IgG levels with different dose adjustments, and of the steady 
state serum levels with different SCIg doses. When switching a patient from IVIg to SCIg, 
individualizing the dosage based on measured serum IgG levels and the clinical response is 
preferable to using mean pharmacokinetic parameters.45 In a prospective, open-label, 
multicentre, single-arm, phase III clinical trial conducted in the US, the mean SC IgPro20 : IV 
IgPro10 dose ratio (dose adjustment coefficient) was 1.53 (range 1.26-1.87). The resulting 
mean AUCs were 105.6 g · day/L for IgPro20 versus 103.2 g · day/L for IgPro10 (geometric 
mean ratio 1.002; lower one-sided 95% confidence limit [CL] 0.951). Thus, the primary 
endpoint of the study was met, as this result exceeded the pre-specified criterion of the lower 
one-sided 95% CL of ≥0.8 for non-inferiority. At these AUCs, which were considered 
equivalent, the mean serum IgG trough level on SC IgPro20 was 129% of that on IV (range 
1.18-1.73). Titers of specific antibodies tested were well above respective product 
specifications, suggesting that protection against infection would be effective.46  
 
Little is known about SCIg in myasthenia gravis (MG). A Pubmed search using the search 
terms myasthenia and subcutaneous immunoglobulin yields no relevant study. A prior 
controlled study found that IVIg-treated (2 g/kg of IVIg) MG patients with progressive 
symptoms experienced a clinically meaningful improvement in the QMG score at day 14 
which persisted at day 28.1 More recently, IVIg was found to have comparable efficacy to 


 
 
Version Date: 22-Aug-2016 
 
7 
PLEX in the treatment of patients with moderate to severe MG defined as QMG > 10.5.2 As 
part of routine clinical care, we have treated MG cases with chronic outpatient IVIg. In those 
patients, SCIg would be easier to administer. 
 
Data on SCIg use is limited in MG. In a review of IVIg dispensing records of a specialty 
pharmacy, forty-six patients (median age, 56.5 years; range, 8-86 years) fulfilled the 
inclusion criteria. Thirty-one patients with CIDP received IgG at 7- to 92-day intervals (mean 
[standard deviation (SD)], 28 [16] days). The mean (SD) IgG dose was 75 (60) g/dose, 
equivalent to 866 (623) mg/kg/dose and 1145 (778) mg/kg/month. Six patients with stable 
MG received IVIg or subcutaneous IgG at 3.5- to 61-day intervals (28 [20] days) at a mean 
(SD) IgG dose of 39 (15) g/dose, equivalent to 405 (108) mg/kg/dose and 783 (680) 
mg/kg/month. One patient with CIDP and 4 patients with MG were treated with weekly 
subcutaneous IgG injections.47  
 
 
3.3. Preliminary Studies 
While little is known about SCIg in myasthenia gravis (MG) and even though IVIg is not FDA-
approved in MG, two class 1 studies suggest IVIg is efficacious in MG.1,2 As part of routine 
clinical care, we have treated MG cases with chronic outpatient IVIg. In those patients, SCIg 
would be easier to administer. 
 
A prior randomized, placebo-controlled, masked study aimed to determine the effectiveness 
of IVIg in MG patients with worsening weakness.1 Fifty-one patients with worsening 
weakness due to MG were randomized to infusion with 2 g/kg of IVIg or an equivalent 
volume of IV dextrose 5% in water. The Quantitative Myasthenia Gravis (QMG) Score for 
Disease Severity, a validated clinical composite scale, was calculated by a masked observer 
at baseline and days 14 and 28. In IVIg-treated patients, a clinically meaningful improvement 
in QMG Score for Disease Severity was observed at day 14 and persisted at day 28. The 
greatest improvement occurred in patients with more severe disease as defined by a QMG 
Score for Disease Severity greater than 10.5. 
 
More recently, 84 patients with moderate to severe MG defined as QMG>10.5 and worsening 
weakness were randomized to receive IVIg, 1 g/kg/day for 2 consecutive days, or 
plasmapheresis (PLEX), 1.0 plasma volume exchanges for 5 exchanges.2 The patients were 
evaluated at day 14 after treatment for the primary efficacy parameter of change in QMG and 
secondary clinical and electrophysiologic parameters and were followed for a total of 60 
days. 
 
Both IVIg and PLEX reduced the QMG, and IVIg was comparable to PLEX in efficacy. The 
presence of AChR Abs and greater baseline disease severity predicted a better response to 
therapy. The post intervention status revealed that the same proportion of patients improved 
with treatment: 69% on IVIg and 65% on PLEX. The duration of improvement was similar 
with both treatments and both treatments are well-tolerated.  
 
 
Previous Clinical Trials Experience  
The principal investigator and the co-investigators have extensive experience in treatment 
trials in a variety of neuromuscular diseases including myasthenia gravis, amyotrophic lateral 
sclerosis, muscular dystrophies, inflammatory myopathies, and peripheral neuropathies. All 
sites have expertise in MG research and four of the participating sites were in the recently 
completed investigator-initiated study of mycophenolate mofetil in MG.29,32 Two centers were 


 
 
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sites in the simultaneous mycophenolate mofetil industry-sponsored mycophenolate trial.30-31 
All of the centers are currently sites for the ongoing NIH-sponsored prospective trial of 
thymectomy in MG.33 Dr. Barohn was on the steering committee for this federally funded 
study. Four sites have participated in the federally-funded trial of methotrexate in MG. These 
centers are experienced in recruiting and enrolling patients into clinical trials. In addition, all 
of the centers are accustomed to working together as a group in clinical trials.  
 
All of the study sites are regional referral centers for patients with neuromuscular diseases, 
and in specific, for myasthenia gravis. Each site has relatively large populations of MG 
patients from which to draw upon for patient enrollment.  
 
3.4. Methods, Expected Results, Data Analysis, Interpretations, and Significance 
 
Study Design 
This is a phase-2 multi-center (5 sites) study to assess the efficacy and safety of SCIg in the 
experimental treatment phase in 20 MG patients who remain stable. We define stability while 
receiving IVIg as the QMG score not increasing by more than 3 points at week 0 compared 
to week -9. We anticipate a 20% drop out rate in the IVIg screening phase such that 20 
subjects will remain out of the 25 initial MG cases.  
 
Twenty-five subjects receiving IVIg as their current treatment are enrolled into the IVIg 
screening phase.  At least 20 subjects are expected to continue to the experimental 
treatment phase and qualify based on QMG stability for a baseline visit at week 0. The 20-25 
subjects will then receive weekly SCIg using a 1:1.2 dosing ratio to IVIg. For example, a 100 
kg subject receiving IVIg dose of 1 gm/kg every 4 weeks would be converted to a 20% higher 
dose of SCIg dose weekly = 30 grams (150 mL) per week.46 We will report serious adverse 
events if they occur during the study using the FDA guidance Safety Reporting Requirements 
for INDS and BA/BE Studies. 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm227351.pdf). 
 
Study Graphic: 
 
 
 
 
 
 
 
 
 
 
Screening Phase on IVIg: 
Subjects will be infused with Privigen at the same dose that was being given for routine 
ongoing care. This will range from a dose of 0.2 to 2 gm/kg/4 weeks. If a subject is on an IVIg 
dosing frequency other than 0.2 to 2 gm/kg/4 weeks the dose will be converted to the 
equivalent dose for every 4-week administration.  
 
 
Experimental Treatment Hizentra® Administration: 
 
Screening 
visit at 
Week -10 
3 monthly 
IVIg 
infusion/ 
screening 
phase 
3 month 
experimental 
treatment 
phase with 
SCIg 
End of 
study visits 
at Week 12 
with one 
more visit 
at Week 13 
Baseline: 1 
week after 
3rd IVIg  
treatment 
of 
screening 


 
 
Version Date: 22-Aug-2016 
 
9 
We will start by estimating that the maximum weight based on which we propose to treat 
myasthenia gravis (MG) subjects is 100 kg. Furthermore, the maximal dose of IVIg of 2 
g/kg/month converts to 0.5 g/kg/week. Therefore, the maximal IVIg weekly treatment in any 
subject is 50 grams per week. In order to be converted to bioequivalent SC route, the dose 
will be 20% higher (60 grams per week) and ramp if needed in the second month up 37% 
higher (about 68.5 grams per week) and if needed in the third month up to 50% higher (75 
grams per week). This translates into a maximum initial SC weekly volume of 312.5 cc 
starting on Week 0 which may be increased by the investigator to 375 cc per week at Week 
4.  
The maximum dose we think a subject may need, as outlined above is 3 ml/kg to 3.75 ml/kg. 
With the current limit of 25 ml per site in the package insert (PI) that will require a lot of 
needles per week. More specifically and assuming 4 injection sites per day (max. 100 cc/ 
day), subjects would ultimately need 4 infusion days, each day about 80 to 95 cc divided 
over 4 sites. For an injection site map see Appendix 1. 
 
There are two other studies of Hizentra® in which the FDA has allowed for volumes larger of 
40 ml per site than the PI lists:  
1) Hizentra CIDP IND (IND # 14694, pivotal Study IgPro20_3003 with 40 mL/site allowed; 
study ongoing) http://clinicaltrials.gov/ct2/show/NCT01545076 
2) Hizentra Primary Immune Deficiency (PID) IND (IND # 13021, US Extension Study 
IgPro20_3001 with 40 mL/site allowed; study completed). The final CSR for this extension 
study was submitted to the IND only (IND 13021, serial #61 on 30 Sep 2011). 
 
We would like to allow the subjects in this study to go up to 50 cc/site, to allow the regimen to 
be more practical and convenient for them, and we have included the following plan to allow 
the subjects to increase to that volume under supervision and with repeated examinations to 
be sure there are no safety problems with that regimen. At the maximal 50 cc per site and 
assuming 4 injection sites per day (max. 200 cc/day), we would need 2 infusion days, each 
day consisting of 157 to 188 cc divided about over up to 4 sites.  At a maximum rate of 25 
ml/hr/site, that could conceivably allow a subject like that to infuse for 2 hrs twice a week. 
The infusion sites would only need to be 2 inches apart, and by the 3rd day, we should be 
able to use the same site again. For patients that do not tolerate the 50 cc per site approach 
as determined by the local investigator team, we could do infusions over 3 days with each 
SC infusion site being no more than 40 cc per site. We are proposing allow subjects to 
ultimately go up to 50 ml per site and accomplish their weekly dosing in 2 hrs twice a week, 
after a ramp-up. A recent update in the IgPro20 package insert outlines the potential dosing 
frequency of 2-7 times per week. Below is a chart with guidance on SC infusion parameters 
for volume per site as patients receive each subsequent infusion. 
 
  
Infusion Parameters* 
Infusion Number 
1st 
2nd to 4th 
5th 
6th and above 
Volume (mL/site) 
Rate (mL/hr/site) 
15 
20 
25 
15 
25 
 
Below is an example of a conservative slower titration rate. Patients who tolerate the SCIg 
administration can be titrated up at the investigators discretion at a faster rate. Volume per 
site and number of infusions per week may be escalated or reduced during the course of the 


 
 
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10 
experimental treatment phase based on patient’s tolerability and the local site investigator 
judgment as long as the weekly dose is maintained.  
 
I. SCIg Week 0 
One week after the last IVIg dose and as per package insert, SC infusions would start at 15 
cc per site x 4 sites (60 cc daily) maximum rate = 15 ml/hr/site and are spaced out over 4 
days in the first week. The first 2 infusions are for training purposes done under nurse 
supervision in the research facility. It is anticipated the subject will demonstrate competency 
and be eligible to self-administer the next 2 infusions in the home setting. 
 
II. SCIg Week 1  
At 72 hours or more after the last infusion, the subject skin is inspected by the local 
investigator or nurse. For example, if the last infusion of the first week was given on Friday, 
the sites would be examined on Monday. If there is no residual reaction at sites other than 
mild erythema or induration, the volume per site would be advanced, as tolerated. Therefore, 
by the 5th infusion, this can be increased by the local investigator team (physician or nurse) 
to 20 ml per site at the research unit. The next 3 infusions are done at home by the subject 
during the rest of Week 1. 
 
III. SCIg Week 2 
If there is no significant local site residual reaction at 72 or more hours after the last infusion 
as judged by phone discussion between the nurse and the patient, the volume per infusion in 
Week 3 can be increased to 25 ml/site (100 cc per 4 sites) on the first day followed on the 
next 2 days and as tolerated by 2 other sets of infusions of 100 cc each over 4 other sites to 
reach a total of 300 cc in Week 2. These infusions are done at home by the subject during 
Week 2. 
 
IV. SCIg Week 3  
If there is no significant residual reaction at sites at 72 or more hours after the last infusion as 
judged by phone discussion between the nurse and the patient, the volume per infusion in 
Week 3 can be increased to 30 ml/site (120 cc daily) on the first day followed on the next 2 
days and as tolerated by 2 other sets of infusions of 120 cc each over 4 other sites to reach a 
total of 360 cc in Week 3. These infusions are done at home by the subject during Week 3. 
 
Therefore, the maximum total volume in the first month of SCIg for a 100-kg subject would 
still be up to 1,220 cc which is equivalent to 244 grams of Ig or a mean weekly dose of 61 
grams of SCIg.  
 
This would accommodate amply the 1:1.20 conversion factor target since this factor 
would yield 60 grams per week... 
 
V. SCIg Week 4 to Week 7: 
The next decision step at Week 4 depends on the patient MG status as judged by the local 
site investigator.  
A) If MG is stable as judged by the site investigator: a 100-kg subject would stay on the 
dose of approximately 60 to 62.5 grams per week or 300 to 312.5 cc per week:  
1. If there is no significant residual reaction at sites at 72 or more hours after the 
last infusion: 
a. Week 4:  If there is no significant residual reaction at sites at 72 or 
more hours after the last infusion, the volume per infusion can be 
increased to 35 ml/site (140 cc daily) after site inspection by the local 


 
 
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11 
investigative team (physician or nurse). A second infusion is repeated 
on the next day at home by the subject during Week 4.   
b. Week 5: If there is no significant residual reaction at sites at 72 or 
more hours after the last infusion as judged by phone discussion 
between the nurse and the patient, the volume per infusion can be 
increased to 40 ml/site (160 cc daily). These infusions are done at 
home by the subject. 
c.  Week 6 (new in-person safety visit): If there is no significant residual 
reaction at sites at 72 or more hours after the last infusion, the volume 
per infusion can be increased to 45 ml/site (180 cc daily) after site 
inspection by the local investigative team (physician or nurse). A 
second infusion is repeated on the next day at home by the subject 
during Week 6.   
d. Week 7: If there is no significant residual reaction at sites at 72 or 
more hours after the last infusion as judged by phone discussion 
between the nurse and the patient, the volume per infusion can be 
increased to 50 ml/site x 3 sites (150 cc daily) by the seventh week. 
These infusions are done at home by the subject during Week 7. 
 
The maximum total volume in the second month of SCIg for a 100-kg subject would be 1,260 
cc which is equivalent to 252 grams of Ig or a mean weekly dose of 63 grams of SCIg. 
 
2. If the skin reaction does not allow for an increase in volume per site, the 100-
kg subject would continue on SCIg 100 cc three times per week which means 
that the per site infusion volume would be reduced from 30 cc per site to the 
FDA labelling of 25 cc per site.  
 
The maximum total volume in the second month of SCIg for a 100-kg subject would be 1,200 
cc which is equivalent to 240 grams of Ig or a mean weekly dose of 60 grams of SCIg.  
A re-challenge can be attempted again once during the study per IV and V. A) 1. above. 
 
B) If the site investigator assesses that the MG is not stable and that the patient is safe 
to continue in the study, the 100-kg subject would increase the dose to approximately 
68.5 grams per week or 342.5 cc per week: 
1. If there is no significant residual reaction at sites at 72 or more hours after the 
last infusion: 
a.  Week 4:  If there is no significant residual skin reaction, the volume 
per infusion can be increased to 35 ml/site (140 cc daily) after site 
inspection by the local investigative team (physician or nurse). A 
second (140 cc) and third infusion (70 cc) is repeated over the next 2 
days at home by the subject during Week 4.   
b. Week 5: If there is no significant residual reaction at sites at 72 or 
more hours after the last infusion as judged by phone discussion 
between the nurse and the patient, the volume per infusion can be 
increased to 40 ml/site (160 cc daily). A second infusion is repeated on 
the next day at home by the subject during Week 5. These infusions 
are done at home by the subject. 
c. Week 6 (new in-person safety visit): If there is no significant residual 
reaction at sites at 72 or more hours after the last infusion, the volume 
per infusion can be increased to 45 ml/site (180 cc daily) after site 
inspection by the local investigative team (physician or nurse). A 


 
 
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12 
second infusion is repeated on the next day at home by the subject 
during Week 6.   
d. Week 7: If there is no significant residual reaction at sites at 72 or 
more hours after the last infusion as judged by phone discussion 
between the nurse and the patient, the volume per infusion can be 
increased to 50 ml/site x 4 sites (200 cc day one and 150 cc day two) 
by the seventh week. These infusions are done at home by the subject 
during Week 7. 
 
The maximum total volume in the second month of SCIg for a 100-kg subject would be 1,380 
cc which is equivalent to 276 grams of SCIg per month or a mean weekly dose of 69 grams 
of SCIg.  
 
This would be more than ample to meet the 1:1.37 conversion factor target since this 
factor would yield 68.5 grams per week. 
 
2. If the skin reaction does not allow for an increase in volume per site, the per 
site infusion volume would be reduced from 30 cc per site to the FDA labelling 
of 25 cc per site. A 100-kg subject would continue on SCIg 100 cc but the 
frequency would have to be increased to four times per week alternating with 
three times a week. 
 
The maximum total volume in the second month of SCIg for a 100-kg subject would be 1,400 
cc which is equivalent to 280 grams of SCIg per month or a mean weekly dose of 70 grams 
of SCIg.  
A re-challenge can be attempted again once during the study per section IV and V. B) 1. 
above. 
 
 
VI. SCIg Week 8 to Week 12: 
The next decision step at Week 8 depends on the patient MG status as judged by the local 
site investigator.  
A) If MG is stable as judged by the site investigator: a 100-kg subject would stay on 
the dose of approximately 68.5 grams per week or 342.5 cc per week.  
1) If the skin reaction at 72 hours allows for a volume per site higher than 25 
cc, the volume per infusion site may be up to 50 ml/site x 3 to 4 sites (150 
cc one day and 200 cc on the other day weekly) by the eighth week with 2 
infusion days per week. These infusions are also done at home by the 
subject Week 8 to Week 12. 
 
The maximum total volume in the third month of SCIg for a 100-kg stable subject would be 
1,400 cc which is equivalent to 280 grams of SCIg per month or a mean weekly dose of 70 
grams of SCIg. This would be more than ample to meet the 1:1.37 conversion factor target 
since this factor would yield 68.5 grams per week.  
 
2) If the skin reaction does not allow for a volume per site higher than 25 cc, 
the 100-kg subject would continue on SCIg 100 cc three to four times per 
week which means that the per site infusion volume would be at the FDA 
labelling amount of 25 cc per site. A 100-kg subject would continue on 
SCIg 100 cc but the frequency would have to be increased to four times 
per week alternating with three times a week. 


 
 
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13 
 
The maximum total volume in the third month of SCIg for a 100-kg subject would be up to 
1,400 cc which is equivalent to 280 grams of Ig or a mean weekly dose of up to 70 grams of 
SCIg.  
 
This would accommodate amply the 1:1.37 conversion factor target since the factor 
would yield 68.5 grams per week. 
 
 
A re-challenge can be attempted again once during the study per IV and V. B) 1. above. 
 
B) If the site investigator assesses that the MG is not stable in a patient who is 
experiencing a worsening that does not qualify as a clinical deterioration and that 
the patient is safe to continue in the study, the subject would continue on 1:1.37 
IVIg to SCIg ratio and the investigator would follow the other recommendations for 
medication adjustment in the section titled “Subject deterioration, worsening, 
rescue medication and improvement”. More specifically, acceptable rescue 
medications include the initiation of prednisone or mestinon or an increase in 
prednisone or mestinon dose. 
C) If the site investigator assesses that the MG is not stable in a patient who is 
experiencing a worsening that qualifies as a clinical deterioration (please refer to 
“Subject deterioration, worsening, rescue medication and improvement”), the 
subject will be withdrawn from the study and considered to be a treatment failure. 
Treatment of clinical deterioration is per standard of care with plasmapheresis or 
IVIg.  
D)  
 
1) Additional guidance and safeguards for dosing titration: 
 
1. If subjects tolerate 50 ml/site, up to 4 sites (maximum of 200 ml) may be used per 
day. Rate should not exceed 25 ml/site/hr.  
 
2. Subject may opt to stop advancing volume per site at any point, and/or may elect to 
go back to a smaller volume.  
 
3. DSMB may stop this forced-upward titration of volume per site at any limit they feel is 
causing excessive numbers or severity of reactions or other forms of intolerance.  
 
4. If any subject wishes to exceed 50 ml per site, limit of 200 ml per day, or rate of 25 
ml/site/hr, this may be allowed at discretion of local investigator, after investigator 
certifies in subject record that subject has tolerated volumes and rates specified 
above.  
 
5. Subject dose may be rounded to the nearest vials size (IgPro20 will be dispensed in 
20ml vials). 
 
        
VII. Home Administration: 
Educating the patient regarding self-administration is essential to optimizing safety of SCIg 
therapy. The goal of therapy is for the MG patient to learn self-administration of SCIg 
therapy. Demonstrated proficiency by each study subject is accomplished by successful 


 
 
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14 
return demonstration on self-administration of the SCIg therapy. Subjects will be provided 
with a self-administration teaching guide of Hizentra. 
  
Since our study subjects will be using the Freedom-60 pump, they will be able to titrate the 
rate of infusion up or down for each infusion based upon their individual tolerability. The 
Freedom-60 flow rate tubing is the piece of equipment that regulates the infusion rate. The 
Freedom-60 pump is a mechanical pump and is simple to use, and does not have the ability 
to dial up or down a specific infusion rate. It is the Freedom-60 flow rate tubing that sets the 
rate during each infusion. 
 
Based upon the total SCIg volume we prescribe weekly it will be easy to identify the number 
of SCIg sites and rate of infusion using the Freedom-60 calculator.  We will obtain from RMS 
Medical the Freedom-60 calculator which automatically calculates / recommends the correct 
administration set (SCIg needle set) and flow rate tubing so that the nurse can provide the 
proper tubing and supplies to the patient. 
 
Baseline Visit: 
Subjects will then be converted over to 20% Hizentra® at a conversion ratio of IVIg:SCIg of 1 
to 1.25. At baseline, the first dose is administered within one week from the third IVIg infusion 
of the Stabilization Phase. The drug is administered through a pump as outlined above 
depending on dose and tolerability and for 3 months duration.  
 
 
 
3-month Treatment Phase on SCIg:  
Nurse training of the patient will occur during Week 0/baseline visit. A portable infusion pump 
will be used to administer the SCIg therapy. Patients must be able to demonstrate proficiency 
in self-administration of the SCIg drug after teaching visits are completed. It is the 
expectation that patients will be able to administer SCIg therapy at home through the end of 
the study at Week 12.  Another dose increase of 25% (1.20 to 1.37 at week 4) is allowed 
(total 150% of original IVIg dose) if a patient worsens and the principal investigator believes 
that it is in the best interest of the patient. Patients requiring increase in SCIg dose will 
undergo additional assessment at unscheduled visits. 
 
Timeline: 
This study will take place over 36 months. The first 12 months will center on full protocol 
development, IRB approval at all sites, contracting with CSL-Behring and contracting with 
other investigator sites, CRF development, database development, investigator meeting, 
project management and administrative activities. During the second year of this project 
investigators will focus on subject enrollment. Enrollment would proceed at the rate of 2 
patients per month with 6 months study participation. After the last patient is completed, data 
clean up; lock and analysis would take place. Presentation at national/international meetings 
and publication preparation would be the final step followed by study closure. 
 
 
Study Eligibility 
Inclusion Criteria: 
Patient selection will be based on a diagnosis of MG by all of the following specific criteria: 
 
1) Patients 18 and older. 


 
 
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15 
2)   Patients must have prior or current documentation of MGFA MG grades 2, 3, or 4 
generalized MG, according to the MGFA classification system.48 These grades 
correspond to mild (2), moderate (3), and severe (4). 
3)  Elevated AChR or MuSK Ab. These tests will have been performed at some time prior 
to entry into the study. Double seronegative MG patients with prior documentation of 
an abnormal decrement (>10%) on slow repetitive nerve stimulation or an abnormal 
single fiber EMG will also be allowed to participate. 
4)  Patient’s signs and symptoms should not be better explained by another disease 
process. 
5) IVIg maintenance dose of 0.2 to 2 gm/kg/4 weeks or equivalent dose administered Q 
2-4 weeks±3days  
6)  Stable IVIg for at least 3 cycles (definition of stability: no change in prescribed dosage 
or frequency by the treating physician) 
7)   Patient must be receiving no more than 200g/4weeks of IVIg.  
8)   Patients must be willing to complete the study and return for follow-up visits. 
9)  Patients must be willing to give written informed consent before participating in this 
study. A copy of the signed consent must be kept in the patient’s medical record.  
10) Patients can be on the following drugs as long as there has been no dose change for 
60 days: azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, 
tacrolimus, methotrexate or other immunosuppressive drugs. 
11) Patients can be on prednisone as long as there has been no dose change for 30 
days. 
 
 
 
 
Exclusion Criteria: 
 
1) MGFA grade V within 6 months of screening. 
2) A history of chronic degenerative, psychiatric, or neurologic disorder other than MG 
that can produce weakness or fatigue. 
3) Other major chronic or debilitating illnesses within six months prior to study entry. 
4) Female patients who are premenopausal and are: (a) pregnant on the basis of a 
serum pregnancy test, (b) breast-feeding, or (c) not using an effective method of 
double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) 
birth control (birth control pills, male condom, female condom, intrauterine device, 
Norplant, tubal ligation, or other sterilization procedures). 
5) Altered levels of consciousness, dementia, or abnormal mental status. 
6) Thymectomy in the previous three months. 
7) Evidence of renal insufficiency (Cr>1.5 x elevated) or liver disease (transaminases > 
2.5 x elevation) at screening. 
8) Skin disease that would interfere with assessment of injection site reaction 
9) History of severe reactions to IVIg or SCIg. 
10) Participation in a research study within the last 3 months 
11) Treatment with rituximab or other biologics within 12 months of study entry 
12) Inability to provide informed consent. 
13) History of thrombotic episodes within the last year prior to enrollment 
14) Known allergic or other severe reactions to blood products including intolerability to 
previous normal human immunoglobulin for intravenous administration (IVIG) and/or 
subcutaneous immunoglobulin (SCIG), such as history of clinically relevant hemolysis 


 
 
Version Date: 22-Aug-2016 
 
16 
after IVIG infusion, aseptic meningitis, recurrent severe headache, hypersensitivity, 
severe generalized or severe local skin reaction. 
15) History of IgA deficiency or evidence of IgA deficiency at screening. 
 
 
 
Study Procedures (Table 1) 
 
A clinical evaluator (CE) will perform evaluations at the study visits. The CE can be a 
physical therapist, physical therapist assistant, nurse, or physician who is not one of the 
investigators. All CEs will have undergone extensive, standardized training in Quantitative 
MG and Activities of Daily Living scoring before the study is initiated. This training will be 
performed by the principal CE, Laura Herbelin, from the University of Kansas Medical 
Center. The evaluations performed by the CE will include:  
 
1) A battery of quantitative functional tests from which a Quantitative MG score (QMG) is 
calculated. The QMG is a 13-item test that objectively measures ocular, bulbar, 
extremity fatigue/strength, and respiratory function.49-51  
2) MG activities of daily living (MG-ADL) score. The MG-ADL is a subjective survey of 
the subject on how their activities of daily living are affected.52 MG-ADL is still a 
relevant outcome measure.53 
3) MG composite score. Specific components of the QMG, the MG-ADL, and the MMT 
are combined to obtain the MG composite score.54-55   
4) MG quality of life-15 (MG QOL-15). A new MG-specific quality of life questionnaire 
that the subject fills out.56  
 
 
The principal investigator or a co-investigator will perform the following procedures: 
1) History 
2) Physical examination 
3) Neurological examination 
4) Assign a MGFA MG grade.48 The investigator will assign a MGFA clinical 
classification grade. The grades are Class I- Any ocular muscle weakness, 
may have weakness of eye closure, all other muscle strength is normal 
(subject will be excluded with this grade), Class II – Mild weakness affecting 
other than ocular muscles, may also have ocular muscle weakness of any 
severity. Class III – Moderate weakness affecting other than ocular muscles, 
may also have ocular muscle weakness of any severity. Class IV – Severe 
weakness affecting other than ocular muscles, may also have ocular muscle 
weakness of any severity. Class V – Defined by intubation, with or without 
mechanical ventilation, except when employed during routine postoperative 
management. Patients rated as Class V will be excluded. 
 
The study coordinator will perform the following: 
 
1) Record concomitant medications 
2) Review any adverse events 
3) Vital signs including weight. 
4) Labs: CBC with Diff, Chem 20 and IgG levels, serum pregnancy test for 
women of childbearing potential. IgA levels will be drawn as screening only. 
5) Distribute study medication. 
6) TSQM 


 
 
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17 
7) Instructions in subcutaneous injections will be given by either the study 
coordinator or the designee.  
 
Screening and Informed Consent (Week [-10]): Patients identified as a potential candidate 
will sign informed consent and will undergo a complete blood count (CBC), chemistry profile 
(Chem 20) and IgG levels, IgA levels, general physical and neurological examination, serum 
pregnancy test, vital signs including weight, and MGFA.  If the inclusion criteria are met, the 
patient can be entered into the study. Women of child bearing potential will be instructed to 
take proper precautions to avoid pregnancy for three months after stopping the study 
medication. When inclusion/exclusion criteria are met, protocol eligibility and admission 
information consisting of demographic data including age, sex, past medical history, 
concomitant medications including prednisone dose, and prior AChR-Ab and MuSK Ab result 
on each patient will be documented. This visit can occur within 4 weeks of the subject’s first 
IVIg stabilization. 
 
Screening Phase: IVIg Infusion Stabilization Weeks [-9, -5 and -1])  
Subjects will be asked to refrain from taking pyridostigmine for at least 12 hours prior to 
testing. Once testing is completed pyridostigmine may be restarted. Pre-medications may be 
administered if the patient has had adverse reaction prior to study entry while on IVIg or if 
they developed such events during study drug administration. These will be captured and 
followed in the concomitant medication log. All study visit procedures must be performed 
prior to infusion. These procedures include for all three visits QMG (including FVC), and MG-
ADL, adverse events, concomitant medications, vital signs including weight, safety labs and 
a general physical exam. Additionally, MG composite score (including MMT), and MG-QOL-
15 will be done at the Week -9 visit.  
 
Experimental Treatment Phase: 
Baseline Visit (within 1 week of the last screening phase IVIg infusion) (Week 0):   
Within 1 week of the last infusion of the Screening Phase, patients will be instructed at 
baseline not to take pyridostigmine for at least 12 hours prior to all visits. Pyridostigmine may 
be restarted after testing is completed. All study visit procedures will be performed prior to 
infusion. These procedures include QMG (including FVC), MG-ADL, MG composite score 
(including MMT), and MG-QOL-15, adverse events and concomitant medications, vital signs 
including weight, safety labs, general physical examination, neurological examination, and 
the TSQM. 
 
 
Treatment Satisfaction Questionnaire for Medication (TSQM) is a generic measure of 
treatment satisfaction for medication. It has undergone rigorous development with sound 
psychometric properties and is available in multiple linguistically validated languages. The 
domains tested include effectiveness, side effects, convenience and global satisfaction.57-58  
We will be using the TSQM version II for this study.  
 
Instruction on subcutaneous injection will be given by the study coordinator or designee at 
the baseline visit. The subjects must return for baseline day 2 (Week 0.1) the day 
immediately following baseline day 1 (Week 0, first SCIg infusion). At this visit the subject will 
be evaluated on their ability to self-administer the subcutaneous injections. If the subject is 
still not comfortable, or the site personnel determine the subject needs additional training the 
subject may return for additional visits Week 0.2, and 0.3 if necessary.  
 
 


 
 
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18 
Week 1: 
Subjects will return the first week to assess how effective they are in performing their own 
subcutaneous infusion. Additionally, a general physical exam, vital signs including weight, 
safety labs, and a review of the subject’s concomitant medications and adverse events will 
be done at this visit. 
 
Week 2 and 3: 
The study coordinator will contact the subject to evaluate if they are having trouble 
performing their subcutaneous infusions. The subjects may return for more education if 
needed. 
 
Follow-up Visits (Weeks 4, 8 and 12) 
Patients will be instructed not to take pyridostigmine for at least 12 hours prior to each 
evaluation. Patient visits will be carried out at each institution’s General Clinical Research 
Center (GCRC) or other facilities suitable for clinical research.  
 
 
 
Every four weeks, the CE will perform the following tests: 
1) Quantitative MG score (including FVC). 
2) MG ADL (Activities of Daily Living) score. 
3) MG Composite score (including MMT). 
4) MG QOL-15. 
 
 
Every four weeks the study investigator will perform the following: 
1) History and physical exam. 
2) Neurological examination (Week 12) 
3) MGFA MG grade (Week 12 only). 
 
 
The study coordinator will perform the following every month: 
1) Review any adverse events 
2) Review concomitant medications 
3) Vital signs, including weight. 
4) CBC and Chem 20, IgG levels 
5) Serum pregnancy test for women of childbearing potential. 
6) Collect unused medication, reconcile drug usage 
7) Distribute study medication at month 3 only 
8) TSQM at Week 12 only 
 
Week 6: 
This is an added safety visit. Subjects will return to have infusion sites inspected prior to 
dose escalation per site above 40 cc per site. If there is no residual reaction at sites other 
than mild erythema or induration, the volume per site would be advanced, as tolerated. If this 
escalation occurs at another time interval, an unscheduled visit will be performed. 
 
Week 13: 
This is a completion visit that will be conducted in-person one week after SCIg treatment is 
completed. Adverse events will be reviewed and closed if resolved. Safety labs will be draw 
only if results were clinically significant at Week 12, vital signs including weight and a general 
physical exam will be done. 
 
 


 
 
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19 
Unscheduled Visits: 
Unscheduled visits may be done for subject difficulty with subcutaneous drug administration, 
intolerable adverse events or for suspected worsening. 
If the subject appears to have trouble with administering the subcutaneous medication, you 
may bring the subject in for as many visits as necessary.  
If the subject appears to have an intolerable adverse event, you may bring the subject in for 
as many visits as necessary if these cannot be addressed by a phone call.  
If the subject reports suspected worsening in between visits, you may bring the subject in. 
Testing at unscheduled visits is done only to assess for clinical worsening via QMG and MG-
ADL. If no worsening is found, patients will continue to be a part of the study. If a patient 
experiences a worsening event that does not qualify as clinical deterioration (per pg. 22) and 
the investigator determines it is safe for that patient to continue, the patient will remain in the 
study. On the other hand, if a patient experiences a worsening event that qualifies as clinical 
deterioration the patient will be withdrawn from the study. 
 
End of Study Visit Follow Up Calls (Week 14, 16): The study coordinator will call each 
subject bi-monthly for one month to close out all study drug related adverse events still open. 
Ongoing active AEs will be considered permanent after the one month follow up. 
 
Concomitant Medication: Every effort should be made to keep subjects on a stable treatment 
regimen through Week 16. The study coordinator will obtain at each visit, the current list of 
concomitant medication. See Subject deterioration and rescue medication section below for 
guidance. 
 
 
Medication Reconciliation: Records of all SCIg study drug dispensed and returned dosages 
administered, and intervals between visits will be kept during the study. Subjects will be 
asked to return all unused medication at each visit and at the end of the study.  
 
 
Adverse Events:  Adverse events (AE) will be reported using FDA guidance Safety Reporting 
Requirements for INDs and BA/BE Studies. AEs will be grouped into the following 
categories:  
 
A. Adverse Event (21 CFR 312.32(a))  
 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related 
 
B. Suspected Adverse Reaction (21 CFR 312.32(a))  
 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a 
drug. 
 
 
 
 


 
 
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20 
C. Adverse Reaction  
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the drug 
caused the event. 
 
Severity of Adverse Events 
 
The severity of each AE is to be assess by the investigator as follows: 
Severity 
Definition 
Mild 
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
Moderate 
A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily 
living causing discomfort but poses no significant or permanent risk of harm to 
the research participant. 
Severe 
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
 
Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model 
(SDTM) Severity Intensity Seale for Adverse Event Terminology.  
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) coding dictionary will be 
used for data entry in the CRIS/VELOS electronic database system for adverse event 
classification using the above CDISC criteria. 
 
Causality of Adverse Events 
The causal relationship of an AE to IgPro20 should always be assessed by the investigator. 
Even if the investigator considers that there is no causal relationship to IgPro20, the AE must 
still be reported.  
 
One of the following categories will be used for assessing the causal relationship of each AE, 
including a laboratory test abnormality, to IgPro20: 
• 
Not Related 
o Event or laboratory test abnormality with a time to IgPro20 intake that makes a 
relationship impossible. 
o Is most likely explained by concurrent disease or other drugs or chemicals 
(either pathophysiologically or clinically). 
o Has occurred prior to administration of IgPro20 in comparable severity and/or 
frequency. 
• 
Related 
o Event or laboratory test abnormality with plausible time relationship to IgPro20 
intake. 
o Cannot be explained by disease or other drugs. 
o Response to withdrawal plausible (pharmacologically, pathologically). 
o Event definitive pharmacologically or phenomenologically (i.e., an objective 
and specific medical disorder or a recognized pharmacological phenomenon). 
o Rechallenge satisfactory, if necessary. 
 


 
 
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21 
The degree of certainty with which an AE is attributed to IgPro20 or an alternative cause 
(e.g., natural history of the underlying disease, concomitant therapy, etc.) will be determined 
by how well the event can be understood in terms of: 
• 
Known pharmacology of IgPro20. 
• 
Clinically and/or pathophysiologically plausible context. 
• 
Reaction of a similar nature previously observed with similar products, or reported in 
the literature for similar products as being product related e.g., headache, facial 
flushing, and pallor. 
• 
Plausibility supported by the temporal relationship e.g., the event being related by 
time to administration or termination of treatment with IgPro20, drug withdrawal, or 
reproduced on rechallenge. 
 
  
D. Unexpected (21 CFR 312.32(a)) 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed 
in the investigator brochure or is not listed at the specificity or severity that has been 
observed. "Unexpected," as used in this definition, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under investigation.  
 
E. Serious (21 CFR 312.32(a)) 
A serious adverse event is defined as:  
1. 
Death;  
2. 
Life-threatening (report if the patient was at substantial risk of dying at the time of 
the adverse event or it is suspected that the use or continued use of the product 
would result in the patient’s death); 
3. 
Hospitalization for any reason; 
4. 
Disability (report if the adverse event resulted in a significant; persistent, or 
permanent change, impairment, damage or disruption in the patient’s body 
function/structure, physical activities or quality of life; 
5. 
Congenital anomaly (report if there are suspicions that exposure to a medical 
product prior to conception or during pregnancy resulted in an adverse outcome in 
the child); 
6. 
Requires intervention to prevent permanent impairment or damage (report if you 
suspect that the use of a medical product may result in a condition which required 
medical or surgical intervention to preclude permanent impairment or damage to a 
patient).  
 
The PI or Co-I will monitor AEs monthly, grade them, and indicate if the AE is related to the 
study medication (definite, probable, possible, unlikely, not related).  For each AE, the PI will 
determine if the study medication should be continued.  Patients will be instructed to call the 
PI’s office (or on-call resident if at night or on the weekend) to report events that occur 
between study visits. All SAEs will be reported to the medical monitor, HSC, Clinical 
Research Center (if applicable), and FDA per guidelines, as soon as possible, but no later 
than five working days. 
 
Hemolysis Risk: 
Cases of hemolysis can occur can occur in treatment with IgPro20. If a subject experiences a 
confirmed hemolysis requiring transfusion or medical intervention (e.g. steroids), experiences 


 
 
Version Date: 22-Aug-2016 
 
22 
catastrophic consequences of hemolysis (e.g. renal failure, hypotension, bronchospasm, 
emergency splenectomy), or death during the study, the subject should be withdrawn. 
Hemolysis of this nature will be considered an expected serious adverse event. 
 
Thrombosis Risk: 
 
Arterial and venous thromboembolic events including myocardial infarction, stroke, deep 
venous thrombosis and pulmonary embolism have been associated with the use of 
immunoglobulins. Caution should be exercised in patients with preexisting risk factors for 
thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of 
vascular disease or thrombotic episodes, patients with acquired of inherited thrombophilic 
disorders, patients with prolonged periods of immobilization, severely hypovolemic patients, 
patients with diseases which increase blood viscosity). Patients should be informed about 
first symptoms of thromboembolic events including shortness of breath, pain and swelling of 
a limb, focal neurological deficits, and chest pain and should be advised to contact their 
physician immediately upon onset of symptoms. Patients should be sufficiently hydrated 
before use of immunoglobulins. 
 
 If patient is suspected to have deep vein thrombosis, such as new calf swelling or calf pain, 
we will apply Wells’ pretest probability scoring as outlined below and the Wells’ pretest 
probability scoring form (see appendix 2) should be completed as source documentation.59 
Subjects will be examined for possible thromboembolic events at each visit. In any subject in 
whom the history or routine physical exam suggests the possibility of DVT, a detailed 
examination will be performed and the Wells score will be calculated according to the online 
Calculator below.60  
Calculator: DVT probability: Wells score system 
 
 
 
 
 
 
 
Clinical Findings 
Paralysis, paresis or recent orthopedic casting of lower extremity (1 point) 
Recently bedridden (more than 3 days) or major surgery within past 4 weeks (1 point) 
Localized tenderness in deep vein system (1 point) 
Swelling of entire leg (1 point) 
Calf swelling 3 cm greater than other leg (measured 10 cm below the tibial tuberosity) (1 point) 
Pitting edema greater in the symptomatic leg (1 point) 
Collateral non- varicose superficial veins (1 point) 
Active cancer or cancer treated within 6 months (1 point) 
 
 
Alternative diagnosis more likely than DVT (Baker's cyst, cellulitis, muscle damage, superficial venous 
thrombosis, post phlebitic syndrome, inguinal lymphadenopathy, external venous compression) (-2 
points) 


 
 
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23 
 
 
 
  
Total 
Criteria 
Point 
Count: 
 
  
Reset Form
 
 
 
DVT Risk Score Interpretation  
 
  
3-8 Points: High probability of DVT 
1-2 Points: Moderate probability 
-2-0 Points: Low Probability 
 
 
 
In any subject with a Wells’ score higher than 2.0, further evaluation will be performed 
according to the 2012 ACCP Guidelines61 for "Diagnosis of DVT- Antithrombotic Therapy and 
Prevention of Thrombosis." For scores of 1.0 to 2.0, we will exert an abundance of caution by 
obtaining a D-dimer, and if that is normal proceed with close follow up and reevaluation at 
the next visit. If D-dimer is abnormal (defined as elevated above the upper limit of normal), 
we will pursue leg sonogram. 
 
Renal Failure Risk: 
Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human 
immune globulin products. We will ensure that patients are not volume depleted and assess 
renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, 
before the initial infusion of Hizentra and at appropriate intervals thereafter. Periodic 
monitoring of renal function and urine output is particularly important in patients judged to 
have a potential increased risk of developing acute renal failure. If renal function deteriorates, 
we will consider discontinuing Hizentra. For patients judged to be at risk of developing renal 
dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure 
(such as those with diabetes mellitus or hypovolemia, those who are overweight or use 
concomitant nephrotoxic medicinal products, or those who are over 65 years of age), we plan 
to administer Hizentra at the minimum rate practicable.  
 
Transfusion-Related Acute Lung Injury (TRALI): 
Noncardiogenic pulmonary edema may occur in patients administered human immune 
globulin products. TRALI is characterized by severe respiratory distress, pulmonary 
edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs 
within 1 to 6 hours following transfusion. Patients with TRALI may be managed using 
oxygen therapy with adequate ventilatory support. 
We will monitor drug recipients for pulmonary adverse reactions. If TRALI is suspected, 
We will perform appropriate tests for the presence of anti-neutrophil antibodies in both the 
product and patient’s serum. 
 
 


 
 
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24 
Procedures: 
Elective procedures that were pre-planned prior to the time that written informed consent was 
obtained are not AEs. Any complication or worsening of a preexisting condition leading to the 
procedure must be considered an AE. In addition, any AE that could occur as an outcome of 
the planned procedure should be considered as an AE. 
 
Diagnostic and therapeutic procedures (invasive and non-invasive) such as surgery or 
angiography should not be reported as an AE or SAE. However, the medical condition or the 
diagnosis that was responsible for the procedure should be recorded. The procedure should 
be recorded in the narrative as treatment for the AE or SAE (e.g., laparoscopic 
cholecystectomy is the procedure or treatment for an SAE of necrotic gall bladder). 
 
Laboratory monitoring: 
The frequency of safety laboratory testing is monthly. Besides, complete blood count, IgG 
levels and complete metabolic panel, we are obtaining direct antiglobulin (Coombs) testing 
and reticulocyte count. We will therefore screen for hemolysis with CBC, Coombs, 
unconjugated bilirubin and reticulocytes. If there is unexplained new anemia as evidenced by 
hemoglobin decrease by ≥2g/dL, or if the history or physical suggest any symptoms of 
hemolysis such as tachycardia, shortness of breath, dark urine or jaundiced appearance, or 
positive result of direct antiglobulin test or increased reticulocyte count, hemolysis will be 
confirmed via low haptoglobin level. 
 
Treatment Failures 
Treatment failure will be defined as any one or more of the following during the SCIg 
Treatment Phase: 
 
1) Progression of respiratory insufficiency such that the subject requires mechanical 
ventilation. 
2) Progression of dysphagia so that the subject has frequent choking and requires 
mechanical feeding. 
3) The investigator believes the subject has deteriorated to the point that, despite an up 
titration of SCIg to 1.37 fold the original IVIg dose, a new immunotherapy is needed 
(except for prednisone). The time to initiation or increase of the new immunotherapy 
will be documented. 
4) The patient is unwilling to continue in the study because of progressive or continuing 
disability. 
5) The patient’s study physician feels that it would not be in the best interest of the 
patient to continue in the study due to MG symptoms. 
 
Subject Withdrawal: 
 
Patients will withdraw from the study during the IV or SC phase if they meet any of the above 
treatment failure criteria. We will monitor renal function monthly and if there is an elevation in 
creatinine > 1.7 mg/dl, the patient will be withdrawn. 
 
In addition, subjects will be withdrawn from the study if there is a change in IVIg dose during 
the ISP (IVIg Stabilization Phase) as compared to the entry (Week -9) dose. 
 
 
 
 


 
 
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25 
Subject deterioration, worsening, rescue medication and improvement: 
Subjects may experience clinical deterioration, clinical worsening (that does not qualify as 
deterioration), and clinical improvement or disease stability. 
  
Subjects may withdraw at any point during the course of the study. For this protocol, clinical 
deterioration is defined as one the following:  
1) Subjects who experience an MG crisis, which is defined as weakness from MG that is 
severe enough to necessitate intubation or to delay extubation following surgery. The 
respiratory failure is due to weakness of respiratory muscles, severe bulbar 
(oropharyngeal) muscle weakness, or may be the predominant feature in some 
subjects. Or 
2) Significant symptomatic worsening to a score of 3 or a 2-point worsening on any one 
of the individual MG-ADL items other than double vision or eyelid droop in 
comparison to Week -9 in the IVIg screening phase and in comparison to Week 0 in 
the experimental treatment phase. Or  
3) Subjects for whom the treating physician believes that the subject’s health is in 
jeopardy if rescue therapy is not given (for example emergency situations).  
 
Patients experiencing a clinical deterioration are also considered treatment failures and are 
withdrawn from the screening phase or experimental treatment phase as applicable.  
Treatment of clinical deterioration is per standard of care with plasmapheresis or IVIg. These 
patients will be withdrawn from the study and are treatment failures.  
 
 
For this protocol, clinical worsening is defined as one the following: 
1) 
Patient worsening that does not qualify as a clinical deterioration. Or 
2) 
Significant symptomatic worsening to a score of 3 or a 2-point worsening on the 
double vision or eyelid droop items of MG-ADL in comparison to Week -9 in the IVIg 
screening phase and in comparison to Week 0 in the experimental treatment phase. Or  
3) 
Increase in total QMG score by more than 3 points in comparison to Week -9 in the 
IVIg screening phase and in comparison, to Week 0 in the experimental treatment phase   
 
For patients that are withdrawn by the investigator due worsening that does not qualify as 
deterioration or for personal reasons (travel or family situation), rescue medication includes 
increasing or instituting prednisone or adjuvant immunosuppressive therapy as well as 
restarting previously effective IVIg per standard of medical care and based on the treating 
physician best judgment. If the subject wish to withdraw at their own request due perceived 
worsening that does not qualify as deterioration, the investigator will offer them a treatment 
plan that would allow them continued study participation (see below). 
 
For patients who are experiencing a worsening that does not qualify as a clinical 
deterioration and in whom the investigator assesses it is safe to continue with study 
participation, acceptable rescue medications include the initiation of prednisone or mestinon 
or an increase in SCIg, prednisone or mestinon dose. We do not consider subjects with less 
severe worsening requiring an increase in concomitant medication to be either withdrawals 
or treatment failures. Since MG is a variable disease from week to week, it would not be 
unusual in the course of the study that the dose of other medications such as prednisone be 
changed based on disease status and adverse events. The SCIg dose may be increased by 
25% (from 1.20x to 1.37x the IVIg dose at week 4). Patients requiring increase in SCIg dose 
or other treatments (prednisone or mestinon) will undergo additional assessment at 
unscheduled visits. Other alternatives are that the prednisone dose may be increased, or if 


 
 
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26 
the investigator determines it is appropriate (for example worsening ptosis) that the patient 
be closely followed up until clinical condition reassessment at the next visit. The exact 
prednisone increase schedule is left up to the local site investigator judgment. As an 
example, for patients on >15 mg daily or the equivalent for every other day dosing, it is 
suggested that the prednisone daily dose be increased by 20 mg. For patients on <15 mg 
daily or the equivalent for every other day dosing, it is suggested that prednisone be 
increased by 10 or 20 mg, at the physician’s discretion. Further increments in dose are at the 
physician’s discretion. However, the exact prednisone increase schedule is left up to the 
local site investigator judgment. 
 
The exact prednisone tapering schedule is left up to the local site investigator judgment. For 
subjects taking prednisone every other day, below is an example of a monthly tapering 
schedule: 
 
Every other day  
 
Taper to 
                                           dose (mg) 
120 
100 
100 
80 
80 
60 
60 
40 
40 
30 
30 
20 
20 
15 
15 
10 
10 
7.5 
7.5 
5.0 
5.0 
2.5 
2.5 
0 
 
 
The exact prednisone tapering schedule is left up to the local site investigator judgment. For 
subjects taking prednisone daily, below is an example of a monthly tapering schedule: 
 
Daily dose (mg)           Taper to 
60 
50 
50 
40 
40 
30 
30 
20 
20 
15 
15 
10 
10 
7.5 
7.5 
5 
5 
3 
3 
2 
2 
1 
1 
0 
 
In subjects that do not fulfill criteria for worsening or deterioration, clinical improvement in the 
experimental treatment phase is defined as one the following at Week 12 compared to Week 
0:1) 
Improvement (decrease) in the MG-ADL by 2 or more points Or  


 
 
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27 
2) 
Improvement (decrease) in total QMG score by 3 or more points 
 
 
Finally, subjects that do not fulfill criteria for worsening, deterioration or clinical improvement 
at Week 12 compared to Week 0 are considered to have stable MG disease.  
 
 
Study timeline: 
Year 1: Write manual of operations and study forms, develop computerized CRIS Database 
and install at all sites, including training, complete IRB approval for all center, hold a start of 
study meeting, do training and reliability testing for investigators, evaluators, and 
coordinators, send out supplies. 
Year 2: Begin recruiting subjects.  
Year 3: Complete the subjects enrolled continue the yearly site audits, cleaning up the data, 
data analysis. Meeting presentation and drafting manuscript. 
 
Data Analysis Plan and Statistical Considerations:  
 
1. Analysis of Primary Outcome: 
 
At the end of the 9-week IVIg screening phase, baseline QMG scores of all the patients will 
be recorded. At the end of SCIg experimental treatment phase (Week 12), the QMG score 
will be captured and compared to Week 0. If the increase in QMG scores from Week 0 to 
Week 12 in the experimental treatment phase is found to be no more than 3 points, then they 
will be considered to be a ‘success’ in terms of their response. We hypothesize that the 
positive response rate of these patients is at least 70%. Allowing a margin of 5%, our 
hypotheses are formally stated below: 
 
Null hypothesis H0: Proportion of patients whose QMG scores are increased by more than 3 
points at the end of the SCIg treatment phase ≤ 0.65  
 
Alternate hypothesis HA: Proportion of patients whose QMG scores are increased by no more 
than 3 points at the end of the SCIg treatment phase > 0.65  
 
This hypothesis will be tested using a one sided one sample test of proportions with the 
normal approximation, at the 5% significance level. We will also report a 95% confidence 
interval for the true proportion of subjects who experience a ‘success’ as with a sample size 
of 25 patients, we will have a margin of error of 0.19. In the experimental treatment phase, 
patients who either experience treatment failure (as previously defined on pg. 22) or clinical 
deterioration (as defined above on pg. 22) will be withdrawn before Week 12 and we will 
therefore impute for both non-positive responses at Week 12, a discrete QMG score increase 
of more than 3 points. For example, if the largest deterioration score observed is 8, then a 
QMG score ranging between 4 and 8 will be imputed at Week 12. Although we do not expect 
many missing observations at Week 12 of the SCIg phase, the outcomes recorded at these 
intermediate time points will allow us the ability to impute data at this endpoint. Specifically, 
in the case where no outcome is available for a subject at Week 12 due to the subject’s 
perception of a worsened condition, we will impute for this subject a QMG score increase at 
Week 12 of more than 3 points. In cases where subjects refuse to proceed to Week 12 or are 
lost to follow-up even though they were responding well on the treatment (as evidenced by 
the intermediate measurements), we will impute their Week 12 observation using the last 
observation carried forward (LOCF) approach. We will complement our LOCF approach with 
sensitivity analyses covering the following alternate approaches: (1) Multiple imputation with 


 
 
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28 
5 replicates per imputation to account for the uncertainty inherent to the imputation (2) Mixed 
model calculations accounting for the trend in QMG values over time (3) Best case and worst 
case scenarios. 
 
 
2. Additional Exploratory Analysis of Primary Outcomes: 
 
Additional exploratory analysis will be carried out treating QMG scores at baseline, Week 4, 
Week 8 and Week 12, as a continuous response variable. Descriptive statistics will be 
reported using means and standard deviations if the distribution of QMG scores is found to 
be normal and using medians and interquartile range if they are found to be non-normal. One 
advantage of reporting scores at the intermediate weeks is that it will allow us to assess 
whether or not some patients on SCIg stabilize early in terms of the QMG scores. It will also 
allow us to study the trend over time in an exploratory manner. We will further complement 
our exploratory analysis by conducting a two-sided non-parametric signed rank test in order 
to assess whether the QMG scores changed significantly after switching from IVIg to SCIg. 
Also, we will dichotomize the QMG into two groups (high and low) based on clinically 
relevant thresholds and compare the differences in proportions at end of study and baseline. 
 
3. Analysis of Secondary Outcomes: 
 
Analysis of secondary outcome measures as listed in the Aims section such as MG-ADL, MG 
QOL-15, the MG composite score and TSQM will primarily be conducted only for those who 
complete the study. We will conduct a two-sided signed-rank test to assess whether these 
scores changed significantly from baseline (Week 0) to Week 12. In case of missing values 
for the MG-ADL, MG QOL-15, and the MG composite score in cases where subjects refuse 
to proceed to Week 12 even though they were responding well on the treatment (as 
evidenced by the intermediate measurements) or are lost to follow-up, we will impute their 
Week 12 observation using the last observation carried forward (LOCF) approach.  We will 
also report the proportion of subjects enrolled in the subcutaneous experimental treatment 
study phase (Week 0 to Week 12) fulfilling our definition of improvement (as mentioned on 
pg. 24) along with a 95% confidence interval. We will compare between the two phases the 
percent of subjects meeting the definition of deterioration, worsening, stability and 
improvement. We will analyze the effect of prednisone dosage (Increase vs Not Increased) 
on clinical improvement (Yes vs No) using a 2x2 Fisher’s exact test in the SCIg phase of the 
study by comparing dose levels at Week 12 to Week 0 for those patients who complete 
Week 12 of the study. To do this, we will ask the patients at Week 0, Week 4, Week 8 and 
Week 12 about their prednisone dosage levels. Those patients who exit the study 
prematurely due to deterioration before Week 12 will be excluded from this Fisher’s test 
calculations. In the event that the Week 12 prednisone dose observation is missing even 
when patients have completed Week 12 (QMG or MGADL done), we will use the LOCF 
approach to impute this missing value as long as at the last available assessment, the 
patient was deemed to be improving (in terms of QMG or MGADL scores as defined under 
“Subject deterioration, worsening, rescue medication and improvement”). A two-sided 
signed-rank test will be also conducted to assess whether IgG levels changed significantly 
between the intravenous screening phase (Week -10 to Week 0) to the subcutaneous 
experimental treatment study phase (Week 1 to Week 12). All tests will be conducted at the 
5% level of significance. For the secondary outcome measures related to monitoring the 
safety profile of patients between the two study phases, a similar test will be conducted when 
the safety parameters measured are continuous variables and a one sample test for the 
difference in proportions will be conducted when they are measured as treatment-related 


 
 
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29 
severity rates. The comparison epochs for safety are also between the intravenous screening 
phase (Week -10 to Week 0) and the subcutaneous experimental treatment study phase 
(Week 0 [after first SCIg dose] to Week 12). Adverse events occurring in the two phases 
(mild, moderate/severe) will be summarized using a McNemar’s test. 
 
4. Sample Size Considerations: 
 
With a sample size of 25 patients, we have at least 70% power to detect a success rate of 
85% or higher using the chi-square test compared to an expected success rate of 65% or 
lower. We anticipate we will be able to assess efficacy, safety and tolerability of SCIg with 
the current sample size over 12 weeks and compare that these parameters to the 12 week 
IVIg phase. The selected sample size will enable us to complete study enrollment with the 
current number of sites.  
MG is a rare disease and MG studies have consistently experienced difficulty enrolling 
subjects due to a multiplicity of poorly understood reasons.34 In the Methotrexate study of MG 
and similar to other previous MG studies, enrollment has been a challenge. However, we 
managed to complete enrollment of 50 subjects by adding sites. In the current SCIg study 
protocol, the eligible study population is narrowed due to the inclusion criterion requiring MG 
cases to be on stable IVIg doses. While 85 to 90% of MG patients are seropositive for either 
the AchR or MuSK autoantibodies, some of these cases are treated in clinical practice with 
IVIg maintenance. Based on the pre-site selection feasibility survey, 25 subjects is a 
reasonable and achievable goal with the selected five sites. If enrollment is found to be 
slower than predicted, we are ready to add more sites to complete this study.  
5. Study Populations: 
Safety population: All patients enrolled at baseline constitute the safety population. The 
subjects in this population will included in the analysis of adverse events, vital signs, clinical 
laboratory findings, and other safety data. But for the purpose of statistical analyses, the 
rates of adverse events experienced by these subjects in the SCIg phase will be compared 
to the rates experienced during the IVIg phase of the study. Adverse events will be tabulated 
by treatment group, severity, and perceived relationship to study drug. For each adverse 
event, the treatment groups will be compared regarding the occurrence of at least one event 
using the Fisher’s exact test. The comparisons will be repeated excluding all mild symptoms. 
Continuous measures such as vital signs and laboratory test results will be analyzed in a 
manner similar to that for the primary outcome variable.  
Intent to treat population (ITT): Only those patients who receive at least one dose of SCIg are 
considered to be the primary population which is the same as ITT population. The ITT will be 
included in the analysis of baseline findings and efficacy results. Only those patients who 
receive at least one dose of SCIg are considered to be the primary population and the intent-
to-treat population. 
Unscheduled visits: In the event that there are unscheduled patient visits, we will report the 
frequency of such visits for the two phases of the study. We will also document the date and 
reason for such visits and assess if these visits are systematic or random. If occurrence of 


 
 
Version Date: 22-Aug-2016 
 
30 
such visits is due to side effects we will compare the rates of such events across the two 
phases of the study. Testing at unscheduled visits is done only to check and assess clinical 
worsening. If no worsening is found, patients will continue to be a part of the study. If a 
patient experiences a worsening event that does not qualify as clinical deterioration (per pg. 
22) and the investigator determines it is safe for that patient to continue, the patient will 
remain in the study. On the other hand, if a patient experiences a worsening event that 
qualifies as clinical deterioration the patient will be withdrawn from the study. We will 
compare the within-person variation to the cross-person variation for the overall data. If the 
within-person variation is found to be less than the cross-person variation, we will use a 
LOCF approach to impute the patient’s QMG score at the next time point and do a sign rank 
test on that time point and baseline. On the other hand, if the within-person variation is found 
to be greater than the cross-person variation, we will impute the observation at the next time 
point followed by a sign rank test.  
SAS 9.4 will be used for all analyses. All data management and statistical analysis will be 
performed in the Department of Biostatistics at the University of Kansas Medical Center. The 
Velos Clinical Research Information System (CRIS) will be used at all sites to enter and view 
data.  This will be available to the safety monitors (see below).   
 
 
 
Safety Monitoring 
Subjects will be interviewed at each visit about possible side effects of medications and MG-
related symptoms. Complete blood count (CBC) with differential, chemistry profile (Chem 20) 
including liver and renal function, direct antiglobulin (Coombs) testing and reticulocyte count 
will be performed at each visit. We will therefore screen for hemolysis with CBC, Coombs, 
unconjugated bilirubin and reticulocytes. If there is unexplained new anemia or positive result 
of direct antiglobulin test or increased reticulocyte count, hemolysis will be confirmed via low 
haptoglobin level. Safety will also be assessed by physical examinations and evaluations of 
vital signs at clinic visits. The site investigator will then evaluate any changes and determine 
the need for any intervention.  
 
Data Safety Monitoring Committee 
A data safety monitoring committee will be established through the University of Kansas 
Medical Center Office of Compliance. The DSMB will meet every 4 months by phone to 
review recruitment, adverse events, and serious adverse events. They will meet with the 
study statistician and medical monitor prior to the meeting to review the event reports and 
identify any issues that need to be addressed.  
 
Annual Site Monitoring 
Patient safety will be a top priority and adverse events will be closely monitored. Patients will 
be provided phone numbers on the consent forms so they can reach investigators at any 
time should problems arise. Study forms have been designed to record adverse events and 
document actions taken when they occur. Criteria have been established for treatment 
failures, and patients will be treated appropriately should their disease progress during the 
course of the study. 
 
Stopping Rule 


 
 
Version Date: 22-Aug-2016 
 
31 
Taking into account patient safety considerations, following stopping rules will be 
incorporated based on a binomial calculator assuming >65% treatment success rate.  
 (1) Treatment failures in ≥ 5 subjects in the first 10 subjects 
(2) Treatment failures in > 7 subjects in the first 14 subjects 
(3) Treatment failures in > 8 subjects in the first 17 subjects 
(4) Treatment failures in > 9 subjects in the first 20 subjects if additional patients 
(more than 20) are recruited in the study 
 
The number of these events will be tracked by the Department of Biostatistics at the 
University of Kansas Medical Center. 
 
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immunodeficiencies. Clin Immunol. 2011 May;139(2):133-41. 
46. Wasserman RL, Melamed I, Nelson RP Jr, Knutsen AP, Fasano MB, Stein MR, Rojavin 
MA, Church JA. Pharmacokinetics of subcutaneous IgPro20 in patients with primary 
immunodeficiency. Clin Pharmacokinet. 2011 Jun;50(6):405-14. 
47. Broyles R, Rodden L, Riley P and Berger M. Variability in intravenous immunoglobulin G 
regimens for autoimmune neuromuscular disorders. Postgrad Med 2013;125:65-72.  
48. Jaretzki III A, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al. 
Myasthenia gravis: recommendations for clinical research standards. Neurology 
2000;55:16-23. 
49. Barohn RJ, McIntire D, Herbelin L, et al. Reliability testing of the quantitative myasthenia 
gravis score. Ann NY Acad Sci 1998;841:769-772. 
50. Barohn RJ. How to administer the quantitative myasthenia test. Video. Myasthenia 
Gravis Foundation of America, Inc. 1996. 
51. Barohn R. Standards of measurement in myasthenia gravis. Ann NY Acad Sci  
2003;998:432-439. 
52. Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn. Myasthenia gravis 
activities of daily living profile. Neurology 1999;52:1487-1489. 
53. Muppidi S, Wolfe GI, Conaway M, Burns TM; MG COMPOSITE AND MG-QOL15 
STUDY GROUP. Muscle Nerve. 2011 Nov;44(5):727-31. 
54. Sadjadi R, Conaway M, Cutter G, Sanders DB, Burns TM; MG Composite MG-QOL15 
Study Group. Psychometric evaluation of the myasthenia gravis composite using Rasch 
analysis.Muscle Nerve. 2012 Jun;45(6):820-5. 
55. Burns TM, Conaway M, Sanders DB; MG Composite and MG-QOL15 Study Group. The 
MG Composite: A valid and reliable outcome measure for myasthenia gravis. Neurology. 
2010 May 4;74(18):1434-40. 
56. Burns TM, Grouse CK, Wolfe GI, Conaway MR, Sanders DB; MG Composite and MG-
OL15 Study Group. The MG-QOL15 for following the health-related quality of life of 
patients with myasthenia gravis. Muscle Nerve. 2011 Jan;43(1):14-8. 
57. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment 
satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a 
national panel study of chronic disease. Health Qual Life Outcomes. 2004;2:12.  
58. Atkinson MJ, Kumar R, Cappelleri JC, et al. Hierarchical construct validity of the 
treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
pharmacy consumers. Value Health 2005;8 Suppl 1:S9-S24.  
59. Wells PS, Anderson DR, Bormanis J, et. al. Value of assessment of pretest probability of 
deep-vein thrombosis in clinical management. Lancet. 1997 Dec 20-27;350(9094):1795-
8. 
60. http://www.uptodate.com/contents/calculator-dvt-probability-wells-score-
system?source=search_result&search=Wells%27+Criteria+for+DVT&selectedTitle=1%7
E4    Accessed 3/11/2014 


 
 
Version Date: 22-Aug-2016 
 
34 
61.  Bates SM, Jaeschke R, Stevens SM, Goodacre S, Wells PS, Stevenson MD, Kearon C, 
Schunemann HJ, Crowther M, Pauker SG, Makdissi R, Guyatt GH; American College of 
Chest Physicians. Diagnosis of DVT: Antithrombotic Therapy and Prevention of 
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical 
Practice Guidelines.Chest. 2012 Feb;141(2 Suppl):e351S-418S. 
 
 
 


 
 
Version Date: 22-Aug-2016 
 
35
Table 1: Study Visits 
 
Screening Phase 
Experimental Treatment Phase 
 
 
Week 
-10 
(Screen) 
-9 
1stIVIg 
stabilization 
 
-5 
2ndIVIg 
stabilization 
-1 
3rd 
IVIg 
stabilization  
0 
Baseline 
0.1 
0.2 
0.3 
1 
2 
**** 
3 
**** 
4 
6 
 
8 
12 
13 
14 
**** 
16 
**** 
Consent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
(including weight) 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
General 
Physical 
Examination  
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
Neurological 
Examination 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Infusion 
at 
research 
facility 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subcu 
instruction/infusion at 
research facility 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Safety labs* 
X 
 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X* 
 
 
IgA level evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Pregnancy 
Test** 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Concomitant 
Medication 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing 
of 
Medication 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Medication 
collection 
and reconciliation 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
MGFA 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
QMG (including FVC) 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
MG-ADL 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
MG Composite Score 
(including MMT) 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
MG-QOL-15 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
TSQM 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Call/Email **** 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
*    =  Full Safety Labs: Complete blood count (CBC) with differential, complete metabolic panel, serum IgG level, direct antoglobulin test and reticulocyte 
count. Safety labs will only be drawn at Week 13 if clinically significant at Week 12. 
**   =  Serum pregnancy test for women of child-bearing potential. 
**** = Phone Call/Email to assess how subject is doing administering medication/Optional in person visit 


 
 
Version Date: 22-Aug-2016 
 
36
Appendix 1: Injection Site Map 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Version Date: 22-Aug-2016 
 
37
Appendix 2: Probability Scoring for DVT  
 
Wells’ Pretest Probability Scoring Form 
Site:                         Subject ID:                
Date: 
Visit Week: 
 
 
___________________________                  Date: _______________ 
PI signature 
 
 
Clinical feature 
Points 
Patient score 
Active cancer (treatment ongoing, within 6 months, or palliative) 
1 
 
Paralysis, paresis or recent plaster immobilisation of the lower 
extremities 
1 
 
Recently bedridden for 3 days or more or major surgery within 
12 weeks requiring general or regional anaesthesia 
1 
 
Localised tenderness along the distribution of the deep  
venous system 
1 
 
Entire leg swollen 
1 
 
Calf swelling at least 3 cm larger than asymptomatic side 
1 
 
Pitting oedema confined to the symptomatic leg 
1 
 
Collateral superficial veins (non-varicose) 
1 
 
Previously documented DVT 
1 
 
An alternative diagnosis is at least as likely as DVT 
−2 
 
Total Score 
 
 
Clinical probability simplified score 
High Probability of DVT 
3-8 points 
 
Moderate Probability 
1-2 points  
 
Low Probability 
-2-0 point  
 


 
 
Version Date: 22-Aug-2016 
 
38
Appendix 3: Pocket Reference Risk Card 
MG-SCIg 
Rare Serious 
Risks 
Signs & Symptoms  
  
Renal 
Dysfunction  or 
Failure 
Changes in urination. Specifically urinating less and 
have dark colored urine. 
Hemolysis 
Fatigued or tired feeling, dizziness, shortness of 
breath, or rapid heart rate 
Thrombosis 
New calf swelling, pain or tenderness in the calf 
Acute  
Meningitis 
Sudden high fever, severe headache, nausea or 
vomiting,  
sensitivity to light, skin rash, stiff neck 
Allergic 
Reaction 
Swelling of the face, mouth, lips, gums, tongue, or 
neck 
Trouble breathing, cough 
Rash,  or hives  
Chest tightness 
Dizziness fainting, fast or weak heartbeat 
Trouble swallowing, throat tightness, hoarse voice 
(Front) 
 
 
 
 
 
 
 
MG-SCIg 
Common effects of Hizentra 
(SCIg) 
Common effects of Privigen (IVIg) 
• Cough 
• Rash 
• Headache 
• Vomiting 
• Abdominal pain 
• Migraine 
• Itching 
• Diarrhea 
• Fatigue 
• Back pain  
• Nausea 
• Pain in extremities 
• Local reactions (swelling, 
redness, heat, pain, and 
itching at injection site 
• Headache 
• Fatigue 
• Chills 
• Vomiting 
• Back pain 
• Pain 
• Elevated body temperature 
• Abdominal pain 
• Diarrhea 
• Cough 
• Stomach discomfort 
• Chest pain 
• Joint swelling 
• Flu-like illness 
  
(Back) 

SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Open Label Study of Subcutaeneous Immunoglobulin (SCIg) 
in Myasthenia Gravis 
 
NCT02100969 
 
February 22, 2019 
 
 


Data Analysis Plan and Statistical Considerations:  
 
1. Analysis of Primary Outcome: 
 
At the end of the 9-week IVIg screening phase, baseline QMG scores of all the patients will be 
recorded. At the end of SCIg experimental treatment phase (Week 12), the QMG score will be 
captured and compared to Week 0. If the increase in QMG scores from Week 0 to Week 12 in 
the experimental treatment phase is found to be no more than 3 points, then they will be 
considered to be a ‘success’ in terms of their response. We hypothesize that the positive response 
rate of these patients is at least 70%. Allowing a margin of 5%, our hypotheses are formally stated 
below: 
 
Null hypothesis H0: Proportion of patients whose QMG scores are increased by more than 3 points 
at the end of the SCIg treatment phase ≤ 0.65  
 
Alternate hypothesis HA: Proportion of patients whose QMG scores are increased by no more 
than 3 points at the end of the SCIg treatment phase > 0.65  
 
This hypothesis will be tested using a one sided one sample test of proportions with the normal 
approximation, at the 5% significance level. We will also report a 95% confidence interval for the 
true proportion of subjects who experience a ‘success’ as with a sample size of 25 patients, we 
will have a margin of error of 0.19. In the experimental treatment phase, patients who either 
experience treatment failure (as previously defined on pg. 22) or clinical deterioration (as defined 
above on pg. 22) will be withdrawn before Week 12 and we will therefore impute for both non-
positive responses at Week 12, a discrete QMG score increase of more than 3 points. For 
example, if the largest deterioration score observed is 8, then a QMG score ranging between 4 
and 8 will be imputed at Week 12. Although we do not expect many missing observations at Week 
12 of the SCIg phase, the outcomes recorded at these intermediate time points will allow us the 
ability to impute data at this endpoint. Specifically, in the case where no outcome is available for 
a subject at Week 12 due to the subject’s perception of a worsened condition, we will impute for 
this subject a QMG score increase at Week 12 of more than 3 points. In cases where subjects 
refuse to proceed to Week 12 or are lost to follow-up even though they were responding well on 
the treatment (as evidenced by the intermediate measurements), we will impute their Week 12 
observation using the last observation carried forward (LOCF) approach. We will complement our 
LOCF approach with sensitivity analyses covering the following alternate approaches: (1) Multiple 
imputation with 5 replicates per imputation to account for the uncertainty inherent to the imputation 
(2) Mixed model calculations accounting for the trend in QMG values over time (3) Best case and 
worst-case scenarios. 
 
 
2. Additional Exploratory Analysis of Primary Outcomes: 
 
Additional exploratory analysis will be carried out treating QMG scores at baseline, Week 4, Week 
8 and Week 12, as a continuous response variable. Descriptive statistics will be reported using 
means and standard deviations if the distribution of QMG scores is found to be normal and using 
medians and interquartile range if they are found to be non-normal. One advantage of reporting 
scores at the intermediate weeks is that it will allow us to assess whether or not some patients on 
SCIg stabilize early in terms of the QMG scores. It will also allow us to study the trend over time 
in an exploratory manner. We will further complement our exploratory analysis by conducting a 
two-sided non-parametric signed rank test in order to assess whether the QMG scores changed 
significantly after switching from IVIg to SCIg. Also, we will dichotomize the QMG into two groups 


(high and low) based on clinically relevant thresholds and compare the differences in proportions 
at end of study and baseline. 
 
3. Analysis of Secondary Outcomes: 
 
Analysis of secondary outcome measures as listed in the Aims section such as MG-ADL, MG 
QOL-15, the MG composite score and TSQM will primarily be conducted only for those who 
complete the study. We will conduct a two-sided signed-rank test to assess whether these scores 
changed significantly from baseline (Week 0) to Week 12. In case of missing values for the MG-
ADL, MG QOL-15, and the MG composite score in cases where subjects refuse to proceed to 
Week 12 even though they were responding well on the treatment (as evidenced by the 
intermediate measurements) or are lost to follow-up, we will impute their Week 12 observation 
using the last observation carried forward (LOCF) approach.  We will also report the proportion of 
subjects enrolled in the subcutaneous experimental treatment study phase (Week 0 to Week 12) 
fulfilling our definition of improvement (as mentioned on pg. 24) along with a 95% confidence 
interval. We will compare between the two phases the percent of subjects meeting the definition 
of deterioration, worsening, stability and improvement. We will analyze the effect of prednisone 
dosage (Increase vs Not Increased) on clinical improvement (Yes vs No) using a 2x2 Fisher’s 
exact test in the SCIg phase of the study by comparing dose levels at Week 12 to Week 0 for 
those patients who complete Week 12 of the study. To do this, we will ask the patients at Week 
0, Week 4, Week 8 and Week 12 about their prednisone dosage levels. Those patients who exit 
the study prematurely due to deterioration before Week 12 will be excluded from this Fisher’s test 
calculations. In the event that the Week 12 prednisone dose observation is missing even when 
patients have completed Week 12 (QMG or MGADL done), we will use the LOCF approach to 
impute this missing value as long as at the last available assessment, the patient was deemed to 
be improving (in terms of QMG or MGADL scores as defined under “Subject deterioration, 
worsening, rescue medication and improvement”). A two-sided signed-rank test will be also 
conducted to assess whether IgG levels changed significantly between the intravenous screening 
phase (Week -10 to Week 0) to the subcutaneous experimental treatment study phase (Week 1 
to Week 12). All tests will be conducted at the 5% level of significance. For the secondary outcome 
measures related to monitoring the safety profile of patients between the two study phases, a 
similar test will be conducted when the safety parameters measured are continuous variables and 
a one sample test for the difference in proportions will be conducted when they are measured as 
treatment-related severity rates. The comparison epochs for safety are also between the 
intravenous screening phase (Week -10 to Week 0) and the subcutaneous experimental 
treatment study phase (Week 0 [after first SCIg dose] to Week 12). Adverse events occurring in 
the two phases (mild, moderate/severe) will be summarized using a McNemar’s test. 
 
4. Sample Size Considerations: 
 
With a sample size of 25 patients, we have at least 70% power to detect a success rate of 85% 
or higher using the chi-square test compared to an expected success rate of 65% or lower. We 
anticipate we will be able to assess efficacy, safety and tolerability of SCIg with the current sample 
size over 12 weeks and compare that these parameters to the 12-week IVIg phase. The selected 
sample size will enable us to complete study enrollment with the current number of sites.  
MG is a rare disease and MG studies have consistently experienced difficulty enrolling subjects 
due to a multiplicity of poorly understood reasons.34 In the Methotrexate study of MG and similar 
to other previous MG studies, enrollment has been a challenge. However, we managed to 
complete enrollment of 50 subjects by adding sites. In the current SCIg study protocol, the eligible 


study population is narrowed due to the inclusion criterion requiring MG cases to be on stable 
IVIg doses. While 85 to 90% of MG patients are seropositive for either the AchR or MuSK 
autoantibodies, some of these cases are treated in clinical practice with IVIg maintenance. Based 
on the pre-site selection feasibility survey, 25 subjects is a reasonable and achievable goal with 
the selected five sites. If enrollment is found to be slower than predicted, we are ready to add 
more sites to complete this study.  
5. Study Populations: 
Safety population: All patients enrolled at baseline constitute the safety population. The subjects 
in this population will included in the analysis of adverse events, vital signs, clinical laboratory 
findings, and other safety data. But for the purpose of statistical analyses, the rates of adverse 
events experienced by these subjects in the SCIg phase will be compared to the rates 
experienced during the IVIg phase of the study. Adverse events will be tabulated by treatment 
group, severity, and perceived relationship to study drug. For each adverse event, the treatment 
groups will be compared regarding the occurrence of at least one event using the Fisher’s exact 
test. The comparisons will be repeated excluding all mild symptoms. Continuous measures such 
as vital signs and laboratory test results will be analyzed in a manner similar to that for the primary 
outcome variable.  
Intent to treat population (ITT): Only those patients who receive at least one dose of SCIg are 
considered to be the primary population which is the same as ITT population. The ITT will be 
included in the analysis of baseline findings and efficacy results. Only those patients who receive 
at least one dose of SCIg are considered to be the primary population and the intent-to-treat 
population. 
Unscheduled visits: In the event that there are unscheduled patient visits, we will report the 
frequency of such visits for the two phases of the study. We will also document the date and 
reason for such visits and assess if these visits are systematic or random. If occurrence of such 
visits is due to side effects we will compare the rates of such events across the two phases of the 
study. Testing at unscheduled visits is done only to check and assess clinical worsening. If no 
worsening is found, patients will continue to be a part of the study. If a patient experiences a 
worsening event that does not qualify as clinical deterioration (per pg. 22) and the investigator 
determines it is safe for that patient to continue, the patient will remain in the study. On the other 
hand, if a patient experiences a worsening event that qualifies as clinical deterioration the patient 
will be withdrawn from the study. We will compare the within-person variation to the cross-person 
variation for the overall data. If the within-person variation is found to be less than the cross-
person variation, we will use a LOCF approach to impute the patient’s QMG score at the next 
time point and do a sign rank test on that time point and baseline. On the other hand, if the within-
person variation is found to be greater than the cross-person variation, we will impute the 
observation at the next time point followed by a sign rank test.  
SAS 9.4 will be used for all analyses. All data management and statistical analysis will be 
performed in the Department of Biostatistics at the University of Kansas Medical Center. The 
Velos Clinical Research Information System (CRIS) will be used at all sites to enter and view data.  
This will be available to the safety monitors (see below).