Clinical trial NCT03315130
Conditions: Generalized Myasthenia Gravis
Sponsor: Ra Pharmaceuticals
Start date: 2017-10-11; Completion date: 2020-11-19
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the safety and efficacy of RA101495 in patients with generalized Myasthenia Gravis (gMG). Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo for 12 weeks.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: zilucoplan (RA101495) intervention 2: Placebo
Intervention descriptions: intervention 1: Daily subcutaneous (SC) injection intervention 2: Daily subcutaneous (SC) injection

Protocol documents:
Prot_000.pdf: 
 
RA PHARMACEUTICALS, INC. 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of 
RA101495 in Subjects with Generalized Myasthenia Gravis 
 
Protocol Number:  RA101495-02.201 
Protocol Version/Date: Version 3.0/10-Apr-2019 
Indication Studied: Generalized Myasthenia Gravis 
Developmental Phase of Study: 2 
Sponsor Address: Ra Pharmaceuticals, Inc. 
87 Cambridge Park Drive 
Cambridge, MA, 02140 | USA 
 
This study will be conducted by Ra Pharmaceuticals, Inc. and affiliates in compliance 
with the protocol, Good Clinical Practice, and all other applicable regulatory 
requirements, including the archiving of essential documents. 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior 
written consent of Ra Pharmaceuticals, Inc. is strictly prohibited except to the extent required under 
applicable laws or regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
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CENTER INVESTIGATOR SIGNATURE PAGE 
I have read this protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study as outlined herein and will complete the study within 
the time designated. This trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal 
and regulatory requirements and International Council for Harmonisation guidelines. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure they are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by the Sponsor or its representative 
and will fulfill all responsibilities for submitting pertinent information to the Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) responsible for this study. 
I agree that the Sponsor or its representatives shall have access to any source documents 
from which case report form information may have been generated. I agree that 
regulatory authorities [Food and Drug Administration (FDA), European Medicines 
Agency (EMA), and other local and country-related agencies] can audit and review 
source documents. 
I further agree not to originate or use the name of Ra Pharmaceuticals, Inc. or any of its 
employees, in any publicity, news release, or other public announcement, written or oral, 
whether to the public, press, or otherwise, relating to his protocol, to any amendment 
hereto, or to the performance hereunder, without the prior written consent of Ra 
Pharmaceuticals, Inc. 
 
 
________________________________________________ 
_________________ 
Signature of Investigator 
 
 
 
 
 
Date 
 
________________________________________________ 
Name of Investigator (Typed or Printed) 
 
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1 
SYNOPSIS 
Protocol Title 
A Phase 2, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety, 
Tolerability, and Preliminary Efficacy of RA101495 in 
Subjects with Generalized Myasthenia Gravis 
Protocol Number 
RA101495-02.201 
Phase of Clinical Development 
Phase 2 
Investigational Medicinal Product 
RA101495 administered by daily subcutaneous (SC) 
injection 
Study Population 
Adults with generalized myasthenia gravis (gMG) 
Investigative Sites 
Approximately 30 centers are planned worldwide 
Planned Number of Subjects  
Approximately 36 subjects (12 per treatment arm) 
Study Objectives 
• To assess the safety and tolerability of RA101495 in subjects with gMG  
• To assess preliminary efficacy of RA101495 in subjects with gMG 
Study Design 
Study RA101495-02.201 is a multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the safety, tolerability, and preliminary efficacy of RA101495 in subjects with 
gMG. The planned enrollment is approximately 36 subjects.  
Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495, 
0.3 mg/kg RA101495, or matching placebo. Randomization will be stratified based on the 
screening Quantitative Myasthenia Gravis (QMG) Score (≤ 17 versus ≥ 18). 
Design of RA101495-02.201 Study 
 
The Main Portion of the study includes a Screening Period of up to 4 weeks and a 12-week 
Treatment Period. During the Treatment Period, subjects will return to the clinic weekly for the 
first 2 visits (Day 8 and Day 15) after the Day 1 visit, followed by visits at Week 4 (Day 29), 
Week 8 (Day 57), and Week 12 (Day 84) to evaluate safety, tolerability, and preliminary 
efficacy. Additional assessments will include quality of life (QOL) questionnaires, biomarker 
samples, pharmacokinetics, pharmacodynamics, and optional pharmacogenomics. Safety 
assessments will include physical examinations, vital signs, electrocardiogram (ECG), clinical 
laboratory tests, adverse events (AEs), and immunogenicity. 
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Randomized subjects will receive 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching 
placebo administered SC at the Day 1 visit. Following in-clinic education and training, all 
subjects will self-inject daily SC doses of blinded study drug, according to randomized 
treatment allocation, for the subsequent 12 weeks. An injection device will be provided for use 
during the study. 
Subjects are expected to remain on stable doses of standard of care (SOC) therapy for gMG 
throughout the study, including pyridostigmine, corticosteroids, or immunosuppressive drugs. 
If, in the opinion of the investigator, escalation of gMG therapy (i.e., ‘rescue therapy’) 
becomes necessary due to deterioration of a subject’s clinical status, the subject may receive 
immunoglobulin or plasma exchange treatment. 
The safety of subjects will be monitored in a blinded manner on an ongoing basis. If an 
unblinded data review should become necessary to ensure subject safety, a Safety Monitoring 
Committee (SMC) will convene and evaluate study data as appropriate.  
The risk of Neisseria meningitidis infection will be closely monitored during the study. All 
subjects who have not been previously vaccinated against Neisseria meningitidis prior to study 
entry must be vaccinated with a quadrivalent meningococcal vaccine and, where available, 
meningococcal serotype B vaccine at least 14 days prior to the first dose of study drug at the 
Day 1 visit. A booster vaccination should also be administered as clinically indicated, 
according to the local SOC. 
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled and 
reminded of the early signs and symptoms of Neisseria meningitidis infection. A patient safety 
card detailing the signs and symptoms of infection, with instructions to seek immediate 
medical attention, will be provided to each subject.  
At the conclusion of the Treatment Period in the Main Portion of the study, all subjects will 
have the option to receive RA101495 in the Extension Portion of the study provided they meet 
the Extension Portion selection criteria. Subjects assigned to a RA101495 treatment arm during 
the Main Portion of the study will continue to receive the same dose of study drug during the 
Extension Portion.  Subjects assigned to the placebo arm during the Main Portion of the study 
will be randomized in a 1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495 or 0.3 
mg/kg RA101495. Visits during the first 12 weeks of the Extension Portion will be identical to 
Main Portion of the study for all subjects to ensure appropriate monitoring of subjects 
transitioning from placebo to active treatment and to maintain blinding of treatment 
assignment. The study will remain double-blinded during the Extension Portion until after the 
data from the Main Portion of the study have been cleaned, locked, and unblinded. 
Following implementation of the present Amendment (v.3.0), and upon appropriate reconsent, 
all subjects ongoing in the Extension Portion will receive the 0.3 mg/kg dose that has been 
selected for the pivotal Phase 3 study (See Section 5.5.3 for details).  
If a subject discontinues study drug treatment prior to the Day 84 visit for any reason, he/she 
will not be eligible for the Extension Portion. Subjects who undergo rescue treatment and 
continue receiving study drug are eligible for participation in the Extension Portion. For 
subjects who do not participate in the Extension Portion, a safety follow-up telephone call will 
be performed at 40 days after the last dose of study drug, to collect information on any ongoing 
AEs or new serious adverse events (SAEs) since the last study visit. 
 
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Duration of Study Participation 
During the Main Portion of the study, the total duration of study participation for all subjects 
will include a Screening Period of up to 4 weeks and a 12-week Treatment Period for a total of 
up to approximately 16 weeks. 
During the Extension Portion of the study, RA101495 will continue to be provided by the 
Sponsor until RA101495 is approved and available in the territory, or the Sponsor terminates 
development of RA101495 for gMG. In countries where RA101495 is not approved or 
marketed, but in which sponsored clinical studies have been conducted, subjects may continue 
to receive RA101495 through a compassionate use pathway. 
Inclusion/Exclusion Criteria 
To be eligible for this study, subjects must meet ALL of the following inclusion criteria: 
1. Male or female ≥ 18 years and < 85 years. 
2. Able to provide informed consent, including signing and dating the informed consent form 
(ICF). 
3. Diagnosis of gMG [Myasthenia Gravis Foundation of America (MGFA) Class II-IVa] at 
Screening. 
4. Positive serology for acetylcholine receptor (AChR) autoantibodies. 
5. QMG score ≥ 12 at Screening and baseline (off acetylcholinesterase inhibitor therapy for at 
least 10 hours) with ≥ 4 test items scored at ≥ 2.  
6. No change in corticosteroid dose for at least 30 days prior to baseline or anticipated to 
occur during the 12-week Treatment Period. 
7. No change in immunosuppressive therapy, including dose, for at least 30 days prior to 
baseline or anticipated to occur during the 12-week Treatment Period. 
8. Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test within 24 hours prior to the first dose of 
study drug. 
9. Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation) and all male subjects (who have not been surgically sterilized by vasectomy) 
must agree to use effective contraception during the study.  
Subjects who meet ANY of the following exclusion criteria must be excluded from the study: 
1. Thymectomy within 6 months prior to baseline or scheduled to occur during the 12-week 
Treatment Period. 
2. Abnormal thyroid function as determined by local standard. 
3. Known positive serology for muscle-specific kinase (MuSK) or lipoprotein receptor-
related peptide 4 (LRP4). 
4. Minimal Manifestation Status of myasthenia gravis based on the clinical judgement of the 
investigator. 
5. Calculated glomerular filtration rate of < 60 mL/min/1.73 m2 based on the Modification of 
Diet in Renal Disease (MDRD) equation at Screening. 
GFR ൬
mL min
ൗ
1.73 m2൰= 175 × (Scr)−1.154 × (Age)−0.203 × (0.742 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) × (1.212 𝑖𝑖𝑖𝑖 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴)  
6. Elevated liver function tests defined as total bilirubin or transaminases [aspartate 
aminotransferase (AST)/alanine aminotransferase (ALT)] > 2 times the upper limit of 
normal (× ULN). 
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7. History of meningococcal disease. 
8. Current or recent systemic infection within 2 weeks prior to baseline or infection requiring 
intravenous (IV) antibiotics within 4 weeks prior to baseline. 
9. Pregnant, planning to become pregnant, or nursing female subjects. 
10. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or surgery 
expected to occur during Screening or the 12-week Treatment Period. 
11. Treatment with an experimental drug or another complement inhibitor within 30 days or 
5 half-lives of the experimental drug (whichever is longer) prior to baseline. 
12. Treatment with rituximab within 6 months prior to baseline. 
13. Ongoing treatment with IVIG or plasma exchange or treatment within 4 weeks prior to 
baseline. 
14. Active neoplasm (other than benign thymoma) requiring surgery, chemotherapy, or 
radiation within the prior 12 months (subjects with a history of malignancy who have 
undergone curative resection or otherwise not requiring treatment for at least 12 months 
prior to Screening with no detectable recurrence are allowed). 
15. Fixed weakness [‘burnt out’ myasthenia gravis (MG)] based on the clinical judgement of 
the investigator. 
16. History of any significant medical or psychiatric disorder that in the opinion of the 
investigator would make the subject unsuitable for participation in the study. 
17. Participation in another concurrent clinical trial involving an experimental therapeutic 
intervention (participation in observational studies and/or registry studies is permitted).  
18. Unable or unwilling to comply with the requirements of the study. 
Endpoints and Assessments for the Main Portion 
Safety and Tolerability: 
Safety assessments will include reporting of AEs and SAEs, clinical laboratory tests, ECGs, 
vital signs, and physical examination.  
Primary Efficacy Endpoint: 
• 
Change from baseline to Week 12 (Day 84) in QMG score. 
Secondary Efficacy Endpoints: 
• 
Change from baseline to Week 12 in the Myasthenia Gravis-Activities of Daily Living 
(MG-ADL) scale 
• 
Change from baseline to Week 12 in the MG-QOL15r survey 
• 
Change from baseline to Week 12 in the MG Composite 
• 
Subjects with ≥ 3-point reduction in QMG score at Week 12 
• 
Subjects requiring rescue therapy over the 12-week Treatment Period 
Pharmacokinetic (PK): 
• 
Plasma concentrations of RA101495 and its major metabolites 
• 
Maximum plasma concentration (Cmax) on Day 1 
• 
Time corresponding to Cmax (tmax) on Day 1 
Pharmacodynamic (PD): 
• 
Sheep red blood cell (sRBC) lysis assay for evaluation of classical complement pathway 
activation 
• 
Complement component 5 (C5) levels 
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Exploratory: 
• 
Mechanistic biomarkers pertinent to MG pathophysiology [e.g., complement fixation, 
complement function, complement pathway proteins, autoantibody characterization (titer 
and immunoglobulin class) and inflammatory markers]  
• 
Pharmacogenomic analyses (optional) 
 
Endpoints and Assessments for Extension Portion 
Endpoints in the Extension Portion will be similar to those in the Main Portion and detailed in 
the statistical analysis plan (SAP).  
Statistical Considerations 
Study Populations:  The following study populations are defined: 
• 
Intention-to-Treat (ITT) Population:  All subjects randomized 
• 
Modified ITT (mITT) Population:  All subjects in the ITT Population who have received at 
least 1 dose of study drug 
• 
Per Protocol Population:  All subjects in the mITT Population who have completed the 
12-week Treatment Period and have no major protocol deviations  
• 
Safety Population:  All subjects who have received at least 1 dose of study drug (i.e., mITT 
Population), with subjects to be analyzed based on the actual study treatment received  
• 
PK Population: All subjects in the mITT Population who have at least 1 evaluable PK 
assessment. All PK analyses will be performed using this population. 
• 
PD Population: All subjects in the mITT Population who have at least 1 evaluable PD 
assessment. All PD analyses will be performed using this population. 
General Considerations:  A disposition of all consented subjects will be provided and will 
include a breakdown of subjects who consented, were randomized, were treated, discontinued 
treatment, were lost to follow-up, or withdrew consent. 
Continuous variables will be summarized using the number of observations, number of 
observations above the limit of quantification (if applicable), mean, standard deviation (SD), 
median, and range. Categorical variables will be summarized using frequency counts and 
percentages. 
Stratification of Randomization:  Subjects will be randomized in a 1:1:1 ratio to receive 
daily SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo. 
Randomization will be stratified based on the screening QMG Score (≤ 17 versus ≥ 18).  
Safety:  AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
Version 18.0 or higher). Incidence rates for treatment-emergent AEs will be summarized 
overall, by maximum severity, and by relationship to study drug for each treatment group. 
SAEs will also be summarized by treatment group.  
Quantitative laboratory endpoints will be summarized by treatment group at each scheduled 
assessment time point using descriptive statistics. 
Descriptive statistics for ECG parameters [i.e., heart rate (HR), PR interval, RR interval, QRS 
interval, QT interval, QT interval corrected by Bazett’s formula (QTcB), and QT interval 
corrected by Fridericia’s formula (QTcF)] at each assessment time point will be presented by 
treatment group. 
Descriptive statistics for vital signs (HR, body temperature, and blood pressure) will be 
presented by treatment group. 
The complete set of physical examination findings will be provided in listings. Clinically 
significant physical examination abnormalities will be reported as AEs, when appropriate. 
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Efficacy:  For the primary efficacy endpoint, change from baseline to Week 12 (Day 84) in 
QMG score, treatment group differences will be assessed using an Analysis of Covariance 
(ANCOVA) model, with treatment as a factor and baseline QMG score as a covariate. The 
primary efficacy analysis will be the comparison of the 0.3 mg/kg RA101495 dose group 
versus placebo based on the ANCOVA model at a 1-sided 0.10 significance level. 
The secondary efficacy endpoints, Week 12 change from baseline in MG-ADL, MG-QOL15r, 
and MG Composite, will be analyzed by an ANCOVA model similar to the primary endpoint 
analysis, with treatment as a factor and the corresponding baseline value as a covariate. Each of 
the active doses will be compared to the placebo group based on the ANCOVA model at the 
1-sided 0.10 level. 
For the ‘Subjects with ≥ 3-point reduction in QMG score at Week 12’ and ‘Subjects requiring 
rescue therapy over the 12-week Treatment Period’ secondary efficacy endpoints, the rate of 
subjects meeting the endpoint for each of the active treatment groups will be compared to the 
placebo group using a Fisher’s exact test at the 1-sided 0.10 level.   
Pharmacokinetics:  Drug exposure will be evaluated using PK parameters derived from non-
compartmental methods. All calculations for the final analysis will be based on actual sampling 
times. Individual PK parameters will be presented in listings and summarized using descriptive 
statistics. 
Pharmacodynamics:  Pharmacodynamic endpoints will be summarized using descriptive 
statistics. 
Determination of Sample Size:  For the primary efficacy endpoint, change from baseline to 
Week 12 (Day 84) in QMG score, assuming a difference in treatment group means of 4.5, an 
SD of 5.0, and 12 subjects per group, the study has approximately 81% power to detect a 
difference between an active and placebo treatment group based on a 1-sided t-test with a 0.10 
type I error rate. 
 
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2 
TIME AND EVENTS TABLES 
Assessments to be performed during the study are shown in Table 1 and Table 2. 
Table 1 
MAIN PORTION: Time and Events Table 
Study Procedure 
Screening 
Days -28 to -1 
Day 1 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 57 
(± 7 days) 
End of Studya 
Day 84 
(± 2 days) 
Safety 
Follow-up Call  
(last dose + 40d) 
 
Rescue 
Therapy Visitb  
(if applicable) 
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
Review eligibility and randomizationc 
X 
 
 
 
 
 
 
 
 
 
Medical historyd and demographics 
X 
 
 
 
 
 
 
 
 
 
Heighte and weight 
X 
 
 
 
X 
 
X 
 
 
 
Prior and concomitant medicationsf 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
12-Lead electrocardiogram 
X 
 
 
 
 
 
X 
 
 
X 
Neisseria meningitidis vaccinationi 
X 
 
 
 
 
 
 
 
 
 
Hematology/Chemistryj 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Coagulationk 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy testl 
X 
X 
 
 
 
 
X 
 
 
 
Adverse eventsm 
 
X 
X 
X 
X 
X 
X 
Xm 
 
X 
Anti-drug antibody 
X 
 
 
 
X  
 
X 
 
 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
 
QMG Test/Scoren 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
MG-ADL 
 
X 
X 
X 
X 
X 
X 
 
 
X 
MG-QOL15r 
 
X 
X 
X 
X 
X 
X 
 
 
X 
MG Composite 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
RA101495 plasma PKo 
 
Xo 
X 
X 
X 
X 
Xo 
 
 
Xo 
Pharmacodynamic analysiso 
 
Xo 
X 
X 
X 
X 
Xo 
 
 
Xo 
Exploratory 
 
 
 
 
 
 
 
 
 
 
Additional biomarker samplesp 
 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacogenomic analysis (optional) 
X 
 
 
 
 
 
 
 
 
 
Study Drug 
 
 
 
 
 
 
 
 
 
 
RA101495 or placebo administrationq 
 
X 
X 
X 
X 
X 
X 
 
 
Xq 
See footnotes on following page. 
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1-a. If a subject prematurely discontinues study drug at any time prior to completion of the Day 84 visit during the Treatment Period, the subject should return to clinic for an End 
of Study Visit. 
1-b. For subjects who require rescue therapy (see Section 10.1.3.1), a Rescue Therapy Visit should be conducted prior to the initiation of rescue therapy. If the Rescue Therapy 
Visit coincides with a regularly scheduled study visit, then overlapping study procedures do not need to be duplicated.  
1-c. Procedures performed as SOC during the Screening Period may be used to determine eligibility. Informed consent must be obtained prior to performing any study-specific 
procedures that are not SOC. 
1-d. Screening includes disease history with diagnosis of gMG by the MGFA criteria (Class II-IVa), serology for AChR autoantibodies. 
1-e. Height will be measured only at Screening. 
1-f. All prescriptions and over-the-counter medications taken during the 30 days prior to baseline (i.e., Day 1) through the last study visit will be documented. NOTE: A complete 
history of medications taken for the treatment of gMG will be collected.  
1-g. A full physical examination will be performed on all subjects at Screening. On all other study visit days, the physical examination will be symptom-directed.  
1-h. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
1-i. All subjects must have documentation of prior Neisseria meningitidis vaccination (and booster, if appropriate) prior to study entry. If the subject has not been vaccinated, 
he/she must be vaccinated with a quadrivalent meningococcal vaccine at least 14 days prior to the first dose of study drug on Day 1 and should have a booster vaccination as 
indicated by SOC. Subjects should bring their patient safety card to every study visit. If the subject does not bring their card with them they will be given a new one. 
1-j. All laboratory samples should be obtained prior to administration of study drug at applicable visits unless otherwise noted for PK, PD, and biomarker samples.  
1-k. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
1-l. For all female subjects of childbearing potential, a negative serum pregnancy test must be documented at Screening. All other pregnancy tests will be performed via urine.  
1-m. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the 
procedures outlined in the protocol. Sites will call subjects 40 days after their last dose to gather information on ongoing AEs and report any new SAEs since the last study 
visit. This Safety Follow-up Call will only be required for subjects who choose not to receive RA101495 in the Extension Portion. 
1-n. The assessment of QMG should be performed at approximately the same time of day (preferably in the morning) and administered by the same well-trained evaluator (e.g., 
neurologist, physical therapist, or other study staff) at each visit throughout the study. If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 
10 hours prior to the QMG test.  
1-o. Blood samples for PK and PD analysis will be obtained at the following time points: 
Day 1 
Day 84 
During Rescue Therapy 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is NOT 
administered locally 
predose (within 1 hour before first dose 
of study drug)  
predose (any time prior to Day 84 study 
drug administration) 
Within 1 hour before administration of 
rescue therapy 
Prior to administration of the first 
course of rescue therapy 
1 hour postdose (± 30 minutes) 
1 hour postdose (± 30 minutes) 
For PLEX only: PK will be measured in 
the exchanged plasma 
After administration of the last course 
of rescue therapy 
3 hours postdose (± 30 minutes) 
 
Within 1 hour after administration of 
rescue therapy 
 
6 hours postdose (± 90 minutes) 
 
 
 
 
On all other study visit days, PK/PD samples should be collected prior to administration of study drug. 
1-p. Blood samples for biomarker testing will be obtained prior to administration of study drug (within 1 hour of dosing) and at 6 hours postdose (± 90 minutes) on Day 1. On all 
other study visit days, biomarkers samples should be collected prior to administration of study drug. 
1-q. Dosing on study visit days should be held until QMG scoring, PK, and PD sample blood collection has been completed. On days when rescue therapy is concurrently 
administered, study drug dosing should be held until after administration of rescue therapy and PK/PD sampling.   
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Table 2 
EXTENSION PORTION: Time and Events Table 
Study Procedure 
Day E1a 
(Day 84) 
Day E8 
(± 2 days) 
Day E15 
(± 2 days) 
Day E29 
(± 2 days) 
Day E57 
(± 7 days) 
Day E84 
(± 7 days) 
Rescue 
Therapy Visitb  
(if applicable) 
Please refer to 
 Appendix 2: Extension Portion Visits after Day E84 
 
Final Study 
Visitc 
Informed consent 
X 
 
 
 
 
 
 
 
 
Review eligibility and randomization 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
 
X 
 
 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
Physical examination (symptom directed) 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead electrocardiogram 
 
 
 
 
 
X 
X 
 
X 
Neisseria meningitidis vaccinatione 
SOCe 
 
 
 
 
 
 
 
 
Hematology/Chemistryf 
X 
X 
X 
X 
X 
X 
X 
 
X 
Coagulationg 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy testh 
X 
 
 
 
 
X 
 
 
X 
Adverse eventsi 
X 
X 
X 
X 
X 
X 
X 
 
X 
Anti-drug antibody 
X 
 
 
X  
 
X 
X 
 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
QMG Test/Scorej 
X 
X 
X 
X 
X 
X 
X 
 
X 
MG-ADL 
X 
X 
X 
X 
X 
X 
X 
 
X 
MG-QOL15r 
X 
X 
X 
X 
X 
X 
X 
 
X 
MG Composite 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
RA101495 plasma PKk 
Xk 
X 
X 
X 
X 
X 
Xk 
 
X 
Pharmacodynamic analysisk 
Xk 
X 
X 
X 
X 
X 
Xk 
 
X 
Exploratory 
 
 
 
 
 
 
 
 
 
Additional biomarker samplesl 
Xl 
X 
X 
X 
X 
X 
 
 
X 
Study Drug 
 
 
 
 
 
 
 
 
 
RA101495 administrationm 
X 
X 
X 
X 
X 
X 
Xm 
 
X 
See footnotes on following page. 
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2-a. For subjects that decide and are eligible to continue in the Extension Portion, the Day 84 visit from the Main Portion will serve as the Day E1 visit and will also include review 
of eligibility to continue, treatment group assignment (see Section 8.3), signing of an informed consent for the Extension Portion, and an additional biomarker blood sample. 
2-b. For subjects who require rescue therapy (see Section 10.1.3.1), a Rescue Therapy Visit should be conducted prior to the initiation of rescue therapy. If the Rescue Therapy 
Visit coincides with a regularly scheduled study visit, then overlapping study procedures do not need to be duplicated.  
2-c. If a subject discontinues study drug treatment at any time during the Extension Period, the subject should return to clinic for a Final Study Visit. 
2-d. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
2-e. During the Extension Portion, all subjects should have Neisseria meningitidis booster vaccinations as indicated by SOC. Subjects should bring their patient safety card to 
every study visit. If the subject does not bring their card with them they will be given a new one. 
2-f. All laboratory samples should be obtained prior to administration of study drug at applicable visits unless otherwise noted for PK, PD, and biomarker samples.  
2-g. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
2-h. Urine pregnancy tests will be conducted in female subjects of childbearing potential.  
2-i. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the 
procedures outlined in the protocol.  
2-j. The assessment of QMG should be performed at approximately the same time of day (preferably in the morning) and administered by the same well-trained evaluator (e.g., 
neurologist, physical therapist, or other study staff) at each visit throughout the study. If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 
10 hours prior to the QMG test.  
2-k. Blood samples for PK and PD analysis will be obtained at the following time points: 
Day E1 
(Day 84 from the Main Portion) 
During Rescue Therapy   
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is NOT 
administered locally 
predose (any time prior to Day 84 
study drug administration) 
Within 1 hour before administration 
of rescue therapy 
Prior to administration of the first 
course of rescue therapy 
1 hour postdose (± 30 minutes) 
For PLEX only: PK will be 
measured in the exchanged plasma 
After administration of the last 
course of rescue therapy 
 
Within 1 hour after administration 
of rescue therapy 
 
 
 
 
 
On all other study visit days, PK/PD samples should be collected prior to administration of study drug. 
2-l. Biomarkers samples should be collected prior to administration of study drug. 
2-m. Dosing on study visit days should be held until QMG scoring, PK, and PD sample blood collection has been completed. On days when rescue therapy is concurrently 
administered, study drug dosing should be held until after administration of rescue therapy and PK/PD sampling. 
 
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3 
TABLE OF CONTENTS 
1 
SYNOPSIS ........................................................................................................4 
2 
TIME AND EVENTS TABLES ...................................................................10 
3 
TABLE OF CONTENTS ..............................................................................14 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................18 
5 
INTRODUCTION..........................................................................................19 
5.1 
OVERVIEW OF GENERALIZED MYASTHENIA GRAVIS ........................................19 
5.2 
ROLE OF COMPLEMENT IN GENERALIZED MYASTHENIA GRAVIS......................20 
5.3 
MECHANISM OF ACTION OF RA101495 ............................................................21 
5.4 
CLINICAL TRIAL EXPERIENCE WITH RA101495 ...............................................22 
5.5 
RATIONALE FOR THE CURRENT STUDY .............................................................23 
5.5.1 
RATIONALE FOR BLINDING AND PLACEBO CONTROL ........................................23 
5.5.2 
DOSE SELECTION AND PRESENTATION ..............................................................24 
5.5.3 
DOSE SELECTION FOR OPEN LABEL PORTION ...................................................24 
6 
STUDY OBJECTIVES AND ENDPOINTS ................................................25 
6.1 
OBJECTIVES ......................................................................................................25 
6.2 
ENDPOINTS .......................................................................................................25 
6.2.1 
SAFETY AND TOLERABILITY ENDPOINTS ..........................................................25 
6.2.2 
EFFICACY ENDPOINTS .......................................................................................26 
6.2.3 
PHARMACOKINETIC ENDPOINTS ........................................................................26 
6.2.4 
PHARMACODYNAMIC ENDPOINTS .....................................................................26 
6.2.5 
EXPLORATORY ENDPOINTS ...............................................................................26 
7 
STUDY DESIGN ............................................................................................27 
7.1 
OVERVIEW OF STUDY DESIGN ..........................................................................27 
7.2 
STUDY PERIODS ................................................................................................28 
7.2.1 
SCREENING PERIOD ...........................................................................................29 
7.2.1.1 
SCREENING AND ENROLLMENT .........................................................................29 
7.2.2 
TREATMENT PERIOD (MAIN AND EXTENSION PORTIONS) .................................30 
7.2.2.1 
RANDOMIZATION AND BLINDING ......................................................................30 
7.2.2.2 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT ......................30 
7.3 
EARLY STUDY TERMINATION ...........................................................................31 
8 
SELECTION OF STUDY POPULATION .................................................31 
8.1 
INCLUSION CRITERIA ........................................................................................31 
8.2 
EXCLUSION CRITERIA .......................................................................................32 
8.3 
SELECTION CRITERIA FOR THE EXTENSION PORTION: .......................................33 
8.4 
REMOVAL AND REPLACEMENT OF SUBJECTS IN THE STUDY .............................33 
8.4.1 
WITHDRAWAL OF CONSENT ..............................................................................33 
8.4.2 
PREMATURE DISCONTINUATION .......................................................................34 
8.4.3 
REPLACEMENT OF SUBJECTS .............................................................................34 
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9 
INVESTIGATIONAL MEDICINAL PRODUCTS AND TREATMENTS
..........................................................................................................................34 
9.1 
STUDY TREATMENT ADMINISTRATION .............................................................34 
9.1.1 
INVESTIGATIONAL MEDICINAL PRODUCT AND MATCHING 
PLACEBO ...........................................................................................................34 
9.1.2 
DOSING SCHEDULE ...........................................................................................34 
9.1.3 
DOSE PRESENTATION ........................................................................................35 
9.1.3.1 
MISSED DOSES ..................................................................................................35 
9.2 
STUDY TREATMENT MANAGEMENT ..................................................................36 
9.2.1 
PREPARATION AND DISPENSING ........................................................................36 
9.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING ...........................................36 
9.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG ....................................36 
9.2.4 
DRUG ACCOUNTABILITY ...................................................................................36 
10 
STUDY ASSESSMENTS ..............................................................................36 
10.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS .......................................37 
10.1.1 
MEDICAL HISTORY AND DEMOGRAPHICS .........................................................37 
10.1.2 
HEIGHT AND WEIGHT .......................................................................................37 
10.1.3 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................37 
10.1.3.1 
RESCUE THERAPY .............................................................................................38 
10.2 
SAFETY ASSESSMENTS ......................................................................................38 
10.2.1 
PHYSICAL EXAMINATION ..................................................................................38 
10.2.2 
VITAL SIGNS .....................................................................................................39 
10.2.3 
ELECTROCARDIOGRAM .....................................................................................39 
10.2.4 
LABORATORY SAFETY ASSESSMENTS ...............................................................39 
10.2.4.1 
HEMATOLOGY, CHEMISTRY, AND COAGULATION .............................................39 
10.2.4.2 
URINALYSIS ......................................................................................................40 
10.2.4.3 
PREGNANCY TESTING AND CONTRACEPTION ....................................................40 
10.2.5 
ADVERSE EVENT RECORDING ...........................................................................41 
10.2.6 
IMMUNOGENICITY .............................................................................................41 
10.3 
EFFICACY ASSESSMENTS ..................................................................................41 
10.3.1 
QUANTITATIVE MYASTHENIA GRAVIS SCORE ..................................................41 
10.3.2 
OTHER EFFICACY ASSESSMENTS ......................................................................42 
10.4 
PHARMACOKINETIC ASSESSMENTS ...................................................................42 
10.5 
PHARMACODYNAMIC ASSESSMENTS .................................................................43 
10.6 
EXPLORATORY ASSESSMENTS ..........................................................................44 
10.6.1 
BIOMARKERS ....................................................................................................44 
10.6.2 
PHARMACOGENOMIC ASSESSMENTS .................................................................44 
11 
SAFETY REPORTING.................................................................................45 
11.1 
DEFINITIONS .....................................................................................................45 
11.1.1 
ADVERSE EVENTS .............................................................................................45 
11.1.2 
SERIOUS ADVERSE EVENTS ..............................................................................45 
11.1.3 
STOPPING RULES ...............................................................................................46 
11.1.3.1 
MONITORING OF LIVER FUNCTION TESTS .........................................................46 
11.1.3.2 
MONITORING OF PANCREATIC ENZYMES ..........................................................46 
11.1.3.3 
MONITORING OF SKIN AND ORAL MUCOSA ......................................................47 
11.1.3.4 
INFECTION.........................................................................................................47 
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11.1.4 
MONITORING OF INJECTION SITE REACTIONS ...................................................47 
11.2 
EVALUATION AND CLASSIFICATIONS ................................................................48 
11.2.1 
SEVERITY ..........................................................................................................48 
11.2.2 
CAUSALITY .......................................................................................................48 
11.3 
RECORDING, REPORTING, AND MONITORING ....................................................49 
11.3.1 
RECORDING AND REPORTING ............................................................................49 
11.3.1.1 
ADVERSE EVENTS .............................................................................................49 
11.3.1.2 
SERIOUS ADVERSE EVENTS ..............................................................................50 
11.3.1.3 
DEATH ..............................................................................................................51 
11.3.1.4 
ABNORMAL LABORATORY VALUES ..................................................................51 
11.3.2 
SAFETY MONITORING .......................................................................................51 
11.3.2.1 
SAFETY MONITORING COMMITTEE ...................................................................51 
11.3.2.2 
POST-STUDY EVENTS ........................................................................................51 
11.3.3 
EMERGENCY UNBLINDING DURING THE BLINDED PORTION .............................51 
11.4 
SPECIAL CIRCUMSTANCES ................................................................................52 
11.4.1 
PREGNANCY ......................................................................................................52 
11.4.2 
OTHER ..............................................................................................................52 
12 
STATISTICAL AND ANALYTICAL PLANS ...........................................53 
12.1 
ANALYSIS POPULATIONS ..................................................................................53 
12.1.1 
INTENTION-TO-TREAT POPULATION .................................................................53 
12.1.2 
MODIFIED ITT POPULATION .............................................................................53 
12.1.3 
PER PROTOCOL POPULATION ............................................................................53 
12.1.4 
SAFETY POPULATION ........................................................................................53 
12.1.5 
PHARMACOKINETIC POPULATION .....................................................................53 
12.1.6 
PHARMACODYNAMIC POPULATION ...................................................................53 
12.2 
ANALYSIS METHODS ........................................................................................53 
12.2.1 
GENERAL METHODS .........................................................................................53 
12.2.2 
SUBJECT DISPOSITION .......................................................................................54 
12.2.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS ..............................54 
12.2.4 
SAFETY ANALYSIS ............................................................................................54 
12.2.4.1 
ADVERSE EVENTS .............................................................................................54 
12.2.4.2 
CLINICAL LABORATORY EVALUATION .............................................................55 
12.2.4.3 
ELECTROCARDIOGRAMS ...................................................................................55 
12.2.4.4 
VITAL SIGNS .....................................................................................................55 
12.2.4.5 
PHYSICAL EXAMINATION ..................................................................................55 
12.2.5 
EFFICACY ANALYSIS .........................................................................................55 
12.2.5.1 
PRIMARY EFFICACY ANALYSIS .........................................................................55 
12.2.5.2 
SECONDARY ENDPOINT ANALYSES ...................................................................56 
12.2.6 
CLINICAL PHARMACOLOGY ANALYSIS .............................................................56 
12.2.6.1 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES...............................56 
12.2.7 
INTERIM ANALYSIS ...........................................................................................56 
12.3 
SAMPLE SIZE DETERMINATION .........................................................................56 
13 
ETHICAL CONSIDERATIONS ..................................................................57 
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE COMMUNICATIONS .......................................................................57 
13.1.1 
PROGRESS REPORTS ..........................................................................................57 
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13.1.2 
FINAL INVESTIGATOR REPORT ..........................................................................57 
13.2 
INFORMED CONSENT OF STUDY SUBJECTS ........................................................57 
13.3 
PROTOCOL COMPLIANCE ..................................................................................58 
13.4 
PROTECTION OF CONFIDENTIALITY ...................................................................58 
13.5 
DISCLOSURE OF STUDY RESULTS ......................................................................59 
14 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS .........59 
14.1 
QUALITY ASSURANCE .......................................................................................59 
14.1.1 
MONITORING ....................................................................................................59 
14.1.2 
AUDIT ...............................................................................................................59 
14.2 
CLINICAL RESEARCH ORGANIZATIONS .............................................................60 
14.3 
DATA MANAGEMENT ........................................................................................60 
14.3.1 
CASE REPORT FORMS .......................................................................................60 
14.3.2 
SOURCE DOCUMENTS .......................................................................................60 
14.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY .............................61 
14.5 
CLINICAL STUDY REPORT .................................................................................61 
14.6 
PUBLICATION POLICY .......................................................................................61 
15 
REFERENCES ...............................................................................................62 
16 
APPENDIX 1: RESCUE THERAPY PK/PD SAMPLING .......................64 
17 
APPENDIX 2: EXTENSION PORTION VISITS AFTER DAY E84 ......65 
 
LIST OF TABLES 
Table 1 MAIN PORTION: Time and Events Table ........................................................10 
Table 2 EXTENSION PORTION: Time and Events Table ............................................12 
Table 3 RA101495 Dose Presentations by Weight Brackets ...........................................35 
Table 4 Chemistry, Hematology, and Coagulation Analytes...........................................40 
Table 5 Grading the Severity of Local Injection Site Reactions ......................................48 
Table 6 EXTENSION PORTION: Time and Events after Day E84 through Week E36 .65 
Table 7 EXTENSION PORTION: Time and Events for each year after Week E36 .......67 
 
LIST OF FIGURES 
Figure 1 
Mechanism of Action of RA101495 in the Complement System .......21 
Figure 2 
Inhibition of C5a (left) and C5b-9 (MAC; right) Formation by 
RA101495 ............................................................................................22 
Figure 3 
Robust Suppression of Hemolytic Activity by RA101495 in the 
Multiple Dose Cohort (Study RA101495-1001) .................................23 
Figure 4 
Design of RA101495-02.201 Study .....................................................28 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
AChR acetylcholine receptor 
 
ADA anti-drug antibody 
 
AE adverse event 
 
aHUS atypical hemolytic uremic syndrome 
 
ALP alkaline phosphatase 
 
ALT alanine aminotransferase 
 ANCOVA Analysis of Covariance 
 
aPTT activated partial thromboplastin time 
 
AST aspartate aminotransferase 
 
AUC(0-24) area under the drug concentration-time 
curve from 0 to 24 hours 
 
BUN blood urea nitrogen 
 
C5 complement component 5 
 
Cmax maximum plasma concentration 
 
CPK creatine phosphokinase  
 
CRO Clinical Research Organization 
 
CRP C-reactive protein 
 
CTCAE Common Terminology Criteria for 
Adverse Events 
 
DNA deoxyribonucleic acid 
 
ECG electrocardiogram 
 
eCRF electronic case report form 
 
ELISA enzyme-linked immunosorbent assay 
 
EMA European Medicines Agency 
 
FDA Food and Drug Administration 
 
GCP Good Clinical Practice  
 
GGT gamma-glutamyl transferase 
 
gMG generalized myasthenia gravis 
 
HR heart rate 
 
IB Investigator’s Brochure 
 
ICF informed consent form 
 
IEC Independent Ethics Committee 
 
IMP investigational medicinal product 
 
INR international normalized ratio 
 
IRB Institutional Review Board 
 
ISR injection site reaction 
 
IST immunosuppressant therapy 
 
ITT Intention-to-Treat 
 
IV intravenous 
 
IVIG intravenous immunoglobulin G 
 
LFT liver function test 
 
LOCF last observation carried forward 
 
LRP4 lipoprotein receptor-related peptide 4 
 
MAC membrane attack complex 
 
MCV mean corpuscular volume 
 
MD multiple dose 
 
MDRD Modification of Diet in Renal Disease 
 
MedDRA Medical Dictionary for Regulatory 
Activities 
 
MG myasthenia gravis  
 MG-ADL Myasthenia Gravis-Activities of Daily 
Living  
 
MGFA Myasthenia Gravis Foundation of 
America 
 MG-QOL Myasthenia Gravis-Quality of Life 
 
mITT Modified Intention-to-Treat 
 
MuSK muscle-specific kinase 
 
MSE Minimum Symptom Expression 
 
NCI National Cancer Institute 
 
PD pharmacodynamic(s) 
 
PK pharmacokinetic(s) 
 
PLEX plasma exchange 
 
PNH paroxysmal nocturnal hemoglobinuria 
 
PT prothrombin time 
 
PTT partial thromboplastin time 
 
QMG quantitative myasthenia gravis  
 
QOL quality of life 
 
QTcB QT interval corrected by Bazett’s 
formula 
 
QTcF QT interval corrected by Fridericia’s 
formula 
 
SAD single ascending dose 
 
SAE serious adverse event 
 
SAP statistical analysis plan 
 
SAS Statistical Analysis System 
 
SC subcutaneous (ly) 
 
SD standard deviation 
 
SMC Safety Monitoring Committee 
 
SOC standard of care 
 
SOP standard operating procedure 
 
sRBC sheep red blood cell 
 
TEAE treatment-emergent adverse event 
 
tmax time to corresponding Cmax 
 
TMF Trial Master File 
 
ULN upper limit of normal 
 
WBC white blood cell 
 
 
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5 
INTRODUCTION 
Ra Pharmaceuticals, Inc. is developing RA101495, a subcutaneously (SC) administered 
15-amino acid cyclic peptide that inhibits the cleavage of complement component 5 (C5).  
Please refer to the Investigator’s Brochure (IB) for additional information on the 
chemistry, toxicology, pharmacology, and safety of RA101495.  
5.1 
OVERVIEW OF GENERALIZED MYASTHENIA GRAVIS 
Myasthenia gravis (MG) is a rare complement-mediated autoimmune disease 
characterized by the production of autoantibodies targeting proteins that are critical for 
the normal transmission of electrical signals from nerves to muscles. The prevalence of 
MG in the United States is estimated at approximately 36,000 to 60,000 cases 
[Howard, 2016]. In approximately 15% of patients with MG, symptoms are confined to 
the ocular muscles. The remaining patients have MG that affects multiple muscle groups 
throughout the body, which is defined as ‘generalized’ myasthenia gravis (gMG) [Gilhus, 
2016]. 
Patients with gMG present with muscle weakness that characteristically becomes more 
severe with repeated use and recovers with rest. Muscle weakness can be localized to 
specific muscles, but often progresses to more diffuse muscle weakness [Gilhus, 2015; 
Gilhus, 2016]. gMG symptoms can become life-threatening when muscle weakness 
involves the diaphragm and intercostal muscles in the chest wall that are responsible for 
breathing. The most dangerous complication of gMG, known as myasthenic crisis, 
requires hospitalization, intubation, and mechanical ventilation. Approximately 15% to 
20% of patients with gMG will experience a myasthenic crisis within 2 years of diagnosis 
[Ramizuddin, 2014].  
The most common target of autoantibodies in gMG is the nicotinic acetylcholine receptor 
(AChR), located at the neuromuscular junction, the point at which a motor neuron 
transmits chemical signals to a skeletal muscle fiber. Current therapies for gMG focus on 
either augmenting the AChR signal or nonspecifically suppressing the autoimmune 
response. First-line therapy for symptomatic gMG is treatment with acetylcholinesterase 
inhibitors such as pyridostigmine, which is the only approved therapy for MG. Although 
usually adequate for control of mild ocular symptoms, pyridostigmine monotherapy is 
usually insufficient for the treatment of generalized weakness, and dosing of this therapy 
may be limited by cholinergic side effects. Therefore, in patients who remain 
symptomatic despite pyridostigmine therapy, corticosteroids with or without systemic 
immunosuppressives are indicated [Sanders, 2016]. Immunosuppressives used in gMG 
include azathioprine, cyclosporine, mycophenylate mofetil, methotrexate, tacrolimus, 
cyclophosphamide, and rituximab. To date, efficacy data for these agents are sparse and 
no steroidal or immunosuppressive therapy has been approved for the treatment of gMG. 
Moreover, all of these agents are associated with well-documented long-term toxicities. 
Surgical removal of the thymus may be recommended in patients with nonthymomatous 
gMG and moderate to severe symptoms in an effort to reduce the production of AChR 
autoantibodies [Wolfe, 2016]. Intravenous (IV) immunoglobulin and plasma exchange 
are restricted to short-term use in patients with myasthenic crisis or life-threatening signs 
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such as respiratory insufficiency or dysphagia [Sanders, 2016]. There is, therefore, a 
substantial unmet medical need for novel therapies to treat patients with gMG.  
5.2 
ROLE OF COMPLEMENT IN GENERALIZED MYASTHENIA GRAVIS 
There is substantial evidence that supports the role of terminal complement cascade in the 
pathogenesis of AChR autoantibody-positive gMG. Results from animal models of 
experimental autoimmune MG have demonstrated that immune complex formation at the 
neuromuscular junction triggers activation of the classical complement pathway, resulting 
in local activation of C3 and deposition of the membrane attack complex (MAC) at the 
neuromuscular junction, resulting in loss of signal transduction and eventual muscle 
weakness [Kusner, 2012].  
In addition, inhibition of C5 has been recently validated as a target for the treatment of 
refractory gMG based on clinical studies with the C5-blocking antibody, eculizumab. 
Eculizumab is currently approved for use in 2 other complement-driven rare diseases, 
paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome 
(aHUS). In a Phase 2, randomized, double-blind, placebo-controlled trial, eculizumab 
was tested in 14 AChR autoantibody-positive patients with refractory gMG, who had a 
quantitative myasthenia gravis (QMG) score ≥ 12 and previously failed treatment with at 
least 2 immunosuppressant therapies (ISTs) [Howard, 2013]. Patients were randomized in 
a 1:1 ratio to receive either eculizumab or placebo. Patients on eculizumab received 
600 mg per week for 4 weeks, followed by 900 mg every other week by IV infusion, for a 
total of 16 weeks of treatment. After a 5-week washout period, patients were crossed over 
to the opposite arm of the study. Patients who received placebo for the first 16 weeks of 
the study were treated with eculizumab and vice versa. The primary endpoints were 
safety and efficacy, as measured by the percentage of patients who achieved a ≥ 3-point 
reduction in QMG score. The impact of C5 inhibition by eculizumab in QMG score 
occurred rapidly (within 1 week of initiating treatment) and favored eculizumab 
compared with placebo across all study visits (p = 0.0144). Following the initial 16-week 
treatment period, 6 out of 7 patients on eculizumab achieved a ≥ 3-point improvement in 
QMG score, compared with 4 out of 7 patients in the placebo arm. Of those patients who 
responded to eculizumab, 4 achieved an 8-point reduction in QMG score compared with 
only 1 in the placebo arm.  
A Phase 3 trial was also recently completed that enrolled 125 AChR autoantibody-
positive patients with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score 
≥ 6, who had previously failed 2 ISTs or had failed 1 IST and required chronic plasma 
exchange or IV immunoglobulin therapy [Alexion, 2017]. Patients were randomized 1:1 
to receive either placebo or eculizumab for a 26-week treatment period, followed by an 
extension study. Patients receiving eculizumab were treated with 900 mg per week for 
4 weeks followed by 1200 mg every other week by IV infusion. Eculizumab treatment 
was not associated with a statistically significant benefit relative to placebo in the 
primary endpoint of change from baseline in MG-ADL (p = 0.0698) in this study 
[Alexion, 2016]. However, statistically significant results were observed in 18 of 22 
prespecified analyses, including the secondary endpoint of change from baseline in QMG 
score (p = 0.0129). Taken together, the results of these 2 clinical trials establish that 
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inhibition of the terminal complement cascade by blocking cleavage of C5 is a clinically 
validated target for the treatment of gMG. 
5.3 
MECHANISM OF ACTION OF RA101495 
RA101495 is a macrocyclic peptide designed to inhibit complement activation at the 
level of C5, the same molecular target as eculizumab. RA101495 binds to C5 with high 
affinity and prevents its cleavage by the C5 convertase into both cleavage products C5a 
and C5b (Figure 1). Inhibition of C5 cleavage therefore prevents the downstream 
assembly and activity of the MAC, which has been detected in the post-junctional 
membrane of the neuromuscular junction of patients with gMG. Distinct from 
eculizumab, RA101495 binds to the portion of C5 that corresponds to the C5b domain. In 
binding to this region of C5, should any C5b be formed, RA101495 will also block 
binding to C6, which further prevents the subsequent assembly of the MAC (C5b-9). 
Using surface plasmon resonance and analysis of a high-resolution co-crystal structure, 
RA101495 has been shown to bind to a specific site on C5 and to exhibit a strong and 
rapid association with C5, coupled with a slow dissociation rate. 
Thus, RA101495 inhibits MAC formation by a dual mechanism:   
1. Prevention of downstream complement activation by allosterically inhibiting C5 
cleavage  
2. Direct inhibition of the first step in MAC assembly, C5b-C6-binding. 
Figure 1 
Mechanism of Action of RA101495 in the Complement System 
Abbreviations:  AP=alternative pathway; C5=complement component 5; CP=complement pathway; 
MAC=membrane attack complex; MBL= mannose-binding lectin. 
The dose-dependent inhibition by RA101495 of C5a formation upon activation of the 
classical pathway is depicted in the left panel of Figure 2. The right panel of Figure 2 
shows the inhibition by RA101495 of C5b formation (as measured by C5b-9 or MAC 
deposition on a complement activating surface) upon activation of the classical and 
alternative complement pathways. In these experiments, the relative levels of both C5a 
and MAC were measured by enzyme-linked immunosorbent assays (ELISAs) using 
antibodies specific for C5a and C5b-9.  
Alterna ve Pathway
Classical Pathway
MBL Pathway
AP C5 Convertase
(C3bC3bBb)
C5
C5a
C5b
C6
C5b6
C7, C8, C9
MAC
CP C5 Convertase
(C3bC4bC2a)
RA101495
ti
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Figure 2 
Inhibition of C5a (left) and C5b-9 (MAC; right) Formation by RA101495 
Note:  Inhibitor is RA101495.  
Abbreviations:  C5=complement component 5; MAC=membrane attack complex. 
5.4 
CLINICAL TRIAL EXPERIENCE WITH RA101495 
Clinical trial experience with RA101495 to date includes a single Phase 1 study 
(RA101495-1001) in healthy volunteers. Study RA101495-1001 was a randomized, 
double-blind, placebo-controlled, single ascending dose (SAD) and multiple dose (MD) 
study designed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics 
(PD) of RA101495. 
The first part of the RA101495-1001 study (SAD) evaluated a single dose of RA101495 
versus placebo at 4 dose levels (0.05, 0.1, 0.2, and 0.4 mg/kg) in separate cohorts. 
Twenty-two subjects were enrolled; 14 subjects received RA101495 (0.05 mg/kg in 
2 subjects; 0.1, 0.2, and 0.4 mg/kg in 4 subjects each) and 8 subjects received placebo 
(2 subjects per each dose level). The second part of the study (MD) evaluated 7 daily 
doses of RA101495 versus placebo at a single dose level (0.2 mg/kg). A total of 
6 subjects were enrolled; 4 subjects received RA101495 and 2 subjects received placebo. 
The results of this study showed that RA101495 had highly predictable, dose-dependent 
PK after single- and multiple-dose SC injections over the dose range investigated. 
RA101495 demonstrated robust ex vivo hemolysis suppression and complement 
inhibition with daily SC dosing compared with placebo treatment (Figure 3).  
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Figure 3 
Robust Suppression of Hemolytic Activity by RA101495 in the Multiple 
Dose Cohort (Study RA101495-1001) 
Note:  Dosed subjects were treated with 0.2 mg/kg RA101495 daily for 7 days.  
Administration of RA101495 in this study was also associated with an acceptable safety 
and tolerability profile with no serious adverse events (SAEs) reported. The most 
common adverse events (AEs) in subjects who received single doses of RA101495, 
regardless of causality, were injection site erythema (3 subjects, 0.4 mg/kg), upper 
respiratory tract infection (1 subject, 0.05 mg/kg; 2 subjects, 0.4 mg/kg), and headache 
(2 subjects, 0.4 mg/kg). The most common AEs in subjects who received multiple doses 
of 0.2 mg/kg RA101495, regardless of causality, were injection site erythema (3 subjects) 
and headache (2 subjects). A complete overview of results from the RA101495-1001 
study is provided in the RA101495 IB. 
5.5 
RATIONALE FOR THE CURRENT STUDY 
Current therapies for gMG focus on either augmenting the AChR signal or 
nonspecifically suppressing the autoimmune response, and none of these treatments 
target the injury to the post-synaptic muscle endplate caused by complement attack. 
Inhibition of terminal complement activity with RA101495 may block complement-
mediated damage to the motor endplate, thereby preserving responsiveness to signaling 
and potentially reversing or preventing muscle weakness. The current study will evaluate 
the safety and efficacy of 12 weeks of treatment with 2 different doses of RA101495 (0.1 
mg/kg daily and 0.3 mg/kg daily) compared with placebo, as well as the long-term effects 
of administration of RA101495, in subjects with gMG.  
5.5.1 
RATIONALE FOR BLINDING AND PLACEBO CONTROL 
The primary objective of this study is the evaluation of efficacy based on functional 
assessment of weakness measured by the QMG score, as well as additional clinical 
endpoints. Such clinical assessments are prone to placebo effects and may be influenced 
by knowledge of treatment assignment by the clinical evaluator and/or subject. Moreover, 
the evaluation of potential adverse effects may also be influenced by knowledge of 
treatment assignment. To enable rigorous efficacy and safety evaluation without the 
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potential bias caused by knowledge of treatment assignment, this study was designed as a 
double-blind placebo-controlled study.  
Subjects entering the study will have stable disease and will be allowed to continue their 
standard of care (SOC) therapy, including escalation of treatment as medically necessary 
(see Section 10.1.3.1 Rescue Therapy). Therefore, subjects receiving placebo will not be 
subject to increased risk due to withholding of medically necessary interventions. In 
addition, the placebo study drug contains substances that are known to be well-tolerated 
(
) and are delivered in a small volume < 1 mL; therefore, 
placebo administration by daily SC injection over the 12-week study period is expected 
to be well-tolerated. Consequently, administration of a placebo in Study 
RA101495-02.201 is not anticipated to cause undue burden or risk for study subjects. 
Following the completion of the 12-week Treatment Period in the Main Portion of the 
study, all subjects will have the option to receive RA101495 in the Extension Portion of 
the study.  Therefore, subjects originally randomized to placebo will eventually have the 
opportunity to receive active study drug. The study will remain double-blinded during the 
Extension Portion until after the data from the Main Portion of the study have been 
cleaned, locked, and unblinded.  
Following implementation of the present Amendment (v.3.0), and upon appropriate 
reconsent, all subjects ongoing in the Extension Portion will receive the 0.3 mg/kg dose 
that has been selected for the pivotal Phase 3 study (See Section 5.5.3 for details).  
5.5.2 
DOSE SELECTION AND PRESENTATION 
Study drug will be provided in prefilled syringes for self-injection using weight bracketed 
dosing (i.e., subjects will be provided prefilled syringes containing fixed amounts of 
RA101495 based on their weight, and each fixed amount will cover a range of subject 
weights). This weight-bracketed dosing strategy will result in the potential for a range of 
doses to be received at each dose level (see Section 9.1.3).  
The doses to be used in this Phase 2 study were selected based on the following: 
• Preliminary data from ongoing Phase 2 studies in adult subjects with PNH indicates 
that daily dosing of RA101495 at both 0.1mg/kg and 0.3mg/kg is well-tolerated. 
• The predicted steady state Cmax and AUC(0-24) achieved at both doses are expected to 
be within the range of those achieved in the Phase 1 RA101495 study in healthy 
volunteers and/or in Phase 2 studies in subjects with PNH. 
• Based on pharmacodynamic data from the ongoing Phase 2 studies in PNH, both 
doses have been shown to achieve rapid and sustained inhibition of complement 
activity.   
• Additional information on pharmacokinetics, pharmacodynamics, and experience in 
other clinical trials is available in the Investigators’ Brochure. 
5.5.3 
DOSE SELECTION FOR OPEN LABEL PORTION 
After analysis of the results of the Main Portion of this Phase 2 Study, the dose of 0.3 
mg/kg daily was selected for the Open Label Extension Portion based on its superior 
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efficacy, greater inhibition of the terminal complement pathway, and similar safety 
profile as compared with the 0.1 mg/kg and placebo arms.  
In the Main Portion of the Phase 2 Study RA101495-02.201, the magnitude and speed of 
improvement on the primary (QMG) and key secondary (MG-ADL) endpoints were 
greater with the 0.3 mg/kg dose than the 0.1 mg/kg dose, and both active doses were 
superior to placebo. The superior efficacy of the 0.3 mg/kg dose was further 
demonstrated by the complete freedom from the need for rescue therapy with IVIG or 
PLEX in the 0.3mg/kg arm, as compared with a 7% rescue rate in the 0.1 mg/kg arm, and 
a 20% rescue rate in the placebo arm. A higher proportion of subjects achieved MSE 
(Vissing 2018), defined as an MG-ADL of 0 or 1, in the 0.3mg/kg arm (35.7%) as 
compared with the 0.1 mg/kg arm (26.7%) and placebo (13.3%). 
The dose response seen in the clinical outcome measures is consistent with the known 
pharmacodynamic effect of zilucoplan that resulted, as expected, in rapid, sustained and 
complete (97%) inhibition of the terminal complement pathway in all gMG subjects 
receiving the 0.3 mg/kg dose while the 0.1 mg/kg group achieved only submaximal 
(88%) inhibition of the terminal complement pathway.  
The once daily dosing interval will be retained because pharmacokinetic simulations 
indicate that longer dosing intervals cannot achieve adequate exposures and fail to 
maintain the depth of complement inhibition needed for maximum therapeutic benefit.  
For example, once every other day dosing is estimated to reduce the zilucoplan trough 
concentration by approximately 50%, resulting in inadequate pharmacodynamic effect. 
The same weight brackets for the 0.3 mg/kg dose will continue to be used in the Open 
Label Extension Portion. Study drug will continue to be provided in prefilled syringes for 
self-injection using weight bracketed dosing (i.e., subjects will be provided prefilled 
syringes containing fixed amounts of zilucoplan based on their weight, and each fixed 
amount will cover a range of subject weights). This weight-bracketed dosing strategy will 
result in the potential for a range of doses to be received at each dose level (see Section 
9.1.3).  
6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
OBJECTIVES 
The objectives of the study are: 
• To assess the safety and tolerability of RA101495 in subjects with gMG 
• To assess preliminary efficacy of RA101495 in subjects with gMG 
6.2 
ENDPOINTS 
6.2.1 
SAFETY AND TOLERABILITY ENDPOINTS 
Safety assessments will include evaluations of AEs and SAEs, clinical laboratory tests, 
electrocardiograms (ECGs), vital signs, and physical examinations.  
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6.2.2 
EFFICACY ENDPOINTS 
Primary efficacy:   
The primary efficacy endpoint is the change from baseline to Week 12 (Day 84) in QMG 
score. The primary endpoint comparison will be between the 0.3 mg/kg RA101495 group 
and the placebo group.  
Secondary efficacy:   
The secondary efficacy endpoints are: 
• Change from baseline to Week 12 in the MG-ADL scale 
• Change from baseline to Week 12 in the MG-Quality of Life 15r (MG-QOL15r) 
survey 
• Change from baseline to Week 12 in the MG Composite  
• Subjects with ≥ 3-point reduction in QMG score at Week 12 
• Subjects requiring rescue therapy over the 12-week Treatment Period  
6.2.3 
PHARMACOKINETIC ENDPOINTS 
The PK endpoints are:   
• Plasma concentrations of RA101495 and its major metabolites 
• Maximum plasma concentration (Cmax) on Day 1 
• Time corresponding to Cmax (tmax) on Day 1 
6.2.4 
PHARMACODYNAMIC ENDPOINTS 
The PD endpoints are: 
• Sheep red blood cell (sRBC) lysis assay for evaluation of classical complement 
pathway activation 
• C5 levels 
6.2.5 
EXPLORATORY ENDPOINTS 
The following exploratory endpoints will also be examined during the study: 
• Mechanistic biomarkers [e.g., MG pathophysiology, complement fixation, 
complement function, complement pathway proteins, autoantibody characterization 
(titer and immunoglobulin class) and inflammation]  
• Pharmacogenomic analyses (optional)  
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7 
STUDY DESIGN 
7.1 
OVERVIEW OF STUDY DESIGN  
Study RA101495-02.201 is a multicenter, randomized, double-blind, placebo-controlled 
study to evaluate the safety, tolerability, and preliminary efficacy of RA101495 in 
subjects with gMG. The planned enrollment is approximately 36 subjects.  
Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg 
RA101495, 0.3 mg/kg RA101495, or matching placebo.  Randomization will be stratified 
based on the screening QMG Score (≤ 17 versus ≥ 18). 
The Main Portion of the study includes a Screening Period of up to 4 weeks and a 12-
week Treatment Period (Figure 4). During the Treatment Period, subjects will return to 
the clinic weekly for the first 2 visits (Day 8 and Day 15) after the Day 1 visit, followed 
by visits at Week 4 (Day 29), Week 8 (Day 57), and Week 12 (Day 84) to evaluate 
safety, tolerability, and preliminary efficacy. Additional assessments will include quality 
of life (QOL) questionnaires, biomarker samples, pharmacokinetics, pharmacodynamics, 
and optional pharmacogenomics. Safety assessments will include physical examinations, 
vital signs, ECGs, clinical laboratory tests, AEs, and immunogenicity.  
Randomized subjects will receive 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or 
matching placebo administered SC at the Day 1 visit. Following in-clinic education and 
training, all subjects will self-inject daily SC doses of blinded study drug, according to 
randomized treatment allocation, for the subsequent 12 weeks. An injection device will 
be provided for use during the study. 
Subjects are expected to remain on stable doses of SOC therapy for gMG throughout the 
study, including pyridostigmine, corticosteroids, or immunosuppressive drugs. If, in the 
opinion of the investigator, escalation of gMG therapy (i.e., ‘rescue therapy’) becomes 
necessary due to deterioration of a subject’s clinical status, the subject may receive 
immunoglobulin or plasma exchange treatment. 
The safety of subjects will be monitored in a blinded manner on an ongoing basis. If an 
unblinded data review should become necessary to ensure subject safety, a Safety 
Monitoring Committee (SMC) will convene and evaluate study data as appropriate (see 
Section 11.3.2.1).  
The risk of Neisseria meningitidis infection will be closely monitored during the study. 
All subjects who have not been previously vaccinated against Neisseria meningitidis 
prior to study entry must be vaccinated with a quadrivalent meningococcal vaccine and, 
where available, meningococcal serotype B vaccine at least 14 days prior to the first dose 
of study drug at the Day 1 visit. A booster vaccination should also be administered as 
clinically indicated, according to the local SOC. 
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled 
and reminded of the early signs and symptoms of Neisseria meningitidis infection. A 
patient safety card detailing the signs and symptoms of infection, with instructions to 
seek immediate medical attention, will be provided to each subject.  
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At the conclusion of the Treatment Period in the Main Portion of the study, all subjects 
will have the option to receive RA101495 in the Extension Portion of the study provided 
they meet the Extension Portion selection criteria (Section 8.3). Subjects assigned to a 
RA101495 treatment arm during the Main Portion of the study will continue to receive 
the same dose of study drug during the Extension Portion.  Subjects assigned to the 
placebo arm during the Main Portion of the study will be randomized in a 1:1 ratio to 
receive daily SC doses of 0.1 mg/kg RA101495 or 0.3 mg/kg RA101495. Visits during 
the first 12 weeks of the Extension Portion will be identical to Main Portion of the study 
for all subjects to ensure appropriate monitoring of subjects transitioning from placebo to 
active treatment and to maintain blinding of treatment assignment. The study will remain 
double-blinded during the Extension Portion until after the data from the Main Portion of 
the study have been cleaned, locked, and unblinded. 
Following implementation of the present Amendment (v.3.0), and upon appropriate 
reconsent, all subjects ongoing in the Extension Portion will receive the 0.3 mg/kg dose 
that has been selected for the pivotal Phase 3 study (See Section 5.5.3 for details).  
If a subject discontinues study drug treatment prior to the Day 84 visit for any reason, 
he/she will not be eligible for the Extension Portion. Subjects who undergo rescue 
treatment and continue receiving study drug are eligible for participation in the Extension 
Portion. For subjects who do not participate in the Extension Portion, a safety follow-up 
telephone call will be performed at 40 days after the last dose of study drug, to collect 
information on any ongoing AEs or new serious adverse events (SAEs) since the last 
study visit. 
Figure 4 
Design of RA101495-02.201 Study 
7.2 
STUDY PERIODS 
During the Main Portion of the study, the total duration of study participation for all 
subjects will be up to approximately 16 weeks, including a Screening Period of up to 4 
weeks and a 12-week Treatment Period. 
During the Extension Portion of the study, RA101495 will continue to be provided by the 
Sponsor until RA101495 is approved and available in the territory, or the Sponsor 
terminates development of RA101495 for gMG. In countries where RA101495 is not 
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approved or marketed, but in which sponsored clinical studies have been conducted, 
subjects may continue to receive RA101495 through a compassionate use pathway. 
Following implementation of the present Amendment (v.3.0), and upon appropriate 
reconsent, all subjects ongoing in the Extension Portion will receive the 0.3 mg/kg dose 
that has been selected for the pivotal Phase 3 study (See Section 5.5.3 for details).  
7.2.1 
SCREENING PERIOD  
The Screening visit(s) will occur no more than 28 days prior to the first dose of study 
drug on Day 1.  
Subjects that do not meet the entry criteria for the study may rescreen after 3 months. 
Subjects may be rescreened no more than 2 times.   
7.2.1.1 
SCREENING AND ENROLLMENT 
Procedures performed as SOC during the Screening Period may be used to determine 
eligibility. Informed consent must be obtained prior to performing any study-specific 
procedures that are not SOC. 
At the Screening visit, subjects will be assigned a unique subject number. The following 
assessments will be performed during Screening: 
• Informed consent 
• Review of eligibility criteria 
• Review of medical history and demographics, including collection of disease history 
with diagnosis of gMG according to Myasthenia Gravis Foundation of America 
(MGFA) criteria (Class II-IVa), serology for AChR autoantibodies, and QMG score 
assessment  
• Measurement of height and weight 
• Review and documentation of prior and concomitant medications 
NOTE: A complete history of medications taken for the treatment of gMG will be 
collected. 
• Full physical examination  
• Vital signs [heart rate (HR), body temperature, blood pressure in the sitting position] 
• 12-lead ECG  
• Neisseria meningitidis vaccination for all subjects who do not have documentation of 
prior Neisseria meningitidis vaccination (and booster, if appropriate). A booster 
should also be administered, in applicable subjects, as indicated by SOC. All eligible 
subjects must have documentation of prior Neisseria meningitidis vaccination (and 
booster, if appropriate) prior to study entry.  
• Collection of blood samples for laboratory testing:  hematology, chemistry, and 
coagulation (if applicable) 
• Collection of urine sample for urinalysis 
• Serum pregnancy testing for females of childbearing potential only 
• Collection of blood sample for ADA testing 
• Collection of blood sample for pharmacogenomic analysis (optional) 
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• Enrollment and randomization 
7.2.2 
TREATMENT PERIOD (MAIN AND EXTENSION PORTIONS) 
Subjects will receive treatment with 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or 
matching placebo, according to randomization, from Day 1 to Day 84 during the 
Treatment Period of the Main Portion of the study. In consultation with the treating 
physician, subjects who complete the Day 84 visit (including those randomized to the 
placebo arm) will have the option to continue treatment with RA101495 in the Extension 
Portion of the study. Subjects assigned to a RA101495 treatment arm during the Main 
Portion of the study will continue to receive the same dose of study drug during the 
Extension Portion.  Subjects assigned to the placebo arm during the Main Portion of the 
study will be randomized in a 1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495 
or 0.3 mg/kg RA101495. If a subject chooses not to participate in the Extension Portion, 
the subject will receive standard-of-care treatment off-study, as recommended by the 
treating physician. 
Please refer to the Time and Events Tables (Table 1 and Table 2) for details regarding 
assessments that must be completed at visits during the Treatment Period for both the 
Main and Extension Portions of the study.  
7.2.2.1 
RANDOMIZATION AND BLINDING 
Subjects who meet all entry criteria will be randomized in a 1:1:1 ratio to receive daily 
SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo. Subjects 
will be assigned to study arms in a blinded fashion using a computerized randomization 
algorithm. Randomization will be stratified based on the screening QMG Score (≤ 17 
versus ≥ 18). 
This is a double-blind study. Subjects and study staff will remain blinded to treatment 
assignments until after the data from the Main Portion of the study have been cleaned, 
locked, and unblinded. 
Instructions for emergency unblinding, if warranted, for safety reasons are provided in 
Section 11.3.3. 
7.2.2.2 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT 
Upon completion of the 12-week Treatment Period, if a subject chooses not to participate 
in the Extension Portion then they should return to the clinic for the Day 84 (or End of 
Study) visit. If a subject prematurely discontinues study drug at any time prior to 
completion of the Day 84 (see Section 8.3.2), the subject should return to clinic for an 
End of Study Visit. During the Extension Portion, if a subject prematurely discontinues 
study drug at any time (see Section 8.3.2), the subject should return to clinic for a Final 
Study Visit.  
The following procedures will be completed at the End of Study and Final Study Visits:   
• Measurement of weight 
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• Review and documentation of concomitant medications 
• Symptom-directed physical examination  
• Vital signs (HR, body temperature, blood pressure in the sitting position) 
• 12-lead ECG 
• Collection of blood samples for laboratory testing:  hematology, chemistry, and 
coagulation (if applicable)  
• Collection of urine sample for urinalysis 
• Urine pregnancy testing for females of childbearing potential only 
• Record AEs 
• Collection of blood samples for the following assessments: 
o ADA sampling  
o PK analysis 
o PD analyses 
o Additional biomarker analysis 
• QMG score assessment 
• Completion of the following efficacy assessments: 
o MG-ADL 
o MG-QOL15r 
o MG Composite 
• Return of all used and unused study drug syringes to site  
All subjects who prematurely discontinue study treatment during the Main Portion of the 
study will receive a safety follow-up telephone call at 40 days after the last dose of study 
drug, to collect information on any ongoing AEs or new SAEs since the last study visit.  
7.3 
EARLY STUDY TERMINATION  
The Sponsor may terminate this study early (in its entirety, in part, or at 1 or more study 
sites) for reasonable cause provided that written notice is submitted in advance of the 
intended termination. The investigator may also terminate the study at the site for 
reasonable cause, after providing written notice to the Sponsor in advance of the intended 
termination. Advance notice is not required by either party if the study is stopped due to 
safety concerns. If the Sponsor terminates the study for safety reasons, the Sponsor will 
immediately notify the investigator and subsequently provide written instructions for 
study termination. 
If the Sponsor terminates or suspends the study, all applicable Competent Regulatory 
Authorities will be informed as per applicable legislation. 
8 
SELECTION OF STUDY POPULATION 
8.1 
INCLUSION CRITERIA  
To be eligible for this study, subjects must meet ALL of the following inclusion criteria: 
1. Male or female ≥ 18 years and < 85 years. 
2. Able to provide informed consent, including signing and dating the informed consent 
form (ICF). 
3. Diagnosis of gMG (MGFA Class II-IVa) at Screening. 
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4. Positive serology for AChR autoantibodies. 
5. QMG score ≥ 12 at Screening and baseline (off acetylcholinesterase inhibitor therapy 
for at least 10 hours) with ≥ 4 test items scored at ≥ 2.  
6. No change in corticosteroid dose for at least 30 days prior to baseline or anticipated to 
occur during the 12-week Treatment Period. 
7. No change in immunosuppressive therapy, including dose, for at least 30 days prior to 
baseline or anticipated to occur during the 12-week Treatment Period.  
8. Female subjects of childbearing potential must have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test within 24 hours prior to the first 
dose of study drug. 
9. Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation) and all male subjects (who have not been surgically sterilized 
by vasectomy) must agree to use effective contraception during the study (see 
Section 10.2.4.3).  
8.2 
EXCLUSION CRITERIA 
Subjects who meet ANY of the following exclusion criteria must be excluded from the 
study:   
1. Thymectomy within 6 months prior to baseline or scheduled to occur during the 
12-week Treatment Period.  
2. Abnormal thyroid function as determined by local standard. 
3. Known positive serology for muscle-specific kinase (MuSK) or lipoprotein receptor-
related peptide 4 (LRP4). 
4. Minimal Manifestation Status of myasthenia gravis based on the clinical judgement 
of the investigator. 
5. Calculated glomerular filtration rate of < 60 mL/min/1.73 m2 based on the 
Modification of Diet in Renal Disease (MDRD) equation at Screening. 
GFR ൭
mL min
ൗ
1.73 m2൱= 175 × (Scr)−1.154  × (Age)−0.203  × (0.742 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) × (1.212 𝑖𝑖𝑖𝑖 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴) 
6. Elevated liver function tests (LFTs) defined as total bilirubin or transaminases 
[aspartate aminotransferase (AST)/alanine aminotransferase (ALT)] > 2 times the 
upper limit of normal (× ULN). 
7. History of meningococcal disease. 
8. Current or recent systemic infection within 2 weeks prior to baseline or infection 
requiring IV antibiotics within 4 weeks prior to baseline. 
9. Pregnant, planning to become pregnant, or nursing female subjects. 
10. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or 
surgery expected to occur during Screening or the 12-week Treatment Period. 
11. Treatment with an experimental drug or another complement inhibitor within 30 days 
or 5 half-lives of the experimental drug (whichever is longer) prior to baseline. 
12. Treatment with rituximab within 6 months prior to baseline. 
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13. Ongoing treatment with IV immunoglobulin G (IVIG) or plasma exchange or 
treatment within 4 weeks prior to baseline. 
14. Active neoplasm (other than benign thymoma) requiring surgery, chemotherapy, or 
radiation within the prior 12 months (subjects with a history of malignancy who have 
undergone curative resection or otherwise not requiring treatment for at least 
12 months prior to Screening with no detectable recurrence are allowed).  
15. Fixed weakness (‘burnt out’ MG) based on the clinical judgement of the investigator. 
16. History of any significant medical or psychiatric disorder that in the opinion of the 
investigator would make the subject unsuitable for participation in the study. 
17. Participation in another concurrent clinical trial involving an experimental therapeutic 
intervention (participation in observational studies and/or registry studies is 
permitted).  
18. Unable or unwilling to comply with the requirements of the study. 
8.3 
SELECTION CRITERIA FOR THE EXTENSION PORTION: 
1. Completion of the Main Portion of the study. 
2. Continues to meet inclusion criteria 2, 4, 8, and 9 from the Main Portion of the study. 
2. Able to provide informed consent, including signing and dating the informed consent form (ICF). 
4. Positive serology for AChR autoantibodies. 
8. Female subjects of childbearing potential must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test within 24 hours prior to the first dose of study drug. 
9. Sexually active female subjects of childbearing potential (i.e., women who are not postmenopausal 
or who have not had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) and all 
male subjects (who have not been surgically sterilized by vasectomy) must agree to use effective 
contraception during the study (see Section 10.2.4.3). 
3. Did not start any disallowed medication per the exclusion criteria from the Main 
Portion of the study or alter the dose of any other concomitant medication, unless 
medically indicated.  
4. Unable or unwilling to comply with the requirements of the study. 
5. Any new medical condition (since entry into the Main Portion) or any other reason 
that, in the opinion of the investigator, would disqualify the subject from participation 
in the Extension Portion of this study.  
8.4 
REMOVAL AND REPLACEMENT OF SUBJECTS IN THE STUDY 
8.4.1 
WITHDRAWAL OF CONSENT 
A subject may withdraw consent to participate in this study at any time without penalty 
or loss of benefits to which the subject is otherwise entitled to. When a subject wishes to 
withdraw consent, it is important to distinguish between withdrawing his/her consent for 
a particular study procedure or visit versus withdrawing his/her consent from the study 
entirely (i.e., premature discontinuation). 
When a subject withdraws consent from the study (or study procedure), the reason(s) for 
withdrawal will be recorded by the investigator or designee on the relevant page of the 
electronic case report form (eCRF). 
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8.4.2 
PREMATURE DISCONTINUATION 
Every reasonable effort should be made to encourage retention of subjects in the study, 
maximize compliance with study drug, and facilitate attendance at all scheduled study 
visits/assessments.  
All subjects have the right to refuse further participation in the study at any time and for 
any reason. A subject’s participation must, therefore, be terminated immediately upon 
his/her request. 
The investigator will make every attempt to ascertain the reason(s) for discontinuation 
and to document this in detail in the source documentation and the appropriate sections of 
the eCRF. A subject must be withdrawn from the study for any of the following reasons:   
• Withdrawal of consent 
• Noncompliance (defined as refusal or inability to adhere to the study procedures) 
• Pregnancy while receiving study drug 
• At the request of the Sponsor, regulatory agencies, or Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) 
• Loss to follow-up 
Subjects may also be withdrawn from study treatment due to unacceptable or intolerable 
AEs (see Section 11.1.3 for additional details). 
8.4.3 
REPLACEMENT OF SUBJECTS 
Subjects who prematurely discontinue participation prior to the Day 84 visit may be 
replaced in order to obtain at least 12 evaluable subjects per treatment arm. 
9 
INVESTIGATIONAL MEDICINAL PRODUCTS AND 
TREATMENTS 
9.1 
STUDY TREATMENT ADMINISTRATION 
9.1.1 
INVESTIGATIONAL MEDICINAL PRODUCT AND MATCHING PLACEBO 
The investigational medicinal product (IMP), RA101495, and the matching placebo will 
be supplied as a sterile, preservative-free, aqueous solution prefilled into 1 mL glass 
syringes with a 29 gauge, ½ inch, staked needle placed within a self-administration 
device. Subjects will be instructed to self-administer SC doses daily.  
9.1.2 
DOSING SCHEDULE 
During the Main Portion of the study, all eligible subjects will be randomized 1:1:1 to 
receive 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo administered 
SC at the Day 1 visit, which will be performed by the site staff at the study visit. 
Following in-clinic education and training, all subjects will self-inject daily SC doses of 
blinded study drug, according to randomized treatment allocation, for the subsequent 
12 weeks. An injection device will be provided for use during the Main Portion.  
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During the Extension Portion of the study, subjects assigned to a RA101495 treatment 
arm during the Main Portion of the study will continue to receive the same dose of study 
drug.  Subjects assigned to the placebo arm during the Main Portion of the study will be 
randomized in a 1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495 or 0.3 mg/kg 
RA101495. 
Following implementation of the present Amendment (v.3.0), and upon appropriate 
reconsent, all subjects ongoing in the Extension Portion will receive the 0.3 mg/kg dose 
that has been selected for the pivotal Phase 3 study (See Section 5.5.3 for details).  
Dosing on study visit days should be held until QMG scoring, PK, and PD sample blood 
collection has been completed. On days when rescue therapy is concurrently 
administered, study drug dosing should be held until after administration of rescue 
therapy and PK/PD sampling. 
9.1.3 
DOSE PRESENTATION  
Doses of RA101495 will be determined by a target dose and weight, accomplished using 
a fixed dose by weight brackets. These brackets are grouped by body weight category 
such that each subject will receive the no less than the target minimum dose to avoid 
sub-therapeutic dosing. For the 0.1 mg/kg dose, subjects will receive, at a minimum, a 
fixed dose of 0.1 mg/kg (range:  0.10 to 0.14 mg/kg). For the 0.3 mg/kg dose, subjects 
will receive a minimum dose of 0.3 mg/kg (range:  0.30 to 0.42 mg/kg). Table 2 
summarizes the dose presentations for RA101495 0.1 and 0.3 mg/kg doses. Subjects who 
present with a higher body weight (≥ 109 kg) will be accommodated on a case-by-case 
basis, in consultation with the medical monitor. 
Matching placebo will be provided in 2 presentations, 0.220 mL for the 0.1 mg/kg dose 
and 0.574 mL for the 0.3 mg/kg dose.  
Table 3 
RA101495 Dose Presentations by Weight Brackets 
Target Dose 
(mg/kg) 
Dose Presentation 
Weight Range 
(kg) 
Dose Range 
(mg/kg) 
Fill Volume 
Dose 
mL 
mg 
0.1 
0.150 
6 
≥ 43 to < 61 
0.10 to 0.14 
0.1 
0.220 
8.8 
≥ 61 to < 88 
0.10 to 0.14 
0.1 
0.310 
12.4 
≥ 88 to < 109 
0.11 to 0.14 
0.3 
0.416 
16.6 
≥ 43 to < 56 
0.30 to 0.39 
0.3 
0.574 
23 
≥ 56 to < 77 
0.30 to 0.41 
0.3 
0.810 
32.4 
≥ 77 to < 109 
0.30 to 0.42 
9.1.3.1 
MISSED DOSES  
If a subject misses 1 dose (i.e., 1 day) of study drug, he/she should take the next planned 
dose as scheduled and the investigator should be contacted as soon as possible. If a 
subject misses 2 or more doses, he/she must notify the investigator immediately and the 
medical monitor should be consulted. 
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9.2 
STUDY TREATMENT MANAGEMENT 
9.2.1 
PREPARATION AND DISPENSING 
Prefilled syringes will be dispensed to each subject at each study visit, beginning on 
Day 1 of the Treatment Period.  
Subjects will be provided with training and detailed instructions on the administration of 
study drug using the prefilled syringes and the injection device. 
9.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING 
Investigational medicinal product (IMP) will be provided as a sterile, preservative-free, 
aqueous solution for injection containing 40 mg/mL of RA101495 or placebo in a 
 
prefilled into a 1 mL glass syringe with a ½ inch, 29 gauge, staked needle. Six dosage 
strengths of RA101495 will be supplied as shown in Table 2.  
The IMP should be stored at 2°C to 8°C at the study site. Once dispensed to subjects, the 
IMP may be stored at controlled room temperature [20°C to 25°C (68°F to 77°F)] for up 
to 45 days protected from sources of heat, light, and damage. Storage of IMP outside of 
room temperatures should be avoided. Please refer to the study Pharmacy Manual for 
additional details. 
Subjects will be instructed to self-inject SC doses daily. The subjects will be provided 
with an injection device for use during the study. The subject may inject study drug into 
the abdomen (preferred site), thigh, or upper arm. 
All subjects will receive a study drug kit that will include prefilled syringes (pre-loaded 
into self-injection devices) containing study drug (according to randomization), a syringe 
disposal container, alcohol wipes, and adhesive dressings. 
9.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG 
Subjects will receive secure containers to dispose of used syringes while at home. At 
each visit, the subject should return the container containing all used syringes to the site. 
The unused study drug (i.e., unused syringes) should be retained by the subject.  
All unused study drug syringes and disposal containers containing used syringes must be 
returned to the site at the last study visit (i.e., End of Study Visit on the Main Portion or 
Final Study Visit on the Extension Portion). 
9.2.4 
DRUG ACCOUNTABILITY 
It is the responsibility of the pharmacist to ensure that a current record of inventory/drug 
accountability is maintained. Inventory records must be readily available for inspection 
by the study monitor and are open to inspection by regulatory authorities at any time. For 
further details, please consult the Pharmacy Manual.  
10 
STUDY ASSESSMENTS 
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Please refer to Table 1 and Table 2 for the timing of study assessments. Please also refer 
to Appendix 2 for study visits after Week E36 on the Extension Portion.  
10.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS 
10.1.1 
MEDICAL HISTORY AND DEMOGRAPHICS 
Relevant medical history (including surgical history) will be documented at the Screening 
visit to assess subject eligibility. The following demographic data will be collected: date 
of birth, gender, ethnicity, and race.  
The Screening assessment will also include disease history with documentation of the 
diagnosis of gMG by MGFA criteria (Class II-IVa), serology for AChR autoantibodies, 
and QMG score (see Section 10.3.1 for additional instructions).  
10.1.2 
HEIGHT AND WEIGHT  
Height (cm) will be collected at the Screening visit only. Weight (kg) will be measured at 
the study visits indicated in Table 1 and Table 2.  
10.1.3 
PRIOR AND CONCOMITANT MEDICATIONS 
All prescriptions and over-the-counter medications taken during the 30 days prior to 
baseline (i.e., Day 1) through the last study visit will be documented. NOTE: A complete 
history of medications taken for the treatment of gMG will be collected.  
Concomitant medications include any prescription or over-the-counter medication that is 
ongoing on Day 1 or that is initiated following the first dose of study drug on Day 1.  
Medications, including over the counter therapeutics, natural products, and vitamins, 
should not be changed during the Screening or Treatment Periods, unless medically 
necessary. All concomitant medications necessary for the health and well-being of a 
subject will be permitted.  
Subjects are expected to remain on stable doses of SOC therapy for gMG throughout the 
Main Portion of the study and through the Day E84 visit of the Extension Portion, 
including pyridostigmine, corticosteroids, and immunosuppressive drugs. If after that 
period the investigator determines that dose reduction of SOC therapy for gMG may be a 
reasonable course of action, dose reduction should be initiated after a study visit, and the 
new dosing regimen should be stable for at least 4 weeks prior to the next study visit. 
Dose of standard of care treatment should not be increased during the study. Instead, 
rescue therapy as described in 10.1.3.1 should be administered.    
Medications will be recorded on the subject’s source documents and entered on the 
appropriate eCRF. Any changes to concomitant medications will be recorded in the 
eCRF. Physical therapy interventions and medical devices are considered concomitant 
interventions and will be captured in the concomitant medications eCRF.   
 
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10.1.3.1 
RESCUE THERAPY 
Subjects are expected to remain on stable doses of SOC therapy for gMG throughout the 
Main Portion of the study and through the Day E84 visit of the Extension Portion, 
including pyridostigmine, corticosteroids, or immunosuppressive drugs. If, in the opinion 
of the investigator, escalation of gMG therapy (i.e., ‘rescue therapy’) becomes necessary 
due to deterioration of a subject’s clinical status, the subject may receive immunoglobulin 
or plasma exchange treatment. If such rescue therapy becomes necessary, the choice of 
immunoglobulin vs. plasma exchange, as well as the frequency and duration of such 
therapy, will be determined by the investigator. Escalation of doses of pyridostigmine, 
corticosteroids, or immunosuppressive drugs for rescue is not permitted. The Sponsor 
should be notified immediately upon determination that rescue therapy is necessary in 
any given subject. 
A Rescue Therapy Visit should be performed prior to initiation of rescue therapy (see 
Table 1 and Table 2 for a list of applicable study procedures).  
Unblinding of treatment assignment prior to initiation of rescue therapy will not be 
allowed, unless critical for reasons of subject safety. The subject will continue their 
blinded treatment and retain all study-specified assessments while undergoing rescue 
therapy and through the end of the study if the investigator, in consultation with the 
medical monitor, considers this course of action in the best interest of the subject. 
However, for the purpose of the primary efficacy analyses, the last observation prior to 
initiation of rescue therapy will be used as the final assessment (see Section 12 for 
details). Details on the rescue therapy, as well as reasons for initiation of rescue therapy, 
will be collected. 
10.2 
SAFETY ASSESSMENTS 
10.2.1 
PHYSICAL EXAMINATION  
A full physical examination will be performed on all subjects at the Screening visit and 
will include the following assessments: 
• General inspection 
• Examination of the injection site and draining nodes  
• Head/ears/eyes/nose/throat examination 
• Mucosal examination  
• Cardiac examination 
• Auscultation of lungs 
• Abdominal examination (liver, spleen, and lower abdomen) 
• Musculoskeletal assessment 
• Neurological assessment 
Any abnormalities found will be recorded in the eCRF.  
At all other study visits, the physical examination will be symptom-directed.  
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10.2.2 
VITAL SIGNS 
Vital signs (HR, body temperature, and blood pressure) will be measured in the sitting 
position. If blood samples are scheduled at the same time, vital signs should be measured 
before the blood draw. Blood pressure may be measured manually or by automated 
device, preferably using the non-dominant arm. The same measurement technique should 
be used throughout the study for all the subjects.  
10.2.3 
ELECTROCARDIOGRAM  
12-lead ECGs will be assessed as normal or abnormal by the investigator; any abnormal 
findings will be described in the eCRF and the investigator will assess clinical 
significance. The ECG recording strip will be signed and dated by the investigator and 
stored in the medical records. 
ECGs should be performed prior to blood draws when both assessments are required at 
the same visit. 
10.2.4 
LABORATORY SAFETY ASSESSMENTS 
Safety laboratory tests for this study [chemistry, hematology, coagulation (for applicable 
subjects), and urinalysis] are to be performed by a central laboratory, and only values 
from the central laboratory are to be entered into the laboratory section of the study 
database. Values from local laboratories may be used to determine eligibility for study 
enrollment and as the basis for clinical decisions. 
10.2.4.1 
HEMATOLOGY, CHEMISTRY, AND COAGULATION 
Hematology, chemistry, and coagulation analytes that will be assessed during the study 
are identified in Table 3 and should be performed as specified in the Time and Events 
Tables (Table 1 and Table 2). All laboratory samples should be collected prior to the 
administration of study drug at applicable visits, unless otherwise noted for PK, PD, or 
biomarker samples.  
Coagulation tests should only be performed in subjects receiving anticoagulant therapy.  
 
 
 
  
 
 
 
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Table 4 
Chemistry, Hematology, and Coagulation Analytes 
Chemistry 
Hematology 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bile acids 
Bilirubin (total, direct, and indirect) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lipase 
Potassium 
Sodium 
Total protein 
Uric acid 
Hematocrit 
Hemoglobin 
Mean corpuscular volume (MCV) 
Platelet count 
White blood cell (WBC) count and differential (%) 
Coagulation 
International normalized ratio (INR)/prothrombin 
time (PT) 
Fibrinogen 
Partial thromboplastin time (PTT) or activated 
partial thromboplastin time (aPTT) 
Other 
C-reactive protein (CRP) 
Creatine phosphokinase (CPK) 
10.2.4.2 
URINALYSIS 
A urinalysis will be performed to measure pH, specific gravity, protein (qualitative), 
glucose (qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, occult 
blood, hemoglobin, and cells. A microscopic examination will be performed, if 
necessary.  
10.2.4.3 
PREGNANCY TESTING AND CONTRACEPTION 
A serum pregnancy test for human chorionic gonadotropin will be performed on female 
subjects of childbearing potential at Screening.  
A urine dipstick pregnancy test (human chorionic gonadotropin) will be performed on 
female subjects of childbearing potential at all other study visits as specified in the Time 
and Events Tables (Table 1 and Table 2). 
Negative pregnancy tests must be documented for all female subjects of childbearing 
potential prior to dosing at applicable study visits.  
Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation) and all male subjects (who have not been surgically sterilized by 
vasectomy) must agree to use effective contraception during the study. Effective 
contraception is defined as: 
• Hormonal contraception (e.g., oral contraceptive, transdermal contraceptive, 
contraceptive implant, or injectable hormonal contraceptive) for at least 3 months 
prior to study drug administration, throughout the study, and for 4 weeks after the 
last dose of study drug. 
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• Double-barrier birth control (e.g., male condom, female condom, diaphragm 
sponge, or cervical cap together with spermicidal foam/gel/film/suppository) 
starting at the Screening visit, throughout the study, and for 4 weeks after the last 
dose of study drug. 
• Intrauterine contraception/device starting at the Screening visit, throughout the 
study, and for 4 weeks after the last dose of study drug. 
• Total abstinence from sexual intercourse (only acceptable if it is the preferred and 
usual lifestyle of the subject) for at least 1 complete menstrual cycle prior to the 
Screening visit, throughout the study, and for 4 weeks after the last dose of study 
drug. 
• Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy. 
NOTE:  Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are 
not acceptable methods of contraception. 
10.2.5 
ADVERSE EVENT RECORDING  
Guidance on the identification, monitoring, and reporting of AEs is provided in 
Section 11.  
10.2.6 
IMMUNOGENICITY 
Blood samples for ADA assessment will be collected as specified in the Time and Events 
Tables (Table 1 and Table 2) in all enrolled subjects. These samples will be banked and 
used to investigate and characterize any ADA response over time in the general study 
population.  
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites. 
10.3 
EFFICACY ASSESSMENTS  
10.3.1 
QUANTITATIVE MYASTHENIA GRAVIS SCORE 
The primary efficacy endpoint is the change from baseline to Week 12 (Day 84) in QMG 
score. The QMG is a standardized and validated quantitative strength scoring system that 
was developed specifically for MG and has been used previously in clinical trials. Higher 
scores are representative of more severe impairment. Recent data suggest that 
improvements in the QMG score of 2 to 3 points may be considered clinically 
meaningful, depending upon disease severity [Barohn, 1998; Katzberg, 2014].  
QMG evaluators must be adequately trained prior to conducting any QMG score 
assessments. The QMG assessment will be performed at Screening to assess subject 
eligibility and at each study visit according to the Time and Events Tables (Table 1 and 
Table 2). The QMG assessment should be performed at approximately the same time of 
day (preferably in the morning) and administered by the same well-trained evaluator 
(e.g., neurologist, physical therapist, or other study staff) at each visit throughout the 
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study. If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at 
least 10 hours prior to the QMG test.  
Detailed instructions regarding the administration of the QMG test will be provided to 
sites.  
10.3.2 
OTHER EFFICACY ASSESSMENTS 
Efficacy assessments will also include an evaluation of the MG-ADL, MG-QOL15r, and 
MG Composite assessments. 
The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. 
Higher scores are associated with more severe symptoms of MG. The MG-ADL has been 
shown to correlate with other validated MG outcome measures (e.g., MG-QOL15r), and a 
2-point improvement in MG-ADL score is considered clinically meaningful 
[Wolfe, 1999; Muppidi, 2011].  
The MG-QOL15r is a 15-item survey that was designed to assess quality of life in 
patients with MG. Higher scores indicate more severe impact of the disease on aspects of 
the patient’s life [Burns, 2010; Burns, 2016].  
The MG Composite is a 10-item scale that has been used to measure the clinical status of 
patients with MG, both in the practice setting and in clinical trials, in order to evaluate 
treatment response. Higher scores in the MG Composite indicate more severe impairment 
due to the disease. A 3-point change in this instrument is considered clinically 
meaningful [Benatar, 2012; Sadjadi, 2012].  
Detailed instructions regarding the administration of these assessments will be provided 
to sites. 
10.4 
PHARMACOKINETIC ASSESSMENTS 
During the Main Portion of the study, blood samples for PK analysis will be collected 
from all subjects at the following time points:   
Day 1 
Day 84 
During Rescue Therapy* 
At sites where rescue 
therapy is administered 
locally 
At sites where rescue 
therapy is NOT 
administered locally 
predose  
(within 1 hour before first 
dose of study drug)  
predose  
(any time prior to Day 84 
study drug administration) 
Within 1 hour before 
administration of rescue 
therapy 
Prior to administration of 
the first course of rescue 
therapy 
1 hour postdose  
(± 30 minutes) 
1 hour postdose  
(± 30 minutes) 
For PLEX only: PK will 
be measured in the 
exchanged plasma 
After administration of the 
last course of rescue 
therapy 
3 hours postdose  
(± 30 minutes) 
 
Within 1 hour after 
administration of rescue 
therapy 
 
6 hours postdose  
(± 90 minutes) 
 
 
 
* See Appendix 1 for details on PK/PD sampling during Rescue Therapy 
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During the Extension Portion of the study, blood samples for PK analysis will be 
collected from all subjects at the following time points:   
During Rescue Therapy* 
Week E36 
(See Appendix 2) 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is 
NOT administered locally 
Within 1 hour before administration 
of rescue therapy 
Prior to administration of the first 
course of rescue therapy 
predose (within 1 hour before first 
dose of study drug)  
For PLEX only: PK will be 
measured in the exchanged plasma 
After administration of the last 
course of rescue therapy 
1 hour postdose (± 30 minutes) 
Within 1 hour after administration 
of rescue therapy 
 
3 hours postdose (± 30 minutes) 
 
 
6 hours postdose (± 90 minutes) 
* See Appendix 1 for details on PK/PD sampling during Rescue Therapy 
On all other study visit days, a single PK sample will be collected prior to administration 
of study drug. Plasma concentrations of RA101495 and its metabolites will be measured 
and reported in all subjects receiving active RA101495. All samples will be sent to a 
central laboratory for analysis. Detailed instructions regarding PK sample collection, 
processing, and shipping will be provided to sites. 
10.5 
PHARMACODYNAMIC ASSESSMENTS 
During the Main Portion of the study, blood samples for PD analysis will be collected 
from all subjects at the following time points:   
Day 1 
Day 84 
During Rescue Therapy* 
At sites where rescue 
therapy is administered 
locally 
At sites where rescue 
therapy is NOT 
administered locally 
predose  
(within 1 hour before first 
dose of study drug)  
predose  
(any time prior to Day 84 
study drug administration) 
Within 1 hour before 
administration of rescue 
therapy 
Prior to administration of 
the first course of rescue 
therapy 
1 hour postdose  
(± 30 minutes) 
1 hour postdose  
(± 30 minutes) 
 
 
3 hours postdose  
(± 30 minutes) 
 
Within 1 hour after 
administration of rescue 
therapy 
After administration of the 
last course of rescue 
therapy 
6 hours postdose  
(± 90 minutes) 
 
 
 
* See Appendix 1 for details on PK/PD sampling during Rescue Therapy 
During the Extension Portion of the study, blood samples for PD analysis will be 
collected from all subjects at the following time points:   
During Rescue Therapy* 
(ONLY through Day 167 visit) 
Week E36 
(See Appendix 2) 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is 
NOT administered locally 
Within 1 hour before administration 
of rescue therapy 
Prior to administration of the first 
course of rescue therapy 
predose (within 1 hour before first 
dose of study drug)  
For PLEX only: PK will be 
measured in the exchanged plasma 
After administration of the last 
course of rescue therapy 
1 hour postdose (± 30 minutes) 
Within 1 hour after administration 
of rescue therapy 
 
3 hours postdose (± 30 minutes) 
 
 
6 hours postdose (± 90 minutes) 
* See Appendix 1 for details on PK/PD sampling during Rescue Therapy 
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On all other study visit days, a single PD sample will be collected prior to administration 
of study drug. All samples will be sent to a central laboratory for analysis. Detailed 
instructions regarding PD sample collection, processing, and shipping will be provided to 
sites. 
10.6 
EXPLORATORY ASSESSMENTS  
10.6.1 
BIOMARKERS 
Blood samples for analysis of biomarkers will be collected at the following time points 
on Day 1: (i) predose (within 1 hour before first dose administration of study drug) and 
(ii) 6 hours postdose (± 90 minutes).  
At all other study visits, biomarker samples will be collected prior to the administration 
of study drug (Table 1 and Table 2).  
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites.  
The analysis of biomarkers pertaining to the pathophysiology of MG [e.g., complement 
fixation, complement function, complement pathway proteins, autoantibody 
characterization (titer and immunoglobulin class), and inflammatory markers] may 
provide further insight into the clinical efficacy and safety of RA101495 in subjects with 
gMG. Complement protein levels and complement activity will be tested to evaluate 
response to RA101495 and to understand subject characteristics related to variations in 
response to drug. Markers of inflammation may be tested to assess correlation with 
complement function and clinical response to RA101495. A list of analytes will be 
created through review of the literature, ongoing clinical studies, and ongoing exploratory 
work and may be finalized after completion of the study.  
During the Extension Portion of the study, if a subject undergoes a thymectomy, 
lymphadenectomy, or other surgical excision in which a biopsy was obtained, a section of 
the biopsy may be sent for exploratory immunohistochemical and biomarker analysis 
provided the subject has given their consent. Processing and preservation of the tissue 
should be discussed with the Sponsor prior to the intervention if possible. 
The completion of these investigations may be conditional based on the results of this or 
other clinical studies, and samples may be selected for analysis on the basis of clinical 
outcome. The results of the biomarker analysis may be reported separately from the main 
clinical study report. 
10.6.2 
PHARMACOGENOMIC ASSESSMENTS 
Participation in the pharmacogenomic assessment is optional, and subjects must provide 
additional consent for the pharmacogenomic analysis. 
 
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For subjects who choose to participate in pharmacogenomics studies, a blood sample will 
be obtained at Screening. All genomic analyses will be performed at an accredited 
laboratory. Detailed instructions regarding sample collection, processing, and shipping 
will be provided to sites. 
Genomic studies [e.g., deoxyribonucleic acid (DNA) sequencing, DNA copy number 
analysis, and ribonucleic acid expression profiling], including exploration of whether 
specific genomic features correlate with response or resistance to study drug, may be 
performed. 
The completion of these investigations may be conditional based on the results of this or 
other clinical studies, and samples may be selected for analysis on the basis of clinical 
outcome. The results of the genomic investigations may be reported separately from the 
main clinical study report. 
11 
SAFETY REPORTING 
11.1 
DEFINITIONS 
11.1.1 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with study treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The following are not considered to be AEs despite requiring hospitalization: 
• Pre-existing conditions that, in the opinion of the investigator, did not worsen or 
progress during study participation 
• Routinely scheduled procedures or treatment 
• Elective procedures that were scheduled prior to study participation (i.e., signing of 
the ICF) 
All AEs should be appropriately recorded according to the instructions in Section 11.3. 
11.1.2 
SERIOUS ADVERSE EVENTS 
An SAE is any AE that: 
• Results in death 
• Is life-threatening (note that this refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe) 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
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An SAE may also be any other important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events include intensive treatment in an emergency room or at home 
for bronchospasm, hyperkalemia, or convulsions that do not result in a formal 
hospitalization. 
Elective hospitalizations that were scheduled prior to study participation (i.e., signing of 
the ICF) are not considered to be SAEs and should not be reported.  
11.1.3 
STOPPING RULES 
For all ≥ Grade 3 AEs that are considered related to study drug (except for hepatic and 
pancreatic AEs described in Section 11.1.3.1 and Section 11.1.3.2, respectively), study 
drug should be permanently discontinued. 
11.1.3.1 
MONITORING OF LIVER FUNCTION TESTS 
All subjects will be monitored for signs and symptoms of hepatic or biliary dysfunction. 
LFT parameters [alkaline phosphatase (ALP), ALT, AST, gamma-glutamyl transferase 
(GGT), and bilirubin] will be evaluated as part of the chemistry laboratory assessments 
performed at each study visit, as shown in Table 1 and Table 2 (see also Table 4 for a list 
of chemistry analytes). The following guidelines should be followed for all subjects 
during study participation: 
• Subjects with isolated ALT or AST elevation > 2 × ULN with no other explanation 
for the elevation(s):  contact the medical monitor to review the case details and 
determine whether or not the subject should continue study treatment. The subject 
should be monitored until the elevated enzymes return to ≤ 2 × ULN.  
• Subjects with isolated total bilirubin elevation > 2 × ULN with no other explanation 
for the elevation(s):  contact the medical monitor to review the case details and 
determine whether or not the subject should continue study treatment. The subject 
should be monitored until the total bilirubin returns to ≤ 2 × ULN. 
• Subjects with isolated ALT or AST elevations > 3 × ULN concurrently with total 
bilirubin elevation > 2 × ULN and a normal ALP with no other explanation for the 
elevation:  study drug should be permanently discontinued. The medical monitor 
should be contacted as soon as possible to review the case. The subject should be 
monitored until the elevated enzymes return to Grade 1 [National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03] or 
lower, and the total bilirubin is ≤ 2 × ULN.  
11.1.3.2 
MONITORING OF PANCREATIC ENZYMES 
Subjects will be monitored during the study for symptoms of pancreatitis or cholecystitis. 
Pancreatic enzymes (amylase and lipase) will be evaluated as part of the 
hematology/chemistry laboratory assessments performed at each study visit, as shown in 
Table 1 and Table 2 (see also Table 4 for a list of chemistry analytes). The following 
guidelines should be followed for all subjects during study participation: 
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• Subjects with elevations of amylase or lipase to NCI CTCAE (Version 4.03) Grade 3 
(> 2 × ULN):  study drug treatment should be interrupted. The subject should be 
monitored until amylase and/or lipase returns to Grade 1 or lower. The medical 
monitor should be contacted to review the case. 
• Subjects with elevations of amylase or lipase to NCI CTCAE (Version 4.03) Grade 4 
(> 5 × ULN):  study drug should be permanently discontinued. The subject should be 
monitored until amylase and/or lipase returns to Grade 1 or lower. The medical 
monitor should be contacted to review the case. 
11.1.3.3 
MONITORING OF SKIN AND ORAL MUCOSA 
Subjects should be monitored at each study visit for adverse events due to skin or oral 
lesions.  The medical monitor should be contacted to discuss any skin or oral lesions, 
regardless of causality, to determine whether the subject should interrupt or discontinue 
study treatment.  Study drug must be permanently discontinued in the event of any 
moderate or severe skin or oral lesions considered related to study drug (e.g., mucous 
membrane inflammation, oral ulceration, blistering, abrasions, and dermatitis). 
11.1.3.4 
INFECTION 
All subjects will be monitored at every study visit for signs and symptoms of Neisseria 
meningitidis infection.  
To reduce the risk of infection, all subjects must have documentation of prior Neisseria 
meningitidis vaccination (and booster, if appropriate) prior to study entry. All subjects 
who have not been previously vaccinated will be vaccinated against Neisseria 
meningitidis at least 14 days prior to the first dose of study drug on Day 1 and should 
have a booster vaccination as indicated by SOC.  
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled 
and reminded of the early signs and symptoms of Neisseria meningitidis infection. A 
patient safety card detailing the signs and symptoms of infection, with instructions to 
seek immediate medical attention, will be provided to each subject.  
Any subject receiving antibiotics for suspected Neisseria meningitidis infection should 
interrupt study drug administration until Neisseria meningitidis infection can be ruled out.  
If Neisseria meningitidis infection is confirmed the subject should permanently 
discontinue study drug. 
11.1.4 
MONITORING OF INJECTION SITE REACTIONS  
The investigator should assess the injection site (included as part of the physical 
examination) at each scheduled visit for: 
• Pain, tenderness, erythema, and induration severity (Table 5) 
o Erythema and induration:  record the maximum linear diameter  
• Blisters, ulceration, necrosis:  record the maximum linear diameter and severity 
• Lymphadenopathy 
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In addition, the investigator will, whenever possible, take de-identified photos of the 
injection site reaction (ISR). 
Table 5 
Grading the Severity of Local Injection Site Reactions 
Local Reaction to 
Injectable Product 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life 
Threatening) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain reliever 
> 24 hours or interferes 
with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room 
visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant discomfort 
at rest 
Emergency room 
visit or 
hospitalization 
Erythema/ 
redness 
2.5 to 5.0 cm 
5.1 to 10.0 cm 
> 10.0 cm 
Necrosis or 
exfoliative dermatitis 
Induration/ 
swelling 
2.5 to 5.0 cm and does 
not interfere with 
activity 
5.1 to 10.0 cm or 
interferes with activity 
> 10.0 cm or prevents 
daily activity 
Necrosis 
11.2 
EVALUATION AND CLASSIFICATIONS 
11.2.1 
SEVERITY 
The investigator should determine the severity of the reported AE by using the NCI 
CTCAE (Version 4.03).  
For any reported AE not described in the NCI CTCAE, the following guidelines must be 
considered for severity evaluation: 
Adverse Event Severity 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s). 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
11.2.2 
CAUSALITY 
The causal relationship of the AE to study drug will be assessed by both the investigator 
and the Sponsor. The assessment of causal relationship to study drug should be evidence-
based, and not based on the premise that all AEs are causally related to study drug until 
proven otherwise. Default categorization of ‘related’ without supportive evidence for a 
causal relationship to study drug is generally uninformative, and does not contribute to 
understanding of the safety profile of the drug with respect to the intended population. 
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Examples of evidence that would suggest a causal relationship between the study drug 
and the AE include the occurrence of an AE that is known to be strongly associated with 
drug exposure (e.g., ISR) or an AE that is otherwise uncommon in the study population. 
Lack of efficacy of study drug, in isolation, leading to unmasking of underlying 
symptoms and signs of disease, should not be considered evidence of relatedness. 
The causal relationship of each AE is assessed using a binary system, with all AEs 
classified as either ‘related’ or ‘not related’. 
Related:  There is ‘reasonable possibility’ that the study drug caused the AE. The AE 
follows a reasonable temporal association from the time of study drug administration. 
There is supportive evidence to suggest a possible causal relationship, irrespective of the 
degree of certainty, between the observed AE and the study drug. There is no alternative 
more likely explanation for the AE. Lack of study drug efficacy is not considered, by 
itself, to be evidence of relatedness.  
Not Related:  Lack of a reasonable temporal or causal association from the 
administration of the study drug and the occurrence of the AE. There is evidence of an 
alternative explanation that is more likely the cause of the AE. 
11.3 
RECORDING, REPORTING, AND MONITORING 
11.3.1 
RECORDING AND REPORTING 
The investigator must make every effort to properly evaluate all information relevant to 
the reported AE in such a way that a diagnosis can be confidently made and reported. For 
example, it is preferable to report ‘pneumonia’ as the AE rather than its symptoms (e.g., 
‘rales’ or ‘fever’) as separate AEs. 
When recording and/or reporting AEs or SAEs, the following elements must be included: 
• The fulfilled criteria for seriousness as presented in Section 11.1.2 
• The severity of the event as defined in Section 11.2.1 
• The relationship of the event to study treatment as defined in Section 11.2.2 
Actions taken in relation to the AE will be recorded as drug discontinued, drug 
interrupted, concomitant medication, other action (e.g., diagnostic testing), or no action. 
Any medication given to treat the AE will be recorded separately in the concomitant 
medication list of the eCRF. 
The outcome of the AE will be recorded as date ended, ongoing, or resulting in death 
with date of death. 
11.3.1.1 
ADVERSE EVENTS 
Pre-existing conditions that are detected prior to administration of the first dose of study 
drug will be recorded as part of the medical history. For all subjects, the AE reporting 
period will start with the first administration of study drug on Day 1 and will end with the 
last study visit (i.e., End of Study Visit, Day 84 visit, or Final Study Visit), after which no 
new non-serious AEs are to be reported. The subjects will be monitored throughout the 
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study for any AEs, including clinically significant findings at vital signs measurements, 
spontaneous reports by study subjects, and observations by the study personnel. 
When possible, ongoing AEs assessed as related to the study drug will be followed until 
resolved or stabilized. Sites will call subjects 40 days after their last dose to gather 
information on ongoing AEs and report any new SAEs since the last study visit (see 
Section 11.3.1.2 for SAE reporting instructions). This Safety Follow-up Call will only be 
required for subjects who choose not to participate in the Extension Portion of the study. 
All AEs will be recorded in the eCRF. The investigator will assess and record any AE in 
detail including the date and time of onset, event diagnosis (if known) or sign/symptom, 
severity, time course (end date or ongoing), relationship of the AE to study drug, and 
action(s) taken. All AEs should be reported separately (i.e., 1 record per event). 
Reporting of AEs is event-based (i.e., an ongoing event will not be closed until resolved 
or at the end of study). For the AE description, a diagnosis is preferred over symptoms. If 
no diagnosis can be made, each symptom will be reported as a separate AE. 
Abbreviations should be avoided. Descriptive words should be used for ongoing 
conditions as applicable (e.g., 
).  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA; 
Version 18.0 or higher) after the eCRFs have been monitored and signed by the 
investigator. 
11.3.1.2 
SERIOUS ADVERSE EVENTS 
Any SAE experienced by the subject from signing the ICF through to 40 days after the 
last dose of study drug, regardless of severity or causality, must be recorded on the eCRF 
and SAE forms. Sites will call subjects 40 days after their last dose to gather information 
on ongoing AEs and report any new SAEs since the last study visit. This Safety Follow-
up Call will only be required for subjects who do not participate in the Extension Portion. 
The study site must formally notify the Sponsor (or delegate) of the SAE within 24 hours 
from the time the study site becomes aware of the SAE. A formal notification must be 
submitted to the Sponsor regardless of the following: 
• Severity 
• Causality 
• Whether or not the subject received study treatment or underwent study related 
procedures  
The IRB/IEC will be notified as required by local regulations. The investigator will be 
responsible for submitting the required safety information to the appropriate IRB/IEC, 
including any safety reports received from the Sponsor as well as any SAEs occurring at 
his/her site.  
The Sponsor, or designee, will prepare any required safety reports for Competent 
Regulatory Authorities and all active investigators. These reports will be provided as 
addenda to the IB, and the investigator will place these with the IB. All Competent 
Regulatory Authorities will be informed as per applicable legislation.  
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11.3.1.3 
DEATH 
Any event with an outcome of death should be appropriately recorded in the eCRF. All 
identified causes of death, including an assessment of the possible relationship of each to 
study treatment, must be reported as SAEs as outlined in Section 11.3.1.2. Any autopsy 
or other postmortem findings (including a coroner’s report) should be provided if 
available. 
11.3.1.4 
ABNORMAL LABORATORY VALUES 
All central laboratory data generated during the study will be included in standard 
Statistical Analysis System (SAS) datasets. Throughout this study, subjects will have 
samples sent to local laboratories and to the central laboratory. Only the values from the 
central laboratory will be captured in the database and used for the safety analysis. 
Investigators may report AEs based upon local laboratory values, if clinically relevant. In 
this event, the actual value and the normal range for the local laboratory should be 
recorded on the AE eCRF. 
11.3.2 
SAFETY MONITORING 
All AEs should be monitored by the investigator until resolution or stabilization.  
11.3.2.1 
SAFETY MONITORING COMMITTEE 
The safety of study subjects will be monitored throughout the study on an ongoing basis. 
Given the double blind, placebo-controlled design of Study RA101495.02.201, this 
standard safety data review will be performed while blinded to treatment assignment.  
If an unblinded data review should become necessary to ensure subject safety, a separate 
SMC will convene and evaluate study data as appropriate. To ensure the scientific 
integrity of the study, members of the SMC will not be directly involved in management 
of the study.  
11.3.2.2 
POST-STUDY EVENTS 
Any SAE that was continuing at the time of subject discontinuation or study completion 
should be monitored by the investigator until resolution or stabilization. 
SAEs that occur within 40 days after the subject discontinues from or completes the study 
should be reported using the same procedures outlined in Section 11.3.1.2. These SAEs 
should be recorded in the eCRF. Sites will call subjects 40 days after their last dose of 
study drug to gather information on ongoing AEs and report any new SAEs since the last 
study visit (see Section 11.3.1.2 for SAE reporting instructions). This Safety Follow-up 
Call will only be required for subjects who do not participate in the Extension Portion. 
11.3.3 
EMERGENCY UNBLINDING DURING THE BLINDED PORTION 
The study drug treatment assignment may be unblinded only in emergency situations 
when knowledge of the treatment assignment is considered absolutely necessary for 
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medical management of the subject or for clinical decision-making (i.e., when knowledge 
of the treatment assignment would impact a treatment decision). The investigator will 
have unrestricted and immediate access to unblind the treatment code in the IXRS. The 
instructions for unblinding a subject in the IXRS can be found in the IXRS User Guide. 
In the event unblinding is necessary, the investigator is strongly encouraged, but not 
required, to contact the appropriate medical monitor to discuss the situation and the 
subject’s medical status prior to unblinding. 
When a subject’s treatment assignment is unblinded, a comprehensive source note must 
be completed by the unblinding investigator that includes the date and time and the 
reason(s) the subject’s treatment code was unblinded. In the event the investigator 
chooses to discuss the unblinding with the medical monitor, the source note must also 
include a record of the discussion.  
It is mandatory that all personnel who are involved in the unblinding and who have 
access to the unblinded treatment assignment information maintain the confidentiality of 
the information by not divulging the treatment assignment. 
Following emergency unblinding, the subject’s further participation in the study should 
be discussed with the medical monitor. 
11.4 
SPECIAL CIRCUMSTANCES 
11.4.1 
PREGNANCY 
Subjects and their partners should avoid pregnancy throughout the course of the study. 
Pregnancy in a study subject or partner must be reported to the Sponsor within 24 hours 
of the study site becoming aware of the pregnancy. Subjects with a positive pregnancy 
test before study drug dosing must not be dosed. 
Information regarding a pregnancy occurrence in a study subject or partner and the 
outcome of the pregnancy will be collected. 
Pregnancy in a study subject or partner is not, in itself, considered an AE. However, the 
medical outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly 
is considered an SAE and must be reported to the Sponsor within 24 hours of the site 
becoming aware of the event. The procedure of elective abortion should not be reported 
as an AE.  
11.4.2 
OTHER 
Certain safety events, called ‘Special Situations’, that occur in association with study 
drug(s) may require reporting. These Special Situations include, but are not limited to, the 
following: 
• Overdose of the medicinal product, where ‘overdose’ is defined as a subject receiving 
more than 1.5 times the intended dose for any given SC injection 
• Suspected abuse/misuse of the medicinal product 
• Inadvertent or accidental exposure to the medicinal product 
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• Medication error involving study drug (with or without subject exposure to the 
Sponsor’s medicinal product, e.g., name confusion) 
Special situations should be reported on the Special Situations form whether they result 
in an AE/SAE or not. Special Situations associated with an AE/SAE should also be 
reported on the corresponding AE/SAE forms. 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
ANALYSIS POPULATIONS 
12.1.1 
INTENTION-TO-TREAT POPULATION 
The Intention-to-Treat (ITT) Population will include all randomized subjects.  
12.1.2 
MODIFIED ITT POPULATION 
The modified ITT (mITT) Population will include all subjects in the ITT Population who 
have received at least 1 dose of study drug.  
12.1.3 
PER PROTOCOL POPULATION 
The Per Protocol Population will include all subjects in the mITT Population who have 
completed the 12-week Treatment Period and have no major protocol violations. 
12.1.4 
SAFETY POPULATION 
The Safety Population will include all subjects who have received at least 1 dose of study 
drug (i.e., mITT Population), with subjects to be analyzed based on the actual treatment 
received. 
12.1.5 
PHARMACOKINETIC POPULATION 
The PK Population will include all subjects in mITT Population who have at least 
1 evaluable PK assessment. All PK analyses will be performed using this population.  
12.1.6 
PHARMACODYNAMIC POPULATION 
The PD Population will include all subjects in mITT Population who have at least 
1 evaluable PD assessment. All PD analyses will be performed using this population.  
12.2 
ANALYSIS METHODS 
12.2.1 
GENERAL METHODS 
Details of the statistical analysis methodology will be provided in a statistical analysis 
plan (SAP), which will be finalized prior to study unblinding. 
Continuous variables will be summarized using the number of observations, number of 
observations above the limit of quantification (if applicable), mean, standard deviation 
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(SD) median, and range. Categorical variables will be summarized using frequency 
counts and percentages. 
Once all patients have completed the Main Portion of the study, the study database will 
be locked, unblinded, and efficacy analyses for the Main Portion will be performed. 
12.2.2 
SUBJECT DISPOSITION 
Disposition of all consented subjects will be provided overall and by treatment group. 
This will include a breakdown of subjects who consented, were randomized, were 
treated, discontinued treatment, and were lost to follow-up, or withdrew consent. 
Additionally, a summary of subjects included in the analysis populations defined in 
Section 12.1 will be provided. 
12.2.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS 
Quantitative variables will be summarized using mean, median, and range. Categorical 
variables will be summarized using counts and proportions. 
12.2.4 
SAFETY ANALYSIS 
Safety analyses will be performed on the Safety Population. 
12.2.4.1 
ADVERSE EVENTS 
AEs will be coded using the MedDRA (Version 18.0 or higher). 
For each treatment group, incidence rates for TEAEs will be summarized overall, by 
maximum severity, and by relationship to study drug. SAEs will also be summarized by 
treatment group. A TEAE is defined as: 
• An AE that occurs after study treatment start that was not present at the time of 
treatment start. 
• An AE that increases in severity after treatment start, if the event was present at the 
time of treatment start. 
AEs occurring before the first dose of study drug will be summarized separately. 
12.2.4.1.1 
HEPATIC ADVERSE EVENTS 
Hepatic and biliary AEs will be summarized by treatment group, system organ class, and 
preferred term. LFT laboratory values will be summarized by changes from baseline and 
graded in severity using the NCI CTCAE criteria. 
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12.2.4.1.2 
PANCREATIC ENZYME ELEVATIONS 
Pancreatic AEs will be summarized by treatment group, system organ class, and preferred 
term. Elevations in pancreatic function parameters will be summarized by changes from 
baseline and graded in severity using the NCI CTCAE criteria. 
12.2.4.1.3 
INJECTION SITE REACTIONS 
ISRs will be summarized by treatment group, system organ class, and preferred term. The 
summary will include additional details on these events as described in Section 11.1.4. 
12.2.4.1.4 
INFECTION 
AEs related to infection with Neisseria meningitidis will be summarized by system organ 
class and preferred term. 
12.2.4.2 
CLINICAL LABORATORY EVALUATION 
Quantitative laboratory endpoints will be summarized by treatment group at each 
scheduled assessment time point using descriptive statistics. 
12.2.4.3 
ELECTROCARDIOGRAMS 
Descriptive statistics for ECG parameters [i.e., HR, PR interval, RR interval, QRS 
interval, QT interval, QT interval corrected by Bazett’s formula (QTcB), and QT interval 
corrected by Fridericia’s formula (QTcF)] at each assessment time point will be presented 
by treatment group.  
12.2.4.4 
VITAL SIGNS 
Descriptive statistics for vital signs (i.e., HR, body temperature, and blood pressure) will 
be presented by treatment group. 
12.2.4.5 
PHYSICAL EXAMINATION 
The complete set of physical examination findings will be provided in listings. Clinically 
significant physical examination abnormalities will be included and summarized as AEs, 
when appropriate. 
12.2.5 
EFFICACY ANALYSIS 
Additional efficacy endpoints and analyses beyond what is specified in this protocol may 
be identified in the SAP.  
Unless otherwise specified, if a subject receives rescue therapy (as defined in Section 
10.1.3.1), efficacy endpoints occurring after rescue therapy will be imputed using last 
observation carried forward (LOCF) methodology using the closest non-missing endpoint 
value prior to the initiation of rescue therapy. 
12.2.5.1 
PRIMARY EFFICACY ANALYSIS 
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For the primary efficacy endpoint, the change from baseline to Week 12 (Day 84) in 
QMG score, treatment group differences will be assessed by an Analysis of Covariance 
(ANCOVA) model, with treatment as a factor and baseline QMG score as a covariate.  
The primary efficacy analysis will be the comparison of the 0.3 mg/kg dose group versus 
the placebo dose group based on the ANCOVA model at a 1-sided 0.10 significance 
level.  
The comparison of the 0.1 mg/kg dose group versus the placebo dose group will be a 
secondary efficacy analysis tested at the 1-sided 0.10 level. A test of linear trend for the 
across the 3 treatment groups will also be performed. 
12.2.5.2 
SECONDARY ENDPOINT ANALYSES 
The secondary efficacy endpoints: Week 12 change from baseline in MG-ADL, 
MG-QOL15r, and MG Composite will be analyzed by an ANCOVA model similar to the 
primary efficacy endpoint analysis, with treatment as a factor and the corresponding 
baseline value as a covariate. Each of the active doses will be compared to the placebo 
group based on the ANCOVA model at the 1-sided 0.10 level. 
For the ‘Subjects with ≥ 3-point reduction in QMG score at Week 12’ and ‘Subjects 
requiring rescue therapy over the 12-week Treatment Period’ secondary efficacy 
endpoints, the rate of subjects meeting the endpoint for each of the active treatment 
groups will be compared to the placebo group using a Fisher’s exact test at the 1-sided 
0.10 level.   
12.2.6 
CLINICAL PHARMACOLOGY ANALYSIS 
12.2.6.1 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Drug exposure will be evaluated using PK parameters derived from non-compartmental 
methods. All calculations for the final analysis will be based on actual sampling times. 
Individual PK parameters will be presented in listings and summarized using descriptive 
statistics. 
Pharmacodynamic endpoints will be summarized using descriptive statistics by treatment 
and nominal time point. 
Pharmacokinetic and pharmacodynamic assessments in subjects undergoing rescue 
treatment will be analyzed separately, as appropriate. 
12.2.7 
INTERIM ANALYSIS 
No interim analysis is planned for the Main Portion of the study. Interim analyses during 
the Extension Portion of the study may be performed. 
12.3 
SAMPLE SIZE DETERMINATION 
For the primary efficacy endpoint, change from baseline to Week 12 (Day 84) in QMG 
score, assuming a difference in treatment group means of 4.5, an SD of 5.0, and 
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12 subjects per group, the study has approximately 81% power to detect a difference 
between an active and placebo treatment group based on a 1-sided t-test with a 0.10 type 
I error rate. 
13 
ETHICAL CONSIDERATIONS 
This study shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice 
(GCP) and applicable regulatory requirement(s).  
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
COMMUNICATIONS 
Prior to study initiation, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol, written ICF, consent 
form updates, subject recruitment procedures (e.g., advertisements), and any other written 
information to be provided to subjects. A current copy of the IB must be provided to the 
IRB/IEC as part of the written application. During the study, the investigator/institution 
should provide to the IRB/IEC all documents subject for review. 
13.1.1 
PROGRESS REPORTS 
The investigator should submit written summaries of the study status to the IRB/IEC 
annually, or more frequently, if requested by the IRB/IEC. 
13.1.2 
FINAL INVESTIGATOR REPORT 
Upon completion of the study, the investigator/institution should provide a summary of 
the study’s outcome to the IRB/IEC and the regulatory authorities with any required 
reports. 
13.2 
INFORMED CONSENT OF STUDY SUBJECTS 
In obtaining and documenting informed consent, the investigator must comply with the 
applicable regulatory requirement(s) and adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  
The written ICF and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to 
the subject’s consent. Any revised written ICF and written information should receive the 
IRB/IEC’s approval/favorable opinion in advance of use. The subject or the subject’s 
legally acceptable representative will be informed in a timely manner if new information 
becomes available that may be relevant to the subject’s willingness to continue 
participation in the study. The communication of this information should be documented. 
The investigator will fully inform the subject or the subject’s legally acceptable 
representative of all pertinent aspects of the study, including the written information and 
the approval/favorable opinion by the IRB/IEC. Before informed consent may be 
obtained, the investigator should provide the subject or the subject’s legally acceptable 
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representative ample time and opportunity to inquire about details of the study and to 
decide whether or not to participate in the study. All questions about the study should be 
answered to the satisfaction of the subject or the subject’s legally acceptable 
representative.  
Prior to a subject’s participation in the study, the written ICF must be signed and 
personally dated by the subject or by the subject’s legally acceptable representative and 
by the person who conducted the informed consent discussion. If a subject is unable to 
read or if a legally acceptable representative is unable to read, an impartial witness will 
be present during the entire informed consent discussion. 
Prior to participation in the study, the subject or the subject’s legally acceptable 
representative will receive a copy of the signed and dated written ICF and any other 
written information provided to the subjects. During a subject’s participation in the study, 
the subject or the subject’s legally acceptable representative will receive a copy of the 
signed and dated consent form updates and a copy of any amendments to the written 
information provided to subjects. 
Subjects will provide additional consent to participate in optional pharmacogenomic 
testing. 
13.3 
PROTOCOL COMPLIANCE 
The investigator/institution will conduct the study in compliance with the protocol agreed 
to by the Sponsor and regulatory authorities (if required) and which was given 
approval/favorable opinion by the IRB/IEC. The investigator/institution and the Sponsor 
should sign the protocol, or an alternative contract, to confirm agreement. 
The investigator should not implement any deviation from, or changes to, the protocol 
without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate 
immediate hazard(s) to study subjects or when the change involves only logistical or 
administrative aspects of the study (e.g., change in monitor, change of telephone 
number). When an important deviation from the protocol is deemed necessary for an 
individual subject, the investigator must contact the medical monitor for the study. 
Such contact must be made as soon as possible to permit a review by the Sponsor to 
determine the impact of the deviation on the subject’s participation and/or the assessment 
of safety or efficacy in the study. Any significant protocol deviations affecting subject 
eligibility and/or safety must be reviewed and/or approved by the IRB/IEC and regulatory 
authorities, as applicable, prior to implementation. 
The investigator should document and explain any deviation from the approved protocol.  
13.4 
PROTECTION OF CONFIDENTIALITY 
Prior to study participation, the investigator shall inform the subject or the subject’s 
legally acceptable representative that the monitor(s), auditor(s), IRB/IEC, and the 
regulatory authorities will be granted direct access to the subject’s original medical 
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records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations and that, by signing a written ICF, the subject or the subject’s legally 
acceptable representative is authorizing such access.  
In addition, prior to study participation, the subject must be informed that the records 
identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available; if the results of 
the study are published, the subject’s identity will remain confidential. 
13.5 
DISCLOSURE OF STUDY RESULTS 
The Sponsor will post the results of the study in a publicly accessible database in 
accordance with the applicable laws and regulations. 
14 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS 
14.1 
QUALITY ASSURANCE 
Quality assurance and quality control systems shall be implemented and maintained with 
written standard operating procedures (SOPs) to ensure that the study is conducted and 
data are generated, documented (recorded), and reported in compliance with the protocol, 
GCP, and the applicable regulatory requirement(s). Quality control shall be applied to 
each stage of data handling to ensure that all data are reliable and have been processed 
correctly. 
An agreement must be secured from all involved parties to ensure direct access to all 
study related sites, source documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and of inspection by regulatory authorities. 
14.1.1 
MONITORING 
On-site monitoring visits will be conducted before, at regular intervals during, and after 
the study, as appropriate, by Sponsor-approved monitors. At a minimum, the accuracy 
and completeness of the eCRF entries, source documents, and other study-related records 
will be checked against one another during these visits. After each monitoring visit, a 
report of any significant findings/facts, deviations, and deficiencies will be 
communicated to the investigator. The actions taken to address the findings and secure 
compliance should be documented.  
14.1.2 
AUDIT 
An audit may be performed independently of, and separately from, routine monitoring to 
evaluate clinical study conduct and compliance with the protocol, SOPs, GCP, and the 
applicable regulatory requirements.  
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14.2 
CLINICAL RESEARCH ORGANIZATIONS  
A Clinical Research Organization (CRO) will be utilized to assist in the conduct of this 
study. Accredited central laboratories will be used for the analysis of safety laboratory 
samples and for the bioanalytical testing of PK samples.  
14.3 
DATA MANAGEMENT 
14.3.1 
CASE REPORT FORMS 
eCRFs must be completed for each subject screened/enrolled in this study. These forms 
will be used to transmit information collected during the study to the Sponsor and 
regulatory authorities, as applicable. The data for this study are being collected with an 
eCRF. The documentation related to the validation of the eCRFs will be maintained in 
the Trial Master File (TMF). The TMF will be maintained by the CRO and the Sponsor. 
The investigator will document subject data in his/her own subject files. These subject 
files will serve as source data for the study. All eCRF data required by this protocol will 
be recorded by investigative site personnel. All data entered into the eCRF will be 
supported by source documentation. 
The investigator or an authorized member of the investigator’s staff will make any 
necessary corrections to the eCRF. All change information, including the date and person 
performing the corrections, will be available via the audit trail, which will be part of the 
electronic data capture system. For any correction, a reason for the alteration will be 
provided. The eCRFs will be reviewed periodically for completeness and acceptability by 
Sponsor personnel (or their representatives). The Sponsor (or their representatives) will 
also be allowed access to all source documents pertinent to the study in order to verify 
eCRF entries. The investigator will review the eCRFs for completeness and accuracy and 
provide his or her electronic signature and date to eCRFs as evidence thereof. 
Access to the electronic data capture system will be password-protected and will be 
removed from the study site at the end of the site’s participation in the study. Data from 
the eCRF will be archived on appropriate data media and provided to the investigator at 
that time as a durable record of the site’s eCRF data. It will be possible for the 
investigator to make paper printouts from that media. 
14.3.2 
SOURCE DOCUMENTS 
Source documents are defined as original documents, data, and records. These may 
include hospital records, clinical and office charts, laboratory data/information, subjects’ 
diaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, ECGs, X-rays, ultrasounds, angiograms, venograms, computed tomography scans, 
and/or magnetic resonance imaging scans. Data collected during this study must be 
recorded on the appropriate source documents. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC 
review, and regulatory inspection(s), providing direct access to source data documents. 
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14.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY 
If the Sponsor terminates or suspends the study, the investigator/institution should 
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of 
the termination or suspension. If the IRB/IEC terminates or suspends its 
approval/favorable opinion of the study, the investigator/institution should promptly 
notify the Sponsor and provide the Sponsor with a detailed written explanation of the 
termination or suspension. 
14.5 
CLINICAL STUDY REPORT 
Whether the study is completed or prematurely terminated, the clinical study report will 
be prepared and provided to the regulatory agencies as required by the applicable 
regulatory requirement(s). 
14.6 
PUBLICATION POLICY 
The publication policy is outlined in the Clinical Trial Agreement. The data generated in 
this clinical trial are the exclusive property of Ra Pharmaceuticals, Inc. and are 
confidential. Written approval from Ra Pharmaceuticals, Inc.is required prior to 
disclosing any information related to this clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
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15 
REFERENCES 
Alexion Pharmaceuticals. Safety and Efficacy of Eculizumab in Refractory Generalized 
Myasthenia Gravis (REGAIN Study). In:  ClinicalTrials.gov [Internet]. Bethesda (MD):  
National Library of Medicine (US). [cited 2017 March 15]. Available from:  
https://clinicaltrials.gov/ct2/show/study/NCT01997229?term=NCT01997229&rank=1. 
NLM Identifier:  NCT01997229. 
Alexion Pharmaceuticals. (07 July 2016). New Data from Phase 3 REGAIN Study of 
Eculizumab (Soliris®) in Patients with Refractory Generalized Myasthenia Gravis (gMG) 
Presented at ICNMD Annual Congress. [Press release]. Retrieved from:  
http://news.alexionpharma.com/press-release/product-news/new-data-phase-3-regain-
study-eculizumab-soliris-patients-refractory-gene. Accessed:  15 March 2017. 
Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing 
of the quantitative myasthenia gravis score. Ann N Y Acad Sci. 1998;841:769-772. 
Benatar M, Sanders DB, Burns TM, Cutter GR, Guptill JT, Baggi F, et al; Task Force on 
MG Study Design of the Medical Scientific Advisory Board of the Myasthenia Gravis 
Foundation of America. Recommendations for myasthenia gravis clinical trials. Muscle 
Nerve. 2012;45(6):909-917. 
Burns, TM, Grouse CK, Conway MR, Sanders DB, and MG Composite and MG-QOL 15 
study group. Construct and concurrent validation of the MG-QOL 15 in the practice 
setting. Muscle Nerve. 2010;41(2):219-226. 
Burns TM, Sadjadi R, Utsugisawa K, Gwathmey KG, Joshi A, Jones S, et al.International 
clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent 
validation of the MG-QOL15r. Muscle Nerve. 2016;54(6):1015-1022. 
Gilhus NE. Myasthenia gravis:  subgroup classification and therapeutic strategies. Lancet 
Neurol. 2015;14(10):1023-1036. 
Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;37(26):2570-2581. 
Howard JF, Barohn RJ, Cutter GR, Freimer M, Juel VC, Mozaffar T, et al. A 
randomized, double-blind, placebo-controlled Phase II study of eculizumab in patients 
with refractory generalized myasthenia gravis. Muscle Nerve. 2013;48(1):76-84. 
Howard JF. Myasthenia Gravis Foundation of America. Clinical Overview of MG. 
Available from:  
http://www.myasthenia.org/HealthProfessionals/ClinicalOverviewofMG.aspx. Accessed:  
28 February 2017.  
Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference in 
myasthenia gravis:  outcomes from a randomized trial. Muscle Nerve. 
2014;49(5):661-665. 
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Kusner LL, Kaminski HJ. The role of complement in experimental autoimmune 
myasthenia gravis. Ann N Y Acad Sci. 2012;1274(1):127-132.  
Muppidi S, Wolfe GI, Conaway M, Burns TM; MG Composite and MG-QOL15 study 
group. MG ADL:  still a relevant outcome measure. Muscle Nerve. 2011;44(5):727-731. 
Ramizuddin MK. Review on:  Myasthenia gravis and telithromycin-myasthenia crisis. 
IOSR J Dent Med Sci. 2014;13(7):67-97. 
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;45(6):820-825. 
Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International 
consensus guidance for management of myasthenia gravis. Neurology. 2016;87(4):419-
425. 
Vissing J, J. S. (2018). 'Minimal Symptom Expression' with Eculizumab in Myasthenia 
Gravis. AANEM. Washington, DC. 
Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis 
activities of daily living profile. Neurology. 1999;52(7):1487-1489. 
Wolfe GI, Kaminski IB, Minisman G, Kuo H-C, Marx A, Strobel P, et al. Randomized 
trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-522.  
 
 
 
 
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16 
APPENDIX 1: RESCUE THERAPY PK/PD SAMPLING 
Blood samples for PK and PD analysis will be obtained at the following time points 
during rescue therapy: 
 
 
NOTE: On days when rescue therapy is concurrently administered, study drug dosing 
should be held until after administration of rescue therapy and PK/PD sampling 
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17 
APPENDIX 2: EXTENSION PORTION VISITS AFTER DAY E84 
Table 6 
EXTENSION PORTION: Time and Events after Day E84 through Week E36 
Nominal Visit relative to 
Main Portion 
Week 28 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nominal Visit on  
Extension Portion 
Week E16 
(± 7 days) 
Week E20 
(± 7 days) 
Week E24 
(± 7 days) 
Week E28 
(± 7 days) 
Week E32 
(± 7 days) 
Week E36 
(± 7 days) 
 
Rescue 
Therapy Visita  
(if applicable) 
 
Final Study 
Visitb 
Study Procedure 
 
 
Weight 
 
 
X 
 
 
X 
 
 
 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
Physical examination (symptom directed) 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signsc 
 
 
X 
 
 
X 
 
X 
 
X 
12-Lead electrocardiogram 
 
 
 
 
 
X 
 
X 
 
X 
Neisseria meningitidis vaccinationd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
 
 
 
 
Hematology/Chemistrye 
 
 
X 
 
 
X 
 
X 
 
X 
Coagulationf 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
 
 
X 
 
 
X 
 
X 
 
X 
Pregnancy testg 
 
 
X 
 
 
X 
 
 
 
X 
Adverse eventsh 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Anti-drug antibody 
 
 
X 
  
 
X 
 
X 
 
X 
Efficacym 
 
 
 
 
 
 
 
 
 
 
QMG Test/Scorei 
 
 
X 
 
 
X 
 
X 
 
X 
MG-ADL 
 
 
X 
 
 
X 
 
X 
 
X 
MG-QOL15r 
 
 
X 
 
 
X 
 
X 
 
X 
MG Composite 
 
 
X 
 
 
X 
 
X 
 
X 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
RA101495 plasma PKj 
 
 
X 
  
 
Xj 
 
Xj 
 
X 
Pharmacodynamic analysisj 
 
 
X 
  
 
Xj 
 
Xj 
 
X 
Exploratory 
 
 
 
 
 
 
 
 
 
 
Additional biomarker samplesk 
 
 
X 
  
 
X 
 
 
 
X 
Study Drug 
 
 
 
 
 
 
 
 
 
 
RA101495 administrationl 
X 
X 
Xl 
X 
X 
Xl 
 
Xl 
 
Xl 
See footnotes on following page. 
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6-a. For subjects who require rescue therapy (see Section 10.1.3.1), a Rescue Therapy Visit should be conducted prior to the initiation of rescue therapy. If the Rescue Therapy Visit 
coincides with a regularly scheduled study visit, then overlapping study procedures do not need to be duplicated.  
6-b. If a subject discontinues study drug treatment at any time during the Extension Period, the subject should return to clinic for a Final Study Visit. 
6-c. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
6-d. During the Extension Portion, all subjects should have Neisseria meningitidis booster vaccinations as indicated by SOC. Subjects should bring their patient safety card to every 
study visit. If the subject does not bring their card with them they will be given a new one. 
6-e. All laboratory samples should be obtained prior to administration of study drug at applicable visits unless otherwise noted for PK, PD, and biomarker samples.  
6-f. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
6-g. Urine pregnancy tests will be conducted in female subjects of childbearing potential.  
6-h. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the procedures 
outlined in the protocol.  
6-i. The assessment of QMG should be performed at approximately the same time of day (preferably in the morning) and administered by the same well-trained evaluator (e.g., 
neurologist, physical therapist, or other study staff) at each visit throughout the study. If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 
10 hours prior to the QMG test.  
6-j. Blood samples for PK and PD analysis will be obtained at the following time points: 
Week E36 
Approximately 1 year (48 weeks)  
after Day 1 
 
During Rescue Therapy  
 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is 
NOT administered locally 
predose (within 1 hour before study 
drug dosing)  
 
Within 1 hour before 
administration of rescue therapy 
Prior to administration of the first 
course of rescue therapy 
1 hour postdose (± 30 minutes) 
 
For PLEX only: PK will be 
measured in the exchanged 
plasma 
After administration of the last 
course of rescue therapy 
3 hours postdose (± 30 minutes) 
 
Within 1 hour after 
administration of rescue therapy 
 
6 hours postdose (± 90 minutes) 
 
 
 
 
On all other study visit days, PK/PD samples should be collected prior to administration of study drug. 
6-k. Biomarkers samples should be collected prior to administration of study drug. 
6-l. Dosing on study visit days should be held until QMG scoring, PK, and PD sample blood collection has been completed. On days when rescue therapy is concurrently administered, 
study drug dosing should be held until after administration of rescue therapy and PK/PD sampling. 
6-m. If a subject consents to the Open Label Portion of the study, the subject will be required to complete the QMG, MG-ADL, MG-QOL15r, and MGC assessments, even if their visit 
lands on a monthly visit. 
 
 
 
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Table 7 
EXTENSION PORTION: Time and Events for each year after Week E36 
The table below provides an example for a year’s visit schedule on the Extension Portion after Week E36.  
11 monthly visits (4-week months) followed by a yearly visit and will be repeated each year (48-week year) on the Extension Portion.  
After Week E84, subjects will return to the study site monthly for study drug dispensation. 
Nominal Visit relative to 
Main Portion 
Week 
52 
Week 
56 
Week 
60 
Week 
64 
Week 
68 
Week 
72 
Week 
76  
Week 
80 
Week 
84 
Week 
88 
Week 
92 
Week  
96 
 
 
 
 
 
 
 
 
 
 
 
 
Monthly Visits 
Yearly 
Visit 
 
 
 
 
Nominal Visit on  
Extension Portion 
Week E40 
(± 7 days) 
Week E44 
(± 7 days) 
Week E48 
(± 7 days) 
Week E52 
(± 7 days) 
Week E56 
(± 7 days) 
Week E60 
(± 7 days) 
Week E64 
(± 7 days) 
Week E68 
(± 7 days) 
Week E72 
(± 7 days) 
Week E76 
(± 7 days) 
Week E80 
(± 7 days) 
Week E84 
(± 7 days) 
 
Rescue 
Therapy 
Visita  
(if applicable) 
 
Final 
Study 
Visitb 
Study Procedure 
 
 
Weight 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (symptom directed) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Vital signsc 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
12-Lead electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Neisseria meningitidis vaccinationd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
SOCd 
 
 
 
 
Hematology/Chemistrye 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Coagulationf 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Urinalysis 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Pregnancy testg 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Adverse eventsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Anti-drug antibody 
 
 
 
  
 
 
 
 
 
 
 
X 
 
X 
 
X 
Efficacym 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QMG Test/Scorei 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
MG-ADL 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
MG-QOL15r 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
MG Composite 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RA101495 plasma PKj 
 
 
 
  
 
 
 
 
 
 
 
Xj 
 
Xj 
 
X 
Pharmacodynamic analysisj 
 
 
 
  
 
 
 
 
 
 
 
Xj 
 
Xj 
 
X 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional biomarker samplesk 
 
 
 
  
 
 
 
 
 
 
 
X 
 
 
 
X 
Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RA101495 administrationl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
 
Xl 
 
Xl 
See footnotes on following page. 
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RA101495  
Version 3.0 
Protocol RA101495-02.201 
10-Apr-2019 
CONFIDENTIAL 
 
Page 68 of 68 
7-a. For subjects who require rescue therapy (see Section 10.1.3.1), a Rescue Therapy Visit should be conducted prior to the initiation of rescue therapy. If the Rescue Therapy Visit 
coincides with a regularly scheduled study visit, then overlapping study procedures do not need to be duplicated.  
7-b. If a subject discontinues study drug treatment at any time during the Extension Period, the subject should return to clinic for a Final Study Visit. 
7-c. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
7-d. During the Extension Portion, all subjects should have Neisseria meningitidis booster vaccinations as indicated by SOC. Subjects should bring their patient safety card to every 
study visit. If the subject does not bring their card with them they will be given a new one. 
7-e. All laboratory samples should be obtained prior to administration of study drug at applicable visits unless otherwise noted for PK, PD, and biomarker samples.  
7-f. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
7-g. Urine pregnancy tests will be conducted in female subjects of childbearing potential.  
7-h. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the procedures 
outlined in the protocol.  
7-i. The assessment of QMG should be performed at approximately the same time of day (preferably in the morning) and administered by the same well-trained evaluator (e.g., 
neurologist, physical therapist, or other study staff) at each visit throughout the study. If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 
10 hours prior to the QMG test.  
7-j. Blood samples for PK and PD analysis will be obtained at the following time points: 
Yearly Visit 
(e.g., Week E84) 
 
During Rescue Therapy  
 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is 
NOT administered locally 
predose (within 1 hour before study 
drug dosing)  
 
Within 1 hour before 
administration of rescue therapy 
Prior to administration of the first 
course of rescue therapy 
 
 
For PLEX only: PK will be 
measured in the exchanged 
plasma 
After administration of the last 
course of rescue therapy 
 
 
Within 1 hour after 
administration of rescue therapy 
 
 
 
 
 
 
On all other study visit days, PK/PD samples should be collected prior to administration of study drug. 
7-k. Biomarkers samples should be collected prior to administration of study drug. 
7-l. Dosing on study visit days should be held until QMG scoring, PK, and PD sample blood collection has been completed. On days when rescue therapy is concurrently administered, 
study drug dosing should be held until after administration of rescue therapy and PK/PD sampling. 
7-m. If a subject consents to the Open Label Portion of the study, the subject will be required to complete the QMG, MG-ADL, MG-QOL15r, and MGC assessments, even if their visit 
lands on a monthly visit. 
 
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SAP_001.pdf: 
 
 
 
 
 
RA PHARMACEUTICALS, INC. 
 
 
STATISTICAL ANALYSIS PLAN  
 
 A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of 
RA101495 in Subjects with Generalized Myasthenia Gravis 
 
RA101495-02.201 
 
 
 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
 
 
Version 1.0 
 
05Nov2018 
 
Version 2.0 
 
05Mar2020 
 
 
 
 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 2 of 61 
 
SIGNATURE PAGE 
 
 
 
 
 
 
 
 
Date 
 
Prepared by: 
, PhD 
Senior Statistical Consultant 
 
 
 
 
 
 
 
 
 
Date 
 
Reviewed and Approved by:  
, MD 
Senior Director, Clinical Research  
Ra Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
Date 
 
Reviewed and Approved by:  
, MD FACC 
Chief Medical Officer, 
Ra Pharmaceuticals, Inc. 
 
 
 
 
 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 3 of 61 
 
DOCUMENT HISTORY 
 
Version 
Author 
Description 
1.0  
 
Original Version 
2.0 
 
Updated to include Extension Period analyses 
in appendix 
 
 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 4 of 61 
 
Table of Contents 
1 
INTRODUCTION .............................................................................................. 10 
2 
STUDY SUMMARY.......................................................................................... 10 
2.1 
STUDY OBJECTIVES ............................................................................. 10 
2.2 
STUDY DESIGN...................................................................................... 11 
2.2.1 
Number of Subjects............................................................................... 12 
2.2.2 
Randomization and Blinding Procedures .............................................. 12 
2.3 
Safety Assessments ................................................................................... 12 
2.3.1 
Physical Examination............................................................................ 13 
2.3.2 
Vital Signs ............................................................................................. 13 
2.3.3 
Electrocardiogram ................................................................................. 13 
2.3.4 
Laboratory Assessments ....................................................................... 13 
2.3.6 
Immunogenicity .................................................................................... 15 
2.4 
Efficacy Assessments ................................................................................ 16 
2.4.1 
Quantitative Myasthenia Gravis Score ................................................. 16 
2.4.2 
Myasthenia Gravis Activities of Daily Living Score ............................ 16 
2.4.3 
Myasthenia Gravis Quality of Life ....................................................... 17 
2.4.4 
MG Composite ...................................................................................... 17 
2.5 
Pharmacokinetic Assessments .................................................................. 24 
2.6 
Pharmacodynamic Assessments ............................................................... 24 
2.7 
Rescue Therapy ......................................................................................... 25 
2.8 
Schedule of Assessments .......................................................................... 26 
3 
STATISTICAL METHODS ............................................................................... 31 
3.1 
General Methods ....................................................................................... 31 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 5 of 61 
 
3.1.1 
Computing Environment ....................................................................... 31 
3.1.2 
Reporting of Numerical Values ............................................................ 31 
3.1.3 
Baseline Value and Change from Baseline ........................................... 31 
3.2 
Handling of Missing Values ..................................................................... 32 
3.2.1 
Efficacy Endpoints: Main Portion ........................................................ 32 
3.2.2 
Efficacy Endpoints: Extension Portion ................................................. 32 
3.2.3 
Safety, PK and PD Endpoints ............................................................... 34 
3.3 
Analysis Populations ................................................................................. 34 
3.3.1 
Intention-to-Treat Population................................................................ 34 
3.3.2 
Modified ITT Population ...................................................................... 34 
3.3.3 
Per Protocol Population ........................................................................ 34 
3.3.4 
Safety Population .................................................................................. 34 
3.3.5 
RA101495 Safety Population ............................................................... 35 
3.3.6 
Pharmacokinetic Population ................................................................. 35 
3.3.7 
Pharmacodynamic Population .............................................................. 35 
3.4 
Combining RA101495 Data Across Study Portions ................................. 35 
3.5 
Efficacy Endpoints .................................................................................... 36 
3.5.1 
Primary Efficacy Endpoint ................................................................... 36 
3.5.2 
Secondary Efficacy Endpoints .............................................................. 36 
3.6 
Pharmacodynamic Endpoints.................................................................... 36 
3.7 
Exploratory Endpoints .............................................................................. 36 
3.8 
Patient Disposition and Evaluability ......................................................... 37 
3.8.1 
Patient Disposition ................................................................................ 37 
3.8.2 
Protocol Deviations ............................................................................... 37 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 6 of 61 
 
3.9 
Demographics and Baseline Characteristics ............................................. 38 
3.9.1 
Demographics ....................................................................................... 38 
3.9.2 
Medical History .................................................................................... 38 
3.9.3 
Myasthenia Gravis History ................................................................... 38 
3.10 
Prior and Concomitant Medications ......................................................... 39 
3.11 
MG Specific Prior and Concomitant Medications .................................... 41 
3.12 
Exposure to Study Treatment.................................................................... 42 
3.13 
Safety Analysis ......................................................................................... 42 
3.13.1 Adverse Events ..................................................................................... 43 
3.13.2 Clinical Laboratory Evaluation ............................................................. 46 
3.13.3 Vital Signs and Other Physical Findings .............................................. 48 
3.13.4 ECG....................................................................................................... 48 
3.13.5 Physical Examination............................................................................ 48 
3.14 
Efficacy Analyses ..................................................................................... 48 
3.14.1 Primary Efficacy Endpoint Analysis .................................................... 48 
3.14.2 Secondary Efficacy Endpoints Analysis ............................................... 49 
3.15 
Controlling for Multiplicity ...................................................................... 50 
3.15.1 Additional Analyses of Primary and Secondary Endpoints .................. 50 
3.15.2 Pharmacodynamic Endpoints Analysis................................................. 54 
3.15.3 Pharmacokinetic Endpoints Analysis ................................................... 54 
3.15.4 Exploratory Endpoints Analysis ........................................................... 55 
3.16 
Additional Analyses .................................................................................. 55 
3.16.1 Rescue Therapy ..................................................................................... 55 
3.17 
Interim Analysis ........................................................................................ 56 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 7 of 61 
 
3.18 
Timing of Primary Analysis...................................................................... 56 
3.19 
Sample Size Considerations ...................................................................... 56 
3.20 
Replacement of Subjects ........................................................................... 56 
3.21 
Protocol Violations ................................................................................... 56 
4 
References ........................................................................................................... 56 
5 
Appendix 1: Sample SAS code for Repeated Measures Mixed Models ............ 58 
6 
Appendix 2: Analyses Including Data After Day E84 ........................................ 59 
6.1 
Additional Analysis Population: Extension Population ............................ 59 
6.2 
Disposition ................................................................................................ 59 
6.3 
Subject Switching From 0.1 mg/kg to 0.3 mg/kg ..................................... 59 
6.4 
Exposure ................................................................................................... 59 
6.5 
Efficacy Endpoints .................................................................................... 60 
6.6 
Safety Endpoints ....................................................................................... 61 
6.6.1 
Adverse Events ..................................................................................... 61 
6.6.2 
Labs and Vital Signs ............................................................................. 61 
 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 8 of 61 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Full Term 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
aPTT/APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI  
body mass index 
BUN 
blood urea nitrogen 
C5 
complement component 5 
cm 
centimeter 
Cmax 
maximum plasma concentration 
CPK 
creatine phosphokinase  
CRP 
C-reactive protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GGT 
gamma-glutamyl transferase 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
INR  
international normalized ratio 
ISR 
injection site reaction 
ITT 
intent-to-treat 
kg 
kilogram 
LOCF 
last observation carried forward 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG-ADL  
myasthenia gravis activities of daily living 
mg 
milligram 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
NCI 
National Cancer Institute 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 9 of 61 
 
PNH 
paroxysmal nocturnal hemoglobinuria 
PT 
prothrombin time 
PT 
preferred term 
PTT 
partial thromboplastin time 
QMG 
quantitative myasthenia gravis 
QOL 
quality of life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneously 
SOC 
system organ class 
sRBC 
sheep red blood cell  
TEAE 
treatment-emergent adverse event 
tmax 
time to corresponding Cmax 
ULN 
upper limit of normal 
WBC 
white blood cell 
 
 
 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 10 of 61 
 
1 INTRODUCTION 
Ra Pharmaceuticals, Inc. is developing RA101495, a subcutaneously (SC) self-
administered 15-amino acid cyclic peptide that binds to, and inhibits the cleavage of, 
complement component 5 (C5). 
Study RA101495-02.201 is a multicenter, randomized, double-blind, placebo-
controlled study to evaluate the safety, tolerability, and preliminary efficacy of 
RA101495 in subjects with gMG. The planned enrollment is approximately 36 
subjects. 
Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg 
RA101495, 0.3 mg/kg RA101495, or matching placebo.  
This Statistical Analysis Plan (SAP) describes data-handling and statistical 
procedures to be used for the analysis and reporting of efficacy and safety data 
collected under Study RA101495-02.201 (version 2.0 19 October 2017) and 
presented in the clinical study report (CSR). The methods are based on those 
presented in Section 12 of the study protocol. Any post-hoc or exploratory analyses 
not specified in this SAP will be identified as such when they are presented in the 
CSR. This SAP has been developed and finalized prior to locking the clinical 
database for the Main Portion of the study.  
The analyses involving the Main Portion and the first 12 Weeks of the Extension 
Portion (i.e., through study day E84) will be included in the main section of this SAP 
document. Analyses involving the whole study, including the entire open-label 
Extension Portion beyond study day E84 will be in the appendix of this document. 
The reason for the analyses being separated into two distinct sections of the SAP 
document is to allow for the analysis methods relating to the randomized double-blind 
portion of the study to be finalized while allowing for future modifications to the 
analyses of the open-label Extension Portion (note: this method is consistent with the 
study protocol in that the schedule of assessments after day E84 is in the Protocol 
Appendix). 
This SAP was written in accordance with the recommendations outlined in the 
International Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance 
for Industry: Statistical Principles for Clinical Trials” and the most recent ICH-E3 
Guideline, entitled “Guidance for Industry: Structure and Content of Clinical Study 
Reports.”  
2 STUDY SUMMARY 
2.1 STUDY OBJECTIVES 
The objectives of the study are: 
• 
To assess the safety and tolerability of RA101495 in subjects with gMG  
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 11 of 61 
 
• 
To assess preliminary efficacy of RA101495 in subjects with gMG  
2.2 STUDY DESIGN 
Study RA101495-02.201 is a multicenter, randomized, double-blind, placebo-
controlled study to evaluate the safety, tolerability, and preliminary efficacy of 
RA101495 in subjects with gMG. The planned enrollment is approximately 36 
subjects.  
Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg 
RA101495, 0.3 mg/kg RA101495, or matching placebo. Randomization will be 
stratified based on the screening QMG Score (≤ 17 versus ≥ 18).  
The Main Portion of the study includes a Screening Period of up to 4 weeks and a 12-
week Treatment Period (Figure 1). During the Treatment Period, subjects will return 
to the clinic weekly for the first 2 visits (Day 8 and Day 15) after the Day 1 visit, 
followed by visits at Week 4 (Day 29), Week 8 (Day 57), and Week 12 (Day 84) to 
evaluate safety, tolerability, and preliminary efficacy. Additional assessments will 
include quality of life (QOL) questionnaires, biomarker samples, pharmacokinetics, 
pharmacodynamics, and optional pharmacogenomics. Safety assessments will include 
physical examinations, vital signs, ECGs, clinical laboratory tests, adverse events 
(AEs), and immunogenicity.  
Randomized subjects will receive 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or 
matching placebo administered SC at the Day 1 visit. Following in-clinic education 
and training, all subjects will self-inject daily SC doses of blinded study drug, 
according to randomized treatment allocation, for the subsequent 12 weeks. A single-
use, disposable, injection device will be provided for use during the study. 
At the conclusion of the Treatment Period in the Main Portion of the study, all 
subjects will have the option to receive RA101495 in the Extension Portion of the 
study provided they meet the Extension Portion selection criteria (Protocol Section 
8.3). Subjects assigned to a RA101495 treatment arm during the Main Portion of the 
study will continue to receive the same dose of study drug during the Extension 
Portion. Subjects assigned to the placebo arm during the Main Portion of the study 
will be randomized in a 1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495 
or 0.3 mg/kg RA101495. Assessments and visits during the first 12 weeks of the 
Extension Portion will be identical to the Main Portion of the study for all subjects to 
ensure appropriate monitoring of subjects transitioning from placebo to active 
treatment and to maintain blinding of treatment assignment. The study will remain 
double-blinded during the Extension Portion until after the data from the Main 
Portion of the study have been cleaned, locked, and unblinded. 
Figure 1 provides an illustration of the study design.  
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 12 of 61 
 
Figure 1: Design of RA101495-02.201 
 
2.2.1 Number of Subjects 
Approximately 36 subjects will be randomized (i.e., 12 per treatment arm): 
2.2.2 Randomization and Blinding Procedures 
Subjects who meet all entry criteria will be randomized in a 1:1:1 ratio to receive 
daily SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo. 
Subjects will be assigned to study arms in a blinded fashion using a computerized 
randomization algorithm. Randomization will be stratified based on the screening 
QMG Score (≤ 17 versus ≥ 18).  
Subjects assigned to a RA101495 treatment arm during the Main Portion of the study 
will continue to receive the same dose of study drug during the Extension Portion. 
Subjects assigned to the placebo arm during the Main Portion of the study will be 
randomized in a 1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495 or 0.3 
mg/kg RA101495. This randomization will occur at the screening visit when the 
subject is initially randomized to the Main Portion of the study.  
This is a double-blind study. Subjects and study staff will remain blinded to treatment 
assignments until after the data from the Main Portion of the study have been cleaned, 
locked, and unblinded.  
The procedure for emergency unblinding of study drug treatment for an individual 
subject is discussed in protocol section 11.3.3.  
2.3 Safety Assessments 
Safety assessments will include physical examinations, vital signs, ECGs, clinical 
laboratory tests, AEs, and immunogenicity. 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 13 of 61 
 
2.3.1 Physical Examination 
A full physical examination will be performed on all subjects at the Screening visit 
and will include the following assessments:  
• 
General inspection  
• 
Examination of the injection site and draining nodes  
• 
Head/ears/eyes/nose/throat examination  
• 
Mucosal examination  
• 
Cardiac examination  
• 
Auscultation of lungs  
• 
Abdominal examination (liver, spleen, and lower abdomen)  
• 
Musculoskeletal assessment  
• 
Neurological assessment  
Any abnormalities found will be recorded in the electronic case report form (eCRF).  
At all other study visits, the physical examination will be symptom-directed. 
2.3.2 Vital Signs 
Vital signs (Heart Rate (HR), body temperature, and blood pressure) will be measured 
in the sitting position. Blood pressure may be measured manually or by automated 
device, preferably using the non-dominant arm. The same measurement technique 
should be used throughout the study for all the subjects.  
2.3.3 Electrocardiogram 
12-lead ECGs will be assessed as normal or abnormal by the investigator; any abnormal 
findings will be described in the eCRF and the investigator will assess clinical 
significance. The ECG recording strip will be signed and dated by the investigator and 
stored in the medical records.  
ECGs should be performed prior to blood draws when both assessments are required at 
the same visit. 
2.3.4 Laboratory Assessments 
Safety laboratory tests for this study [chemistry, hematology, coagulation (for 
applicable subjects), and urinalysis] are to be performed by a central laboratory, and 
only values from the central laboratory are to be entered into the laboratory section of 
the study database. Values from local laboratories may be used to determine 
eligibility for study enrollment and as the basis for clinical decisions. 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 14 of 61 
 
2.3.4.1 Hematology, Chemistry, and Coagulation  
Hematology, chemistry, and coagulation analytes that will be assessed during the 
study are identified in Table 1. Coagulation tests should only be performed in subjects 
receiving anticoagulant therapy. 
Table 1: Clinical Chemistry, Hematology, and Coagulation Analytes 
Clinical Chemistry 
Hematology 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST) 
Bicarbonate 
Bile acids 
Bilirubin (total, direct, and indirect) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lipase 
Potassium 
Sodium 
Total protein 
Uric acid 
Hematocrit  
Hemoglobin  
Mean corpuscular volume (MCV)  
Platelet count  
White blood cell (WBC) count and differential (%)  
• basophils  
• eosinophils  
• lymphocytes 
• monocytes 
• neutrophils 
Coagulation 
International normalized ratio (INR)/prothrombin 
time (PT) 
Fibrinogen 
Partial thromboplastin time (PTT) or activated 
partial thromboplastin time (aPTT) 
Other 
C-reactive protein (CRP) 
creatine phosphokinase (CPK) 
2.3.4.2 Urinalysis 
A urinalysis will be performed to measure pH, specific gravity, protein (qualitative), 
glucose (qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, 
occult blood, hemoglobin, and cells. A microscopic examination will be performed, if 
necessary. 
2.3.4.3 Pregnancy Test 
A serum pregnancy test for human chorionic gonadotropin will be performed on 
female subjects of childbearing potential at Screening. 
A urine dipstick pregnancy test (human chorionic gonadotropin) will be performed on 
female subjects of childbearing potential at all other study visits as specified in the 
Time and Events Tables (Table 9 and Table 10).  
2.3.5 Adverse Events 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 15 of 61 
 
An AE is any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship 
with study treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  
The following are not considered to be AEs despite requiring hospitalization: 
• Pre-existing conditions that, in the opinion of the investigator, did not worsen or 
progress during study participation 
• Routinely scheduled procedures or treatment 
• Elective procedures that had been scheduled prior to study participation (i.e., 
signing of the informed consent form (ICF)) 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• results in death 
• is life-threatening (note that this refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe) 
• requires hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• results in a congenital anomaly/birth defect 
An SAE may also be any other important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or 
require intervention to prevent one of the other outcomes listed in the definition 
above. Examples of such events include intensive treatment in an emergency room or 
at home for bronchospasm, hyperkalemia, or convulsions that do not result in a 
formal hospitalization. 
Elective hospitalizations scheduled prior to study participation (i.e., signing of the 
ICF) should not be reported as SAEs.  
2.3.6 Immunogenicity 
Blood samples for anti-drug antibody (ADA) assessment will be collected as 
specified in the Time and Events Tables (Table 9 and Table 10) in all enrolled 
subjects. These samples will be banked and used to investigate and characterize any 
ADA response over time in the general study population. 
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RA101495-02.201                                                  
     
                    Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
 
 
 
 
Page 16 of 61 
 
2.4 Efficacy Assessments 
2.4.1 Quantitative Myasthenia Gravis Score 
The primary efficacy assessment is the Quantitative Myasthenia Gravis (QMG) score. 
The QMG is a standardized and validated quantitative muscle strength scoring system 
that was developed specifically for MG and has been used widely in prior clinical 
trials.  
Higher scores are representative of more severe impairment. Recent data suggest that 
improvements in the QMG score of 2 to 3 points may be considered clinically 
meaningful, depending upon disease severity [Barohn, 1998; Katzberg, 2014]. 
Table 2 presents the scoring scale for the 13 individual assessments, each scored on a 
0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is 
the sum of the individual scores; range 0 – 39.  
If a subject is missing a response for one of the 13 individual QMG items, the 
subject’s corresponding item score from the previously scheduled QMG assessment 
will be imputed for the missing item score (and the total score calculated using this 
imputed value and the non-missing item scores). If the item response is also missing 
from the previously scheduled QMG, the QMG total score will be set to missing for 
that visit. If the subject is missing responses to more than one of the 13 items, the 
QMG total score will be set to missing for that visit (note: the LOCF algorithm will 
still be applied, as appropriate). 
2.4.2 Myasthenia Gravis Activities of Daily Living Score 
The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. 
Higher scores are associated with more severe symptoms of MG. The MG-ADL has 
been shown to correlate with other validated MG outcome measures (e.g., MG-
QOL15r), and a 2-point improvement in MG-ADL score is considered clinically 
meaningful [Wolfe, 1999; Muppidi, 2011]. 
Table 3 presents the 8 items with corresponding response scale, each scored on a 0 – 
3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the 
sum of the 8 individual scores; range 0 – 24.  
If a subject is missing a response for one of the 8 individual MG-ADL items, the 
subject’s corresponding item score from the previously scheduled MG-ADL 
assessment will be imputed for the missing item score (and the total score calculated 
using this imputed value and the non-missing item scores). If the item response is also 
missing from the previously scheduled MG-ADL, the MG-ADL total score will be set 
to missing for that visit. If the subject is missing responses to more than one of the 8 
items, the MG-ADL total score will be set to missing for that visit (note: the LOCF 
algorithm will still be applied, as appropriate). 
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2.4.3 Myasthenia Gravis Quality of Life 
The MG-QOL15r is a 15-item survey that was designed to assess quality of life in 
subjects with MG. Higher scores indicate more severe impact of the disease on 
aspects of the subject’s life [Burns, 2010; Burns, 2016]. 
The following are the 15 questions and the corresponding response scales, each 
scored on a 0-2 point scale (0=Not much at all, 1=Somewhat, 2=Very Much). 
1. I’m frustrated by my myasthenia gravis. 
2. I have trouble using my eyes because of my myasthenia gravis. 
3. I have trouble eating because of my myasthenia gravis. 
4. I have limited my social activity because of my myasthenia gravis. 
5. My myasthenia gravis limits my ability to enjoy hobbies and activities. 
6. I have trouble meeting the needs of my family because of my myasthenia 
gravis. 
7. I have to make plans around my myasthenia gravis. 
8. My occupational skills and job status have been negatively affected by my 
myasthenia gravis. 
9. I have difficulty speaking due to my myasthenia gravis. 
10. I have trouble driving due to my myasthenia gravis. 
11. I am depressed about my myasthenia gravis 
12. I have trouble walking due to my myasthenia gravis 
13. I have trouble getting around public places because of my myasthenia gravis. 
14. I feel overwhelmed by my myasthenia gravis. 
15. I have trouble performing my personal grooming needs because of myasthenia 
gravis. 
The MG-QOL15r total score is the sum of the 15 individual item scores with a range 
of 0 – 30.  
If a subject is missing a response for one of the 15 individual MG-QOL15r items, the 
subject’s corresponding item score from the previously scheduled MG-QOL15r 
assessment will be imputed for the missing item score (and the total score calculated 
using this imputed value and the non-missing item scores). If the item response is also 
missing from the previously scheduled MG-QOL15r, the MG-QOL15r total score 
will be set to missing for that visit. If the subject is missing responses to more than 
one of the 10 items, the MG-QOL15r total score will be set to missing for that visit 
(note: the LOCF algorithm will still be applied, as appropriate). 
2.4.4 MG Composite 
The MG Composite is a 10-item scale that has been used to measure the clinical 
status of subjects with MG, both in the practice setting and in clinical trials, in order 
to evaluate treatment response. Higher scores in the MG Composite indicate more 
severe impairment due to the disease. A 3-point change in this instrument is 
considered clinically meaningful [Benatar, 2012; Sadjadi, 2012]. 
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Table 4 presents the 10 items with corresponding response scale scores. The total 
score is the sum of the 10 individual scores; range 0 – 50.  
If a subject is missing a response for one of the 10 individual MG Composite items, 
the subject’s corresponding item score from the previously scheduled MG Composite 
assessment will be imputed for the missing item score (and the total score calculated 
using this imputed value and the non-missing item scores). If the item response is also 
missing from the previously scheduled MG Composite assessment, the MG 
Composite total score will be set to missing for that visit. If the subject is missing 
responses to more than one of the 10 items, the MG Composite total score will be set 
to missing for that visit (note: the LOCF algorithm will still be applied, as 
appropriate). 
 
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RA101495-02.201                                                                         Statistical Analysis Plan 
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Page 19 of 61 
 
Table 2: QMG Items and Scoring 
 
* Circle as appropriate 
 
Grade 
 
Test Item 
Measured value, if 
applicable 
None 
0 
Mild 
1 
Moderate 
2 
Severe 
3 
Score 
(0-3) 
1. 
Double vision  
on lateral gaze  
*right / left / both 
*glasses removed: Y / N / 
NA 
 
____ seconds 
 ≥61 
11-60 
1-10 
Spontaneous 
 
2. 
Ptosis 
(upward gaze) 
____ seconds 
≥61 
11-60 
1-10 
Spontaneous 
 
3. 
Facial Muscles 
NA 
Normal lid 
closure 
Complete, weak, 
some resistance 
Complete, 
without 
resistance 
Incomplete 
 
4. 
Swallowing  
4oz. (½ cup) water  
NA 
Normal 
Minimal 
coughing or 
throat clearing 
Severe 
coughing/chokin
g or nasal 
regurgitation 
Cannot swallow 
(test not 
attempted) 
 
5. 
Speech after counting 
aloud from #1 to 50 
Number ____ 
None at 
 #50 
Dysarthria at  
#30-49 
Dysarthria at  
#10-29 
Dysarthria at  
9 
 
6. 
Right arm outstretched 
(90°, sitting, away from 
back of chair) 
 
____ seconds 
240 
90-239 
10-89 
0-9 
 
7. 
Left arm outstretched 
(90°, sitting, away from 
back of chair) 
 
____ seconds 
240 
90-239 
10-89 
0-9 
 
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8. 
Forced vital capacity 
FVC % predicted [%p] 
FVC [L] 
 
Best of 3-5 attempts 
_____ %p 
_____ FVC [L]  
Normal Range used: 
NHANES III 
≥80% 
65-79% 
50-64% 
<50% 
 
9. 
Right hand grip 
Men  
Women  
*Setting:  2    3 
 
____ kg 
 
≥45 
≥30 
 
15-44 
10-29 
 
5-14 
5-9 
 
0-4 
0-4 
 
10. 
Left hand grip 
Men 
Women 
*Setting:   2    3 
 
____ kg 
 
≥35 
≥25 
 
15-34 
10-24 
 
5-14 
5-9 
 
0-4 
0-4 
 
11. 
Head, lifted 
(45°, supine) 
 
____ seconds 
120 
30-119 
1-29 
0 
 
12. 
Right leg outstretched 
(45°, supine) 
 
____ seconds 
100 
31-99 
1-30 
0 
 
13. 
Left leg outstretched 
(45°, supine) 
 
____ seconds 
100 
31-99 
1-30 
0 
 
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Table 3: MG-ADL Items and Scoring 
 
  
  
  
  
  
  
  
  
Grade 
0 
1 
2 
3 
Score 
Talking  
  
Normal  
  
Intermittent 
slurring of nasal 
speech  
  
Constant slurring 
or nasal, but can 
be understood  
  
Difficult to  
   
understand speech  
  
  
  
Chewing  
  
Normal  
  
Fatigue with solid 
food  
  
Fatigue with soft 
food  
  
Gastric tube  
  
  
  
  
  
Swallowing  
  
Normal  
  
Rare episode of 
choking  
  
Frequent choking 
necessitating 
changes in diet  
  
Gastric tube  
  
  
  
  
  
Breathing  
  
Normal  
  
Shortness of 
breath with 
exertion  
  
Shortness of 
breath at rest  
  
Ventilator 
dependence   
 
  
  
  
Impairment of ability 
to brush teeth or 
comb hair  
  
None  
  
Extra effort, but no 
rest periods 
needed  
  
Rest periods 
needed 
Cannot do one of 
these functions  
  
  
  
  
Impairment of ability 
to arise from a chair  
  
None  
  
Mild, sometimes 
uses arms  
  
Moderate, always 
uses arms  
  
Severe, requires 
assistance  
  
  
  
  
Double vision  
  
None  
  
Occurs, but not 
daily  
  
Daily, but not 
constant  
  
Constant  
  
  
  
  
  
Eyelid droop  
  
None  
  
Occurs, but not 
daily  
  
Daily, but not 
constant  
  
Constant  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Total score _________________    
  
  
  
  
  
  
  
  
  
  
 
 
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Table 4: MG-Composite Assessments and Scoring 
 
 
 
Item 
Seconds,  
if applicable 
 
 
 
 
Score 
Transcribe from QMG 
1. 
Ptosis 
upward ease, seconds 
(physician examination) 
 
____ seconds 
>45 
seconds  
=0 
11-45  
=1 
1-10  
=2 
Immediate  
=3 
 
2. 
Double vision 
on lateral gaze 
left/right/both, seconds 
(physical examination) 
 
____ seconds 
>45 
seconds  
=0 
11-45  
=1 
1-10  
=3 
Immediate 
=4 
 
3. 
Eye closure 
(physician examination) 
NA 
Normal 
=0 
 
Mild weakness 
(can be forced 
open with 
effort)  
=0 
Moderate 
weakness (can 
be forced open 
easily)  
=1 
Severe 
weakness 
(unable to keep 
eye closed)  
=2 
 
Transcribe from MG-ADL 
4. 
Talking 
(patient history) 
NA 
Normal  
=0 
Intermittent 
slurring or nasal 
speech 
=2 
Constant 
slurring or nasal 
but can be 
understood  
= 4 
Difficult to 
understand 
speech 
=6 
 
5. 
Chewing 
(patient history) 
NA 
Normal  
=0 
Fatigue with 
solid food 
=2 
Fatigue with 
soft food 
=4 
Gastric tube 
=6 
 
6. 
Swallowing 
(patient history) 
NA 
Normal  
=0 
Rare episode of 
choking or 
trouble 
swallowing 
=2 
Frequent 
trouble 
swallowing 
=5 
Gastric Tube 
=6 
 
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7. 
Breathing 
thought to be caused by 
MG 
(patient history) 
NA 
Normal  
=0 
Shortness of 
breath with 
exertion 
=2 
Shortness of 
breath at rest 
=4 
Ventilator 
dependence 
=9 
 
 
8. 
Neck flexion or extension 
(weakest) 
(physician examination) 
NA 
Normal  
=0 
Mild weakness 
=1 
Moderate 
weakness 
=3 
Severe 
weakness 
=4 
 
 
9. 
Shoulder abduction 
(physician examination) 
NA 
Normal  
=0 
Mild weakness 
=2 
Moderate 
weakness  
=4 
Severe 
weakness 
=5 
 
 
10. 
Hip Flexion 
(physician examination) 
NA 
Normal  
=0 
Mild weakness 
=2 
Moderate 
weakness  
=4 
Severe 
weakness 
=5 
 
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2.5 Pharmacokinetic Assessments 
The following are the Pharmacokinetic (PK) endpoints:  
• Plasma concentrations of RA101495 and its major metabolites 
• Maximum plasma concentration (Cmax) on Day 1 
• Time corresponding to Cmax (tmax) on Day 1 
• Ratio of parent to metabolites (i.e., 2 metabolites). 
Table 5 and Table 6 present the schedule of PK blood samples for the Main Portion 
and Extension Portion, respectively. 
Table 5: Main Portion: Pharmacokinetic Schedule of Assessments 
Day 1 
Day 84 
During Rescue Therapy* 
At sites where rescue 
therapy is administered 
locally 
At sites where rescue 
therapy is NOT 
administered locally 
predose  
(within 1 hour before first 
dose of study drug)  
predose  
(any time prior to Day 84 
study drug administration) 
Within 1 hour before 
administration of rescue 
therapy 
Prior to administration of 
the first course of rescue 
therapy 
1 hour postdose  
(± 30 minutes) 
1 hour postdose  
(± 30 minutes) 
For PLEX only: PK will be 
measured in the exchanged 
plasma 
After administration of the 
last 
course 
of 
rescue 
therapy 
3 hours postdose  
(± 30 minutes) 
 
Within 
1 
hour 
after 
administration of rescue 
therapy 
 
6 hours postdose  
(± 90 minutes) 
 
 
 
Table 6: Extension Portion: Pharmacokinetic Schedule of Assessments 
During Rescue Therapy* 
Week E36 
(see Study Protocol Appendix 2) 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is 
NOT administered locally 
Within 1 hour before administration 
of rescue therapy 
Prior to administration of the first 
course of rescue therapy 
predose (within 1 hour before first 
dose of study drug)  
For PLEX only: PK will be measured 
in the exchanged plasma 
After administration of the last 
course of rescue therapy 
1 hour postdose (± 30 minutes) 
Within 1 hour after administration of 
rescue therapy 
 
3 hours postdose (± 30 minutes) 
 
 
6 hours postdose (± 90 minutes) 
On all other study visit days, a single PK sample will be collected prior to 
administration of study drug. Plasma concentrations of RA101495 and its metabolites 
will be measured and reported in all subjects receiving RA101495. All samples will 
be sent to a central laboratory for analysis. Detailed instructions regarding PK sample 
collection, processing, and shipping will be provided to sites. 
2.6 Pharmacodynamic Assessments 
The following are the Pharmacodynamic assessments: 
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• 
Sheep red blood cell (sRBC) lysis assay for evaluation of classical complement pathway 
activation 
• 
C5 levels.  
Table 7 and Table 8 present the schedule of Pharmacodynamic (PD) blood samples 
for the Main Portion and Extension Portion, respectively. 
Table 7: Main Portion: Pharmacodynamic Schedule of Assessments 
Day 1 
Day 84 
During Rescue Therapy* 
At sites where rescue 
therapy is administered 
locally 
At sites where rescue 
therapy is NOT 
administered locally 
predose  
(within 1 hour before first 
dose of study drug)  
predose  
(any time prior to Day 84 
study drug administration) 
Within 1 hour before 
administration of rescue 
therapy 
Prior to administration of 
the first course of rescue 
therapy 
1 hour postdose  
(± 30 minutes) 
1 hour postdose  
(± 30 minutes) 
 
 
3 hours postdose  
(± 30 minutes) 
 
Within 
1 
hour 
after 
administration of rescue 
therapy 
After administration of the 
last 
course 
of 
rescue 
therapy 
6 hours postdose  
(± 90 minutes) 
 
 
 
Table 8: Extension Portion: Pharmacodynamic Schedule of Assessments 
During Rescue Therapy* 
(ONLY through Day 167 visit) 
Week E36 
(see Study Protocol Appendix 2) 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is 
NOT administered locally 
Within 1 hour before administration 
of rescue therapy 
Prior to administration of the first 
course of rescue therapy 
predose (within 1 hour before first 
dose of study drug)  
For PLEX only: PK will be measured 
in the exchanged plasma 
After administration of the last 
course of rescue therapy 
1 hour postdose (± 30 minutes) 
Within 1 hour after administration of 
rescue therapy 
 
3 hours postdose (± 30 minutes) 
 
 
6 hours postdose (± 90 minutes) 
2.7 Rescue Therapy  
Subjects are expected to remain on stable doses of standard of care therapy for gMG 
throughout the Main Portion of the study and through the Day E84 visit of the 
Extension Portion, including pyridostigmine, corticosteroids, or immunosuppressive 
drugs. If, in the opinion of the investigator, escalation of gMG therapy (i.e., ‘rescue 
therapy’) becomes necessary due to deterioration of a subject’s clinical status, the 
subject may receive immunoglobulin or plasma exchange treatment. If such rescue 
therapy becomes necessary, the choice of immunoglobulin vs. plasma exchange, as 
well as the frequency and duration of such therapy, will be determined by the 
investigator. Escalation of doses of pyridostigmine, corticosteroids, or 
immunosuppressive drugs for rescue is not permitted. 
A Rescue Therapy Visit should be performed prior to initiation of rescue therapy (see 
Table 9 and Table 10 for a list of applicable study procedures).  
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Unblinding of treatment assignment prior to initiation of rescue therapy will not be 
allowed, unless critical for reasons of subject safety. The subject will continue their 
blinded treatment and retain all study-specified assessments while undergoing rescue 
therapy and through the end of the study if the investigator, in consultation with the 
medical monitor, considers this course of action in the best interest of the subject.  
2.8 Schedule of Assessments 
The following are the time and events tables for the Main Portion (Table 9) and the 
Extension Portion (Table 10). 
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Table 9: Main Portion: Time and Events Table 
Study Procedure 
Screening 
Days -28 to -1 
Day 1 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
Day 57 
(± 7 days) 
End of Studya 
Day 84 
(± 2 days) 
Safety 
Follow-up Call  
(last dose + 40d) 
 
Rescue 
Therapy Visitb  
(if applicable) 
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
Review eligibility and randomizationc 
X 
 
 
 
 
 
 
 
 
 
Medical historyd and demographics 
X 
 
 
 
 
 
 
 
 
 
Heighte and weight 
X 
 
 
 
X 
 
X 
 
 
 
Prior and concomitant medicationsf 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
12-Lead electrocardiogram 
X 
 
 
 
 
 
X 
 
 
X 
Neisseria meningitidis vaccinationi 
X 
 
 
 
 
 
 
 
 
 
Hematology/Chemistryj 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Coagulationk 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy testl 
X 
X 
 
 
 
 
X 
 
 
 
Adverse eventsm 
 
X 
X 
X 
X 
X 
X 
Xm 
 
X 
Anti-drug antibody 
X 
 
 
 
X  
 
X 
 
 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
 
QMG Test/Scoren 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
MG-ADL 
 
X 
X 
X 
X 
X 
X 
 
 
X 
MG-QOL15r 
 
X 
X 
X 
X 
X 
X 
 
 
X 
MG Composite 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
RA101495 plasma PKo 
 
Xo 
X 
X 
X 
X 
Xo 
 
 
Xo 
Pharmacodynamic analysiso 
 
Xo 
X 
X 
X 
X 
Xo 
 
 
Xo 
Exploratory 
 
 
 
 
 
 
 
 
 
 
Additional biomarker samplesp 
 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacogenomic analysis (optional) 
X 
 
 
 
 
 
 
 
 
 
Study Drug 
 
 
 
 
 
 
 
 
 
 
RA101495 or placebo administrationq 
 
X 
X 
X 
X 
X 
X 
 
 
Xq 
See footnotes on following page. 
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1-a. If a subject prematurely discontinues study drug at any time prior to completion of the Day 84 visit during the Treatment Period, the subject should return to clinic for an End 
of Study Visit. 
1-b. For subjects who require rescue therapy (see Protocol Section 10.1.3.1), a Rescue Therapy Visit should be conducted prior to the initiation of rescue therapy. If the Rescue 
Therapy Visit coincides with a regularly scheduled study visit, then overlapping study procedures do not need to be duplicated.  
1-c. Procedures performed as SOC during the Screening Period may be used to determine eligibility. Informed consent must be obtained prior to performing any study-specific 
procedures that are not SOC. 
1-d. Screening includes disease history with diagnosis of gMG by the MGFA criteria (Class II-IVa), serology for AChR autoantibodies. 
1-e. Height will be measured only at Screening. 
1-f. All prescriptions and over-the-counter medications taken during the 30 days prior to baseline (i.e., Day 1) through the last study visit will be documented. NOTE: A complete 
history of medications taken for the treatment of gMG will be collected.  
1-g. A full physical examination will be performed on all subjects at Screening. On all other study visit days, the physical examination will be symptom-directed.  
1-h. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
1-i. All subjects must have documentation of prior Neisseria meningitidis vaccination (and booster, if appropriate) prior to study entry. If the subject has not been vaccinated, 
he/she must be vaccinated with a quadrivalent meningococcal vaccine at least 14 days prior to the first dose of study drug on Day 1 and should have a booster vaccination as 
indicated by SOC. Subjects should bring their patient safety card to every study visit. If the subject does not bring their card with them they will be given a new one. 
1-j. All laboratory samples should be obtained prior to administration of study drug at applicable visits unless otherwise noted for PK, PD, and biomarker samples.  
1-k. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
1-l. For all female subjects of childbearing potential, a negative serum pregnancy test must be documented at Screening. All other pregnancy tests will be performed via urine.  
1-m. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the 
procedures outlined in the protocol. Sites will call subjects 40 days after their last dose to gather information on ongoing AEs and report any new SAEs since the last study 
visit. This Safety Follow-up Call will only be required for subjects who choose not to receive RA101495 in the Extension Portion. 
1-n. The assessment of QMG should be performed at approximately the same time of day (preferably in the morning) and administered by the same well-trained evaluator (e.g., 
neurologist, physical therapist, or other study staff) at each visit throughout the study. If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 
10 hours prior to the QMG test.  
1-o. Blood samples for PK and PD analysis will be obtained at the following time points: 
Day 1 
Day 84 
During Rescue Therapy 
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is NOT 
administered locally 
predose (within 1 hour before first dose of 
study drug)  
predose (any time prior to Day 84 study drug 
administration) 
Within 1 hour before administration of rescue 
therapy 
Prior to administration of the first course of 
rescue therapy 
1 hour postdose (± 30 minutes) 
1 hour postdose (± 30 minutes) 
For PLEX only: PK will be measured in the 
exchanged plasma 
After administration of the last course of 
rescue therapy 
3 hours postdose (± 30 minutes) 
 
Within 1 hour after administration of rescue 
therapy 
 
6 hours postdose (± 90 minutes) 
 
 
 
 
On all other study visit days, PK/PD samples should be collected prior to administration of study drug. 
1-p. Blood samples for biomarker testing will be obtained prior to administration of study drug (within 1 hour of dosing) and at 6 hours postdose (± 90 minutes) on Day 1. On all 
other study visit days, biomarkers samples should be collected prior to administration of study drug. 
1-q. Dosing on study visit days should be held until QMG scoring, PK, and PD sample blood collection has been completed. On days when rescue therapy is concurrently 
administered, study drug dosing should be held until after administration of rescue therapy and PK/PD sampling.  
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Table 10: 
 Extension Portion: Time and Events Table 
Study Procedure 
Day E1a 
(Day 84) 
Day E8 
(± 2 days) 
Day E15 
(± 2 days) 
Day E29 
(± 2 days) 
Day E57 
(± 7 days) 
Day E84 
(± 7 days) 
Rescue 
Therapy Visitb  
(if applicable) 
Please refer to 
Study Protocol Appendix 2  
 
Final Study 
Visitc 
Informed consent 
X 
 
 
 
 
 
 
 
 
Review eligibility and randomization 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
 
X 
 
 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety  
 
 
 
 
 
 
 
 
 
Physical examination (symptom directed) 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead electrocardiogram 
 
 
 
 
 
X 
X 
 
X 
Neisseria meningitidis vaccinatione 
SOCe 
 
 
 
 
 
 
 
 
Hematology/Chemistryf 
X 
X 
X 
X 
X 
X 
X 
 
X 
Coagulationg 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy testh 
X 
 
 
 
 
X 
 
 
X 
Adverse eventsi 
X 
X 
X 
X 
X 
X 
X 
 
X 
Anti-drug antibody 
X 
 
 
X  
 
X 
X 
 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
QMG Test/Scorej 
X 
X 
X 
X 
X 
X 
X 
 
X 
MG-ADL 
X 
X 
X 
X 
X 
X 
X 
 
X 
MG-QOL15r 
X 
X 
X 
X 
X 
X 
X 
 
X 
MG Composite 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
RA101495 plasma PKk 
Xk 
X 
X 
X 
X 
X 
Xk 
 
X 
Pharmacodynamic analysisk 
Xk 
X 
X 
X 
X 
X 
Xk 
 
X 
Exploratory 
 
 
 
 
 
 
 
 
 
Additional biomarker samplesl 
Xl 
X 
X 
X 
X 
X 
 
 
X 
Study Drug 
 
 
 
 
 
 
 
 
 
RA101495 administrationm 
X 
X 
X 
X 
X 
X 
Xm 
 
X 
See footnotes on following page. 
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2-a. For subjects that decide and are eligible to continue in the Extension Portion, the Day 84 visit from the Main Portion will serve as the Day E1 visit and will also include review 
of eligibility to continue, treatment group assignment (see Protocol Section 8.3), signing of an informed consent for the Extension Portion, and an additional biomarker blood 
sample. 
2-b. For subjects who require rescue therapy (see Protocol Section 10.1.3.1), a Rescue Therapy Visit should be conducted prior to the initiation of rescue therapy. If the Rescue 
Therapy Visit coincides with a regularly scheduled study visit, then overlapping study procedures do not need to be duplicated.  
2-c. If a subject discontinues study drug treatment at any time during the Extension Period, the subject should return to clinic for a Final Study Visit. 
2-d. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
2-e. During the Extension Portion, all subjects should have Neisseria meningitidis booster vaccinations as indicated by SOC. Subjects should bring their patient safety card to 
every study visit. If the subject does not bring their card with them they will be given a new one. 
2-f. All laboratory samples should be obtained prior to administration of study drug at applicable visits unless otherwise noted for PK, PD, and biomarker samples.  
2-g. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
2-h. Urine pregnancy tests will be conducted in female subjects of childbearing potential.  
2-i. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the 
procedures outlined in the protocol.  
2-j. The assessment of QMG should be performed at approximately the same time of day (preferably in the morning) and administered by the same well-trained evaluator (e.g., 
neurologist, physical therapist, or other study staff) at each visit throughout the study. If a subject is receiving a cholinesterase inhibitor, the dose must be withheld for at least 
10 hours prior to the QMG test.  
2-k. Blood samples for PK and PD analysis will be obtained at the following time points: 
Day E1 
(Day 84 from the Main Portion) 
During Rescue Therapy  
At sites where rescue therapy is 
administered locally 
At sites where rescue therapy is NOT 
administered locally 
predose (any time prior to Day 84 study 
drug administration) 
Within 1 hour before administration of 
rescue therapy 
Prior to administration of the first course 
of rescue therapy 
1 hour postdose (± 30 minutes) 
For PLEX only: PK will be measured in 
the exchanged plasma 
After administration of the last course of 
rescue therapy 
 
Within 1 hour after administration of 
rescue therapy 
 
 
 
 
 
On all other study visit days, PK/PD samples should be collected prior to administration of study drug. 
2-l. Biomarkers samples should be collected prior to administration of study drug. 
NOTE: For those subjects that consent to the Extension Portion an additional blood sample for biomarker testing will be taken at 6 hours postdose (± 90 minutes) on Day 84.  
2-m. Dosing on study visit days should be held until QMG scoring, PK, and PD sample blood collection has been completed. On days when rescue therapy is concurrently 
administered, study drug dosing should be held until after administration of rescue therapy and PK/PD sampling. 
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3 STATISTICAL METHODS  
3.1 General Methods 
3.1.1 Computing Environment 
All statistical analyses will be performed using SAS Version 9.1.3 or higher for 
Windows. 
3.1.2 Reporting of Numerical Values 
All clinical study data will be presented in subject data listings. Descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) will be calculated by 
treatment group for continuous variables. Confidence intervals will be provided 
where appropriate. For continuous endpoints, the confidence interval for the mean 
will be based on the t-distribution (e.g., CLM in the SAS Proc Means procedure).  
Frequencies and percentages will be presented by treatment group for categorical and 
ordinal variables. If there are missing values, the number of missing values will be 
presented, but without a percentage and the number of non-missing values used as the 
denominator.  
Means, medians, standard deviations, and confidence intervals will be reported to one 
decimal place more than the data reported on the CRF or by the laboratory/vendor. 
Minimum and maximum will be reported to the same number of decimal places 
displayed on the CRF or by the laboratory/vendor. P-values will be reported to 4 
decimal places. 
3.1.3 Baseline Value and Change from Baseline 
Unless otherwise specified, for the Main Portion analyses, the baseline value is 
defined as the most recent non-missing value obtained prior to the subject receiving 
the first dose of study drug. For most endpoints this will be the Day 1 visit 
assessment.  
For analyses which include the Extension Portion, some analyses may utilize a 
“baseline” defined as the value obtained prior to receiving the first administration of 
RA101495 (i.e., first dose of active treatment). For subjects who received RA101495 
during the Main Portion, the baseline remains the same, the most recent non-missing 
value obtained prior to the subject receiving the first dose of study drug. For subjects 
who received placebo in the Main Portion, the value obtained prior to receiving the 
first administration of RA101495 will generally occur on the Day E1 (Day 84) visit, 
and will be the baseline value.  
The cases where baseline is defined as the value obtained immediately prior to 
receiving the first administration of RA101495 will be explicitly defined.   
 
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3.2 Handling of Missing Values 
3.2.1 Efficacy Endpoints: Main Portion 
The primary method for handling missing data in the efficacy analyses will be last 
observation carried forward (LOCF).  For the LOCF algorithm, if a patient is missing 
a value, the closest non-missing endpoint value prior to the missing value will be 
imputed for the missing value (note: this includes the baseline value and values from 
unscheduled visits). 
Additionally, if a subject receives rescue therapy (see Section 2.7), efficacy endpoints 
occurring after rescue therapy will be censored and imputed using the LOCF method. 
The LOCF method is such that the closest non-missing endpoint value prior to the 
initiation of rescue therapy will be imputed, (note: this includes the baseline value and 
values from unscheduled visits). 
For selected efficacy endpoints, observed case analyses will be presented as a 
sensitivity analysis.  
• Observed Case Method: analyses censoring observations post-rescue therapy 
medication. Observations occurring post-rescue therapy will be censored and 
not imputed. Otherwise, missing values will not be imputed. Note that the 
imputation of individual efficacy assessment items to create a total score, as 
discussed in Section 2.4 will still be applied in the Observed Case Method.  
3.2.2 Efficacy Endpoints: Extension Portion  
For analyses which involve the Extension Portion (i.e., analyses of the Extension 
Period data or analyses combining the Main and Extension Periods), the following 
methods will be applied to the Extension Portion efficacy analyses:  
• LOCF method in Extension Period:  
If a subject is missing values for a scheduled assessment the subject’s 
previous non-missing value will be imputed (note: this includes the baseline 
value and values from unscheduled visits).    
Handling of Values Post-Rescue Medication Use:  
If the subject was in one of the active treatment groups in the Main Portion of 
the study: 
• If the subject had received rescue medication in the Main Portion of 
the study (see Section 2.7), then the subject will continue to have post-
rescue medication observations censored and imputed using LOCF 
method in the Extension Period. 
 
If the subject had not received rescue medication in the Main Portion 
of the study but receives rescue medication in the Extension Period, 
the post-rescue medication observations will be censored and imputed 
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via LOCF method (i.e., using the methodology described in Section 
3.2.1). 
 
If the subject was in the placebo treatment group in the Main Portion of the 
study: 
• If the subject had received rescue medication in the Main Portion of 
the study (see Section 2.7), the subject will stop having the post-rescue 
medication observations censored after, but not including, the Day 84 
visit (i.e., LOCF in the Main Portion will not carry over into the 
Extension Portion).  
 
If the subject receives rescue medication in the Extension Period, the 
post-rescue medication observations will be censored and imputed via 
LOCF method (i.e., using the methodology described in Section 3.2.1). 
 
• Observed Case Method in Extension Portion: 
Missing values will not be imputed, and analyses will be performed on the 
observed cases (with the exception of observations occurring post-rescue 
medication use). Note that the imputation of individual efficacy assessment 
items to create a total score, as discussed in Section 2.4, will still be applied in 
the Observed Case Method.  
 
Handling of Values Post-Rescue Medication Use:  
If the subject was in one of the active treatment groups in the Main Portion of 
the study: 
• If the subject had received rescue medication in the Main Portion of 
the study (see Section 2.7), then the subject will continue to have post-
rescue medication observations censored in the Extension Period. 
 
If the subject had not received rescue medication in the Main Portion 
of the study but receives rescue medication in the Extension Period, 
the post-rescue medication observations will be censored. 
 
If the subject was in the placebo treatment group in the Main Portion of the 
study: 
• If the subject had received rescue medication in the Main Portion of 
the study (see Section 2.7), the subject will stop having the post-rescue 
medication observations censored after, but not including, the Day 84 
visit (i.e., the censoring of observations in the Main Portion will not 
carry over into the Extension Portion).  
 
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If the subject receives rescue medication in the Extension Period, the 
post-rescue medication observations will be censored. 
 
3.2.3 Safety, PK and PD Endpoints 
Missing data for safety, PK, and PD endpoints will not be imputed; observed cases 
will be used. This will include observations occurring after a subject receives rescue-
medication. 
3.3 Analysis Populations 
Analysis populations in this study are defined in the sections that follow. If any of the 
analysis populations are identical, duplicate results may not be presented for the 
identical populations. 
3.3.1 Intention-to-Treat Population 
The Intention-to-Treat (ITT) Population will include all randomized subjects.  ITT 
population analyses will be based on the randomized treatment.  
3.3.2 Modified ITT Population 
The modified ITT (mITT) Population will include all subjects in the ITT Population 
who have received at least 1 dose of study drug.  mITT population analyses will be 
based on the randomized treatment. 
3.3.3 Per Protocol Population 
The Per Protocol Population will include all subjects in the mITT Population who 
have completed the 12-week Treatment Period and have no major protocol violations 
during the 12-week Treatment Period. 
If, in the Main Portion of the study, a patient received multiple doses of different 
study drug levels (i.e., placebo, 0.1 mg/kg, and 0.3 mg/kg), the patient will be 
assigned to the dose group which they received at the highest frequency within the 
Main Portion of the study.  
Similarly, if in the Extension Portion of the study, a patient received multiple doses of 
different study drug levels (i.e., 0.1 mg/kg, and 0.3 mg/kg), the patient will be 
assigned to the dose group which they received at the highest frequency within the 
Extension Portion of the study. 
 
3.3.4 Safety Population 
The Safety Population will include all subjects who have received at least 1 dose of 
study drug (i.e., mITT Population), with subjects to be analyzed based on the actual 
treatment received.  
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If, in the Main Portion of the study, a patient received multiple doses of different 
study drug levels (i.e., placebo, 0.1 mg/kg, and 0.3 mg/kg), the patient will be 
assigned to the dose group which they received at the highest frequency within the 
Main Portion of the study.  
Similarly, if in the Extension Portion of the study, a patient received multiple doses of 
different study drug levels (i.e., 0.1 mg/kg, and 0.3 mg/kg), the patient will be 
assigned to the dose group which they received at the highest frequency within the 
Extension Portion of the study. 
3.3.5 RA101495 Safety Population 
The RA101495 Safety Population will include all subjects who are assigned to an 
active treatment group in the Main Portion of the study in the Safety Population or 
received at least 1 dose of RA10495 in the Extension Portion (i.e., this population 
would not include subjects who, in the Safety Population, were assigned to the 
placebo group in the Main Portion and dropped out of the study prior to receiving 
RA101495).  
If, in the Main Portion of the study, a patient received multiple doses of different 
study drug levels (i.e., placebo, 0.1 mg/kg, and 0.3 mg/kg), the patient will be 
assigned to the dose group which they received at the highest frequency within the 
Main Portion of the study.  
Similarly, if in the Extension Portion of the study, a patient received multiple doses of 
different study drug levels (i.e., 0.1 mg/kg, and 0.3 mg/kg), the patient will be 
assigned to the dose group which they received at the highest frequency within the 
Extension Portion of the study. 
3.3.6 Pharmacokinetic Population 
The PK Population will include all subjects in mITT Population who have at least 
1 evaluable PK assessment. All PK analyses will be performed using this population.  
3.3.7 Pharmacodynamic Population 
The PD Population will include all subjects in mITT Population who have at least 
1 evaluable PD assessment. All PD analyses will be performed using this population.  
3.4 Combining RA101495 Data Across Study Portions 
For many of the efficacy and safety endpoints, the data from the Main Portion and the 
Extension Portion will be combined and summarized. Specifically, the Main Portion 
data for subjects in the 0.1 mg/kg dose group will be combined with the Extension 
Portion data for subjects in the placebo−0.1 mg/kg group (i.e., subjects in the placebo 
group for the Main Portion who receive 0.1 mg/kg in the Extension Portion). For the 
efficacy and safety data, the schedule of assessments between the Main Portion and 
Extension Portion are such that the scheduled assessments match up as is indicated by 
the “E1”, “E8”,…,“E84” naming convention used for the Extension Portion visit 
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dates (see Table 10). The same combining of data procedure will be applied to the 0.3 
mg/kg dose group as well. 
In these analyses, the baseline value for the subjects where the data is coming from 
the Extension Portion, will be the value obtained prior to receiving first 
administration of RA101495 (see Section 3.1.3). 
3.5 Efficacy Endpoints 
The following are the primary and secondary efficacy endpoints. For these endpoints 
baseline will be based on Day 1 value.  
3.5.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Week 12 (Day 84) in 
QMG score.   
3.5.2 Secondary Efficacy Endpoints 
The key secondary efficacy endpoint is change from baseline to Week 12 in the MG-
ADL scale.  
Additional secondary efficacy endpoints are: 
• Change from baseline to Week 12 in the MG-ADL scale 
• Minimal symptom expression at Week 12, defined as an MG-ADL scale score of 
0 or 1 
• Change from baseline to Week 12 in the MG-Quality of Life 15r (MG-QOL15r) 
survey 
• Change from baseline to Week 12 in the MG Composite  
• A ≥ 3-point reduction in QMG score at Week 12 
• Requiring rescue therapy over the 12-week Treatment Period.  
3.6 Pharmacodynamic Endpoints 
The PD assessments are: 
• Sheep red blood cell (sRBC) lysis assay for evaluation of classical complement 
pathway activation 
• C5 levels 
3.7 Exploratory Endpoints 
The following exploratory endpoints will also be examined during the study: 
• Responder analysis for changes in QMG, MG-ADL, MG-QOL, and MG-
Composite Scores from baseline to Week 12. 
• Functional sub-scores of the QMG, MG-ADL, MG-QOL, and MG-Composite 
scores  
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o Items for the functional scales are defined in Table 11. The functional sub-
score for a subject is defined as the total score of the corresponding items (or 
the value of the item if it is a single score).   
Table 11: Functional Sub-Scores 
Function 
Scales 
QMG 
 MG ADL 
QOL 
MG Composite 
Ocular 
1-3 
7-8 
2 
1-3 
Bulbar 
4-5 
1-3 
3, 9 
4-6 
Respiratory 
8 
4 
 
7 
Limb/Axial 
6-7, 9-13 
5-6 
12, 15 
8-10 
 
If an item response has a missing value, the methods defined in Section 2.4 for 
imputing missing values will be used.  Specifically, if a subject is missing a 
response for one of the items, the subject’s corresponding item score from the 
previously scheduled assessment will be imputed for the missing item score 
(and the total score calculated using this imputed value and the non-missing 
item scores). If the item response is also missing from the previously 
scheduled assessment, the corresponding function sub-score will be set to 
missing.  
• Mechanistic biomarkers [e.g., MG pathophysiology, complement fixation, 
complement function, complement pathway proteins, autoantibody 
characterization (titer and immunoglobulin class) and inflammation]  
 
• Pharmacogenomic analyses (optional) 
3.8 Patient Disposition and Evaluability 
3.8.1 Patient Disposition 
A disposition of all randomized subjects will be provided. This will include the 
number and percentage of subjects evaluated for each of the analysis populations 
(Section 3.3), which will be presented by treatment group and overall. Percentages 
will be based on the number of subjects in the ITT population in the respective 
treatment group and overall unless otherwise specified.  
The number of subjects completing the Main Portion, entering the Extension Portion, 
completing study Visit Day E84 (i.e., Day 84 of the Extension Portion), discontinuing 
from the study, and the primary reason for discontinuation will also be summarized.  
3.8.2 Protocol Deviations 
A listing of protocol deviations will be presented by treatment group.  
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3.9 Demographics and Baseline Characteristics 
3.9.1 Demographics 
Subject demographics and baseline characteristics will be summarized by treatment 
group and overall for the ITT, mITT, Safety, and PP Populations.  
Descriptive statistics will be provided for age, height, weight, and body mass index 
(BMI, calculated as weight in kilograms divided by height in meters squared). 
Frequencies and percentages will be tabulated for sex, race, and ethnicity. Age will 
also be summarized by <65, 65-<75, and 75. 
Age will be calculated as (informed consent date – date of birth + 1)/365.25, 
truncated and displayed as years. BMI will be calculated as weight (kg)/height2 (m2), 
using the weight and height measurements obtained at screening. 
Baseline and Screening QMG scores will be summarized.  Additionally, for 
Screening QMG, the number and percentage of patients with scores  17 / 18 will be 
presented. Baseline MG-ADL will also be summarized.  
Note: If the day and month are missing for date of birth, impute January 1st, if only 
the day is missing impute the 1st. 
 
Two-sided p-values will be calculated comparing the similarity of the distribution of 
the demographics and baseline characteristics across the treatment groups.  For the 
continuous endpoints, the p-value from the overall F-test from an analysis of variance 
(ANOVA) with treatment group as the factor will be presented. (Note: the set of 
continuous endpoints are: age, weight, BMI, Screening QMG score, Baseline QMG 
Score, Baseline ADL score).  For categorical variables the p-value from the 3×2 
Fisher’s exact test will be presented, with the multi-response categories dichotomized. 
(Note: the set of categorical endpoints are: sex, race [dichotomized as white/non-
white], ethnicity [dichotomized as ‘Hispanic or Latino’ or not]. 
3.9.2 Medical History 
Medical history will be coded using MedDRA version 19.1 (or higher). The coded 
Preferred Terms (PT) will be summarized by treatment group and overall for the 
mITT Population. A subject will be counted only once for each preferred term. The 
summary will present the results alphabetically by System Organ Class (SOC) and, 
within SOC, by decreasing frequency for the Preferred Terms (PT).    
3.9.3 Myasthenia Gravis History  
The following gMG disease history data will be summarized by treatment group and 
overall for the mITT Population.  
• Age at onset (years) 
• Duration of disease (years)  
= (Date of Study Day 1 – Date of Diagnosis)/(365.25) 
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Note: If the Date of Diagnosis day and month are missing impute July 2nd, if only 
the day is missing impute the 15th. If the imputed Date of Diagnosis date is later 
than the date of Study Day 1, impute Study Day 1. 
• Symptoms at onset (Ocular/Generalized)  
• MGFA Disease Class at Screening (Class II, III, or IV) 
• Ever had a Crisis (Yes/No) 
• Time since most recent crisis (months) 
o Time since most recent crisis will be calculated as (Date of Study Day 1– Date 
of Crisis)/(365.25/12) 
Note: If the Date of Crisis day and month are missing impute July 2nd, if only 
the day is missing impute the 15th. If the imputed Date of Crisis date is later 
than the date of Study Day 1, impute the date of Study Day 1. 
• Most Recent Crisis Intervention Required (Hospitalization, ICU, Tracheostomy) 
• Family members have MG (Yes, No) 
• Number of Family members with MG 
• Closest relation with MG (Parent, Sibling, Child, Other) note: more than 1 
relation may be selected 
• Diagnosed with Thymoma (Yes, No) 
• Prior Thymectomy (No: Yes [Total Thymectomy, Subtotal Thymectomy]) 
• Time from Thymectomy (months) 
o Time since  thymectomy will be calculated as (Date of Study Day 1 – Date of 
Thymectomy)/(365.25/12) 
Note: If the Date of Thymectomy day and month are missing impute July 2nd, if only 
the day is missing impute the 15th. If the imputed Date of Thymectomy date is later 
than the date of Study Day 1 impute the date of Study Day 1. 
Additionally, a categorical summary of the age at disease onset overall and by gender 
will be performed by treatment group and overall.  
3.10 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using WHO Drug (Version: 
v.2017JUN01 DDE B2 (enhanced)) and summarized by treatment group and overall 
for the Safety Population.  MG specific medication will be summarized and listed 
separately (see Section 3.11 below) and not included in these summaries. 
 
Incidence of prior and concomitant medication will be presented by treatment group, 
therapeutic class, and preferred (generic) drug name for the Safety Population.  A 
subject is counted only once for each therapeutic class and for each preferred drug 
name. Separate tables will be created for the following study periods: 
A. Prior medications: 
Prior medications are those that started and stopped before the Baseline visit 
 
B. Concomitant Medications in the Main Portion 
Concomitant medications in the Main Portion of the study are those 
concomitant medications taken during the Main Portion of the study (up to, 
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but not including Day 84), including those started before and ongoing at first 
dose. 
 
C. Concomitant Medications in the Main and Extension Portions: 
This analysis will be performed on the RA10495 Safety Population.  This 
combines the Main Portion and the first 12 weeks of the Extension Portion.  
Concomitant medication in the Extension Portion of the study are those 
concomitant medications taken during the Extension Potion of the study (i.e., 
the Extension Portion starting on Day E1/Day 84), including those started 
before and ongoing into the Extension Portion. 
 
The summaries will be performed for the 0.1 mg/kg and 0.3 mg/kg dose 
groups separately and combined, summarizing concomitant medications 
occurring in both the Main Portion and Extension Portion based on the 
following groups: 
 
• 0.1 mg/kg Group: The subjects in the Main Portion 0.1 mg/kg group and 
the subjects in the Extension Portion in the placebo−0.1 mg/kg group.  
• 0.3 mg/kg Group: The subjects in the Main Portion 0.3 mg/kg group and 
the subjects in the Extension Portion in the placebo−0.3 mg/kg group.  
• Combined 0.1 and 0.3 mg/kg Group: Combining the 0.1 mg/kg and 0.3 
mg/kg groups. 
Results will be presented in the following time-frames: 
• Within the First 12 Weeks:  
This will include concomitant medications in in the Main Portion for 
subjects receiving active treatment in the Main Portion and in the first 12 
weeks of the Extension Portion for subjects who received placebo in the 
Main Portion. 
 
• Within the First 24 Weeks: This will include concomitant medications in 
the Main Portion or the first 12 weeks of the Extension Study Period for 
subjects receiving active treatment in the Main Portion. 
 
The following definitions will be used:  
• Prior medications are those that started and stopped before the Baseline visit 
 
• Concomitant medications are all medications taken during the study period, 
including those started before and are ongoing at first dose. 
 
o Concomitant medication in the Main Portion of the study are those 
concomitant medications taken during the Main Portion of the study (up 
to, but not including Day 84), including those started before and ongoing 
at first dose. 
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o Concomitant medication in the Extension Portion of the study are those 
concomitant medications taken during the Extension Potion of the study 
(i.e., the Extension Portion starting on Day E1/Day 84), including those 
started before and ongoing into the Extension Portion.  
 
Where a medication start date is partially or fully missing, and it is unclear as to 
whether the medication is prior or concomitant, it will be assumed that it is 
concomitant and taken in the Main Portion.  
3.11 MG Specific Prior and Concomitant Medications 
MG specific medication will be presented separately from the other prior and 
concomitant medications (for both tables and listings). An MG specific mediation is 
defined by the “indication” value on the Prior and Concomitant Medication eCRF 
form =“Prior therapy for MG”.  
 
The following tables summarizing the incidence of MG medication use will be  
created based on the Safety population: The following 2 tables will be created: 
1) MG specific prior medications:  
MG specific prior medications are those that started prior to the Baseline visit 
 
2) MG specific medications taken at baseline:  
MG specific medications taken at baseline are those where the subject was on 
the medication at baseline (i.e., start date on or prior to Day 1 and stop date on 
or after Day 1 [or ongoing]).  
 
Where an MG medication start date is partially or fully missing, and it is unclear as to 
whether the medication is prior or taken at baseline, it will be assumed that it is taken 
at baseline.    
 
Note that a patient’s MG medication may be in both of these categories.  
 
In addition, a listing of MG specific medications which change from baseline through 
Day E84 will be produced.  
 
Additionally, the number and percentage of patients who are taking one or more of 
the sets of MG specific medications presented in Table 12 (i.e., Groups A-E) will be 
summarized using the same 2 sets of tables: 
1) MG specific prior medications 
2) MG specific medications taken at baseline. 
 
Table 12:  List of MG Medication Groups 
Group 
Concomitant Medication 
Preferred Term 
A 
prednisone for MG 
PREDNISONE 
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other corticosteroids for MG 
TBD* 
B 
Azathioprine 
AZATHIOPRINE 
Mycophenolate 
MYCOPHENOLATE MOFETIL 
C 
IV Ig 
IMMUNOGLOBULINS NOS 
SC Ig 
IMMUNOGLOBULINS NOS 
D 
Cyclosporine 
CICLOSPORIN 
Cyclophosphamide 
CYCLOPHOSPHAMIDE 
Methotrexate 
METHOTREXATE 
Tacrolimus 
TACROLIMUS 
Rituximab 
RITUXIMAB 
other third line 
immunosuppressants 
TBD* 
E 
plasma exchange 
ALL OTHER NON-
THERAPEUTIC PRODUCTS 
* TBD: to be determined; a list of corresponding medications and preferred terms 
will be provided by RA prior to database lock. 
 
3.12 Exposure to Study Treatment 
Study drug will be provided in prefilled syringes for self-injection using weight 
bracketed dosing (i.e., subjects will be provided prefilled syringes containing fixed 
amounts of RA101495 based on their weight, and each fixed amount will cover a 
range of subject weights).  
Prefilled syringes will be dispensed to each subject at each study visit, beginning on 
Day 1 of the Treatment Period.  
Subjects will be provided with training and detailed instructions on the administration 
of study drug using the prefilled syringes and the injection device. 
The location and time of the study drug administrations will be presented in the 
listings for those visits where this information is collected for the Safety Population. 
3.13 Safety Analysis 
Safety analysis results will be presented using the Safety Population by dose group 
and overall.  
For safety analyses, summary results for the 0.1 mg/kg and 0.3 mg/kg dose groups 
will be presented individually and also combining the two dose groups.  
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Listings for all safety data will be presented.  
3.13.1 Adverse Events 
All AEs will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA) Version 20.0 and will be classified by MedDRA system organ class 
(SOC) and preferred term (PT). Analyses of AEs will be performed using the Safety 
Population. 
Treatment emergent AEs (TEAEs) are defined as follows: 
• An AE that occurs after treatment start that was not present at the time of 
treatment start; or 
• An AE that increases in severity after treatment start, if the event was present at 
the time of treatment start. 
TEAE Analyses: 
The following are the set of TEAE summaries to be provided: 
A. Overall summary of Treatment Emergent Adverse Events  
B. Incidence of Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term  
C. Incidence of Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity  
D. Incidence of Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug  
E. Incidence of Treatment Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class and Preferred Term  
For these summaries, the number and percentage of subjects who experienced at least 
one of the TEAE as well as the number and percentage of subjects who experienced 
each specific SOC and PT will be presented by treatment group. The corresponding 
number of TEAEs will also be presented for the Overall Summary of TEAEs table.  
For the presentation of TEAE incidences, the SOCs will be sorted alphabetically, and 
within SOC, the preferred term (PT) will be used and presented by decreasing total 
frequency based on the total population. 
For the overall summary of TEAEs, the following information will be provided  
• Number of subjects with TEAEs 
• Number of subjects with TEAE of Grade 2 or higher 
• Number of subjects with a drug related TEAE 
• Number of subjects with a TEAE leading to study discontinuation  
• Number of subjects with an SAE. 
For reporting, each TEAE will be assigned to either the Main Portion or the 
Extension Portion based on the AE start date: 
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• If the start date of the TEAE is prior to Study Day 84 (i.e., the day the subject 
receives RA101495 in the Extension Portion) the TEAE will be assigned to 
the Main Portion. 
• If the start date of the TEAE is on or after Study Day 84 (i.e., the day the 
subject receives RA101495 in the Extension Portion) the TEAE will be 
assigned to the Extension Portion. 
Additionally, a listing of Serious Adverse Events by System Organ Class and 
Preferred Term will be provided as well as a Listing of Deaths.  
The following are Study Period and Treatment Groups for which the set of TEAE 
analyses (listed as A-E above) will be performed.  
1. Main Portion:  
The set of TEAE analyses will be performed for each of the 3 treatment 
groups (and the RA101495 group combined) summarizing TEAEs occurring 
in the Main Portion. 
2. Main Portion and Extension Portion: 
This combines the Main Portion and the first 12 weeks of the Extension 
Portion. The set of TEAE analyses will be performed for the 0.1 mg/kg and 
0.3 mg/kg dose groups separately and combined, summarizing TEAEs 
occurring in both the Main Portion and Extension Portion based on the 
following groups: 
 
• 0.1 mg/kg Group: The subjects in the Main Portion 0.1 mg/kg group 
and the subjects in the Extension Portion in the placebo−0.1 mg/kg 
group.  
• 0.3 mg/kg Group: The subjects in the Main Portion 0.3 mg/kg group 
and the subjects in the Extension Portion in the placebo−0.3 mg/kg 
group.  
• Combined 0.1 and 0.3 mg/kg Group: Combining the 0.1 mg/kg and 
0.3 mg/kg groups. 
Results will be presented in the following time-frames: 
• Within the First 12 Weeks: This will include AEs with a start date 
within the Main Portion for subjects receiving active treatment in the 
Main Portion and in the first 12 weeks of the Extension Portion for 
subjects who received placebo in the Main Portion. 
• Within the 24 Weeks: This will include AEs with a start date in Main 
Portion or the first 12 weeks of the Extension Study Period for 
subjects receiving active treatment in the Main Portion.  
Note: This is combining the RA101495 data from the Main Portion with the 
RA101495 data from the Extension Portion as described in Section 3.4. 
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3.13.1.1 Treatment Emergent with Adverse Event Date Imputation 
The following rules apply when determining if an AE is treatment-emergent in the 
scenario where the start date is missing or partially missing. These rules provide an 
algorithm to “impute” a complete AE start date which will then be used to determine 
if the AE is treatment emergent.  
AE start date missing day and month: 
• If the year is the same as the year of the treatment start date, the day and 
month of the date of treatment start date will be assigned to the missing fields.  
• If the year is prior to the year of the treatment start date, December 31 will be 
assigned to the missing fields.  
• If the year is after the year of the date of the treatment start date, January 1 
will be assigned to the missing fields.  
AE start date missing month only: 
• The day will be treated as missing, and both month and day will be replaced 
according to the above procedure.  
AE start date missing day only: 
• If the month and year are the same as the month and year of the treatment start 
date, the day of the treatment start date will be assigned to the missing day.  
• If either the year is before the year of the date of the treatment start date or if 
both years are the same, but the month is before the month of the treatment 
start date, the last day of the month will be assigned to the missing day.  
• If either the year is after the year of the treatment start date or if both years are 
the same, but the month is after the month of the treatment start date, the first 
day of the month will be assigned to the missing day.  
AE start date completely missing: 
• If the AE end date is complete and after the treatment start date, the treatment 
start date will be assigned to the missing start date.  
• If the end date is complete and before the treatment start date, the end date 
will be assigned to the missing start date  
• Otherwise the AE start date will be assigned the treatment start date.  
If the end date is complete and the imputed start date as above is after the end date, 
the start date will be imputed by the end date.  
3.13.1.2 Injection Site Reactions 
The investigator should assess the injection site (included as part of the physical 
examination) at each scheduled visit for: 
• Pain, tenderness, erythema, and induration severity (Table 13) 
o Erythema and induration: record the maximum linear diameter  
• Blisters, ulceration, necrosis: record the maximum linear diameter and severity 
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• Lymphadenopathy 
 
Table 13: Grading the Severity of Local Injection Site Reactions 
Local Reaction to 
Injectable 
Product 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life 
Threatening) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room 
visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant discomfort 
at rest 
Emergency room 
visit or 
hospitalization 
Erythema/ 
redness 
2.5 to 5.0 cm 
5.1 to 10.0 cm 
> 10.0 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/ 
swelling 
2.5 to 5.0 cm and 
does not interfere 
with activity 
5.1 to 10.0 cm or 
interferes with activity 
> 10.0 cm or prevents 
daily activity 
Necrosis 
Analysis of injection site reactions (ISRs) will include by treatment summaries of the 
following assessments using the subject’s maximum grade over the corresponding 
study period as well as the number of times a grade was reported for a particular ISR.   
• Any ISR, Pain, tenderness, erythema, and induration severity, and 
lymphadenopathy (categorical variables with grades 1 – 4, and absent). 
This analysis will be performed for the: 
• The Main Portion based on the Safety Population 
• RA10495 Safety Population Within the First 12 Weeks: This will include 
ISRs with an assessment date within the Main Portion for subjects receiving 
active treatment in the Main Portion and in the first 12 weeks of the Extension 
Portion for subjects who received placebo in the Main Portion. 
 
• RA10495 Safety Population Within the 24 Weeks: This will include ISRs 
with an assessment date in Main Portion or the first 12 weeks of the Extension 
Study Period for subjects receiving active treatment in the Main Portion.  
 
3.13.2 Clinical Laboratory Evaluation 
A list of the clinical chemistry, hematology, and coagulation analytes are listed in 
Table 1. 
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Quantitative laboratory endpoints will be summarized (including the value and 
change from baseline) at each scheduled assessment time point using descriptive 
statistics by dose group and combining the active dose groups for the Main Portion.  
For the Extension Portion results will be summarized for the scheduled visits based 
on for the combined 0.1 and 0.3 mg/kg dose groups as defined in Section 3.4.  
Laboratory parameters which do not lend themselves to analyses (e.g., Urinalysis 
“Color”) will be presented in the listings only.  
3.13.2.1 Hepatic Laboratory Tests: NCI CTCAE Grading 
The liver functions test to be summarized via the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) criteria are provided in 
Table 14.  
The number and percentage of subjects meeting these criteria at each scheduled visit 
will be presented for the Main Portion by individual dose group and the combining 
the 0.1 and 0.3 mg/kg dose groups. 
For the Extension Portion, active-dose results will be summarized for the scheduled 
visits based on the individual and combined 0.1 and 0.3 mg/kg dose groups as defined 
in Section 3.3 including results through 24 weeks of active-treatment.  
Table 14: CTCAE Grading Criteria for Selected Liver Function Tests 
Lab Test 
Grade/Criteria 
1 
2 
3 
4 
alanine aminotransferase 
(ALT) 
> 1.0 - 3.0 
(x ULN) 
>3.0 - 5.0  
(x ULN) 
>5.0 - 20.0  
(x ULN) 
> 20.0 
(x ULN) 
alkaline phosphatase 
(ALP) 
>1.0 - 2.5  
(x ULN) 
>2.5 - 5.0 
(x ULN) 
>5.0 - 20.0  
(x ULN) 
> 20.0 
(x ULN) 
direct bilirubin 
> 1.0 – 1.5 
(x ULN) 
>1.5 – 3.0 
(x ULN) 
>3.0 - 10.0  
(x ULN) 
> 10.0 
(x ULN) 
gamma-glutamyl 
transferase  
(GGT) 
>1.0 - 2.5  
(x ULN) 
>2.5 - 5.0 
(x ULN) 
>5.0 - 20.0  
(x ULN) 
>20.0 
(x ULN) 
Grading criteria based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
3.13.2.2 Pancreatic Enzymes: NCI CTCAE Grading 
Amylase and lipase values will be summarized via the NCI CTCAE criteria provided 
in Table 15. 
The number and percentage of subjects meeting these criteria at each scheduled visit 
will be presented for the Main Portion by individual dose group and the combining 
the 0.1 and 0.3 mg/kg dose groups. 
For the Extension Portion, active-dose results will be summarized for the scheduled 
visits based on for the combined 0.1 and 0.3 mg/kg dose groups as defined in Section 
3.3 including results through 24 weeks of active-treatment.  
Table 15: CTCAE Grading Criteria for Selected Pancreatic Enzyme Tests 
Lab Test 
Grade/Criteria 
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1 
2 
3 
4 
amylase 
> 1.0 – 1.5 
(x ULN) 
>1.5 – 2.0 
(x ULN) 
>2.0 - 5.0  
(x ULN) 
> 5.0 
(x ULN) 
lipase 
> 1.0 – 1.5 
(x ULN) 
>1.5 – 2.0 
(x ULN) 
>2.0 - 5.0  
(x ULN) 
> 5.0 
(x ULN) 
Grading criteria based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
3.13.3 Vital Signs and Other Physical Findings 
Descriptive statistics for vital signs (i.e., heart rate, body temperature, and blood 
pressure) values and the change from baseline will be presented for each scheduled 
assessment time points by treatment group. 
3.13.4 ECG 
Descriptive statistics for ECG parameters (i.e., HR, PR interval, RR interval, QRS 
interval, QT interval, QTcB interval, and QTcF interval) at each assessment time 
point will be presented for the values and change from baseline scores by treatment 
group. QTc intervals will be calculated using both Fridericia’s and Bazett’s 
corrections. 
Additionally, the ECG interpretation categorized as Normal, Abnormal – Clinically 
Significant, Abnormal – Not Clinically Significant, Not Evaluable, or Not Done will 
also be provided for each assessment time point (note: ECG interpretations of 
“Abnormal – Clinically Significant” would be recorded as AEs). 
Note: ECG is not performed at Day 1, baseline values will be based on the Screening 
visit. 
3.13.5 Physical Examination 
The complete set physical examination findings will be provided in listings. 
Clinically significant physical examination abnormalities will be included and 
summarized as AEs if appropriate.  
3.14 Efficacy Analyses 
Listings for all efficacy data will be presented.  
3.14.1 Primary Efficacy Endpoint Analysis 
For the primary efficacy endpoint, the change from baseline to Week 12 (Day 84) in 
QMG score, treatment group differences will be assessed by an Analysis of 
Covariance (ANCOVA) model, with treatment as a factor and baseline QMG score as 
a covariate.  
The primary efficacy analysis will be the comparison of the 0.3 mg/kg dose group 
versus the placebo dose group based on the ANCOVA model at a one-sided 0.10 
significance level.  
The comparison of the 0.1 mg/kg dose group versus the placebo dose group will be a 
secondary efficacy analysis tested at the 1-sided 0.10 level. Least-square means for 
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each treatment group will also be presented. The following additional tests will be 
performed:  
• A test of linear trend across the 3 treatment groups: This will be performed by 
an ANCOVA model with treatment as a continuous variable with values of 0, 
0.1, and 0.3 for the placebo, 0.1 mg/kg, and 0.3 mg/kg dose groups 
respectively, and baseline QMG score as a covariate. The test of linear trend 
will be testing the slope of the treatment effect versus 0 using a two-sided p-
value. 
 
• A test for treatment effect pooling the 0.1 mg/kg and 0.3 mg/kg dose groups 
versus placebo: This will be performed by repeating the primary efficacy 
analysis ANCOVA with the 0.1 mg/kg, and 0.3 mg/kg dose groups combined.  
The primary analysis population will be the mITT Population and LOCF is the 
primary method for handling missing data.  
3.14.2 Secondary Efficacy Endpoints Analysis 
The secondary efficacy endpoints are: 
• Change from baseline to Week 12 in the MG-ADL scale 
• Minimal symptom expression at Week 12, defined as an MG-ADL scale score of 
0 or 1 
• Change from baseline to Week 12 in the MG-Quality of Life 15r (MG-QOL15r) 
survey 
• Change from baseline to Week 12 in the MG Composite  
• A ≥ 3-point reduction in QMG score at Week 12 
• Requiring rescue therapy over the 12-week Treatment Period.  
The secondary efficacy endpoints: Week 12 change from baseline in MG-ADL, 
MG-QOL15r, and MG Composite will be analyzed by an ANCOVA model similar to 
the primary efficacy endpoint analysis, with treatment as a factor and the 
corresponding baseline value as a covariate. Each of the active doses will be 
compared to the placebo group based on the ANCOVA model at the 1-sided 0.10 
level. 
For the categorical secondary endpoints: ‘Minimal symptom expression at Week 12, 
defined as an MG-ADL scale score of 0 or 1’, ‘Subjects with ≥ 3-point reduction in 
QMG score at Week 12’ and ‘Subjects requiring rescue therapy over the 12-week 
Treatment Period’, the rate of subjects meeting the endpoint for each of the active 
treatment groups will be compared to the placebo group using a one-sided Fisher’s 
exact test.  
For the secondary endpoints the primary analysis population will be the mITT 
Population and LOCF is the primary method for handling missing data.  
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3.15 Controlling for Multiplicity  
This Phase 2 study will not control for multiple secondary endpoints. 
3.15.1 Additional Analyses of Primary and Secondary Endpoints 
The following are the set of additional analyses for the primary and secondary 
efficacy endpoint analyses: 
a. The primary and secondary efficacy endpoint analyses will be performed on 
the PP population using the LOCF method.  
 
b. The primary and secondary efficacy endpoints will also be performed on the 
PP and mITT populations using the Observed Case analysis method (i.e., as 
defined in Section 3.2).  
 
c. The data from the placebo group Extension Portion (i.e., when the placebo 
group subjects are taking 0.1 mg/kg or 0.3 mg/kg RA101495) will be 
combined with the corresponding 0.1 mg/kg or 0.3 mg/kg RA101495 dose 
group data from the Main Portion following the method described in Section 
3.4. Summary statistics will be provided for the values and change from 
baseline at each of the scheduled assessment time points for this combined 
data. These analyses will be done on the RA101495 Safety population. Note: 
no inferential analyses are planned. This analysis will be done for the change 
from baseline in QMG score and MG-ADL score using the LOCF 
methodology.  
 
d. The ANCOVA model as defined in Section 3.14.1 will be performed on the 
mITT Population using the LOCF method for missing data (as described in 
Section 3.2) including each of the following variables as an additional 
covariate (i.e., a separate ANCOVA model for each variable listed).  
• Sex (dichotomous class variable) 
• Age (continuous variable) 
• Duration of disease (continuous variable) 
• Age at disease onset (continuous variable) 
• Ever had a crisis(dichotomous yes/no class variable) 
• Prior thymectomy (dichotomous yes/no class variable) 
• Prior/current steroid therapya 
• Prior/current immunosuppressive therapy (nonsteroidal)a 
• Prior history of intravenous or subcutaneous Immunoglobulin (IvIg) 
or (plasma exchange) PLEX 
o Prior history of IvIg is defined in Concomitant Medications as 
“IMMUNOGLOBULINS NOS”; this is the ATC code via 
WhoDrug. 
o Prior history of PLEX is defined in Concomitant Medications as 
“ALL OTHER NON-THERAPEUTIC PRODUCTS”; this is the 
ATC code via WhoDrug. 
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a: Prior and concomitant medications will be reviewed and a list of those 
medications meeting this criteria will be finalized prior to database lock.  
This analysis will be done for the change from baseline to Week 12 QMG 
score and MG-ADL score.  
e. For the Main Portion, the frequency distribution of the change from baseline 
will be summarized categorically for the following endpoints:  
• Change from baseline to Week 12 in the QMG score (reduction levels 
from 0 to 20)  
• Change from baseline to Week 12 in the MG-ADL scale (reduction 
levels from 0 to 15)  
• Change from baseline to Week 12 in the MG-QOL15r survey 
(reduction levels from 0 to 15)  
• Change from baseline to Week 12 in the MG Composite (reduction 
levels from 0 to 15)  
Note: the tables may present reduction levels up to the maximum 
reduction level.  
For each of these endpoints the number and % of subjects that have a 
reduction at a particular level and  that particular level (note: for these 
scales reduction from baseline indicates improvement) will be summarized. 
For each level a Fisher’s exact test will be performed testing each active 
group versus the placebo group comparing the number of subjects with a 
change from baseline  that particular level (and the combined active dose 
groups versus placebo).   
These analyses will be done on the mITT population using the LOCF 
method.  
Additionally, the data from the placebo group Extension Portion (i.e., when 
the placebo group subjects are taking 0.1 mg/kg or 0.3 mg/kg RA101495) 
will be combined with the corresponding 0.1 mg/kg or 0.3 mg/kg RA101495 
dose group data from the Main Portion following the method described in 
Section 3.4. A summary of the change from baseline frequencies will be 
provided for the 0.1mg/kg and 0.3 mg/kg (and combined) dose groups.  
 
These analyses will be done on the RA10495 Safety population using the 
LOCF method.  
 
f. A mixed model repeated measures (MMRM) analyzing the Main Portion. 
This analysis will be done on the following endpoints (i.e., a separate 
MMRM will be performed with each of these endpoints as the dependent 
variable): 
• Change from baseline in the QMG score 
• Change from baseline in the MG-ADL scale 
• Change from baseline in the MG-QOL15r survey 
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• Change from baseline in the MG Composite  
 
Treatment, visit, treatment×visit interaction will be factors in the model and 
the corresponding baseline score will be a covariate. The model will adjust 
for repeated measures using a within-subject unstructured covariance matrix 
(note: the covariance matrix structure may be simplified if there are 
convergence issues). The analysis will use the post-baseline scheduled visits 
(Day 8, 15, 29, 57, and 84). 
 
Based on the MMRM model, the treatment differences for each active dose 
group versus placebo as well as the treatment difference of the combined 
active doses versus placebo will be estimated for each of the post-baseline 
scheduled visits using LS means.  
 
The MMRM model will be analyzed using SAS Proc Mixed, example SAS code for 
this MMRM is provided in the  
 
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Appendix. This analysis will be performed on the mITT population using the 
LOCF Method and Observed Case Method for missing data (as described in 
Section 3.2).  
 
g. An MMRM analyzing the data from both the Main Portion and first 12 weeks 
of the Extension Portion will be performed. This analysis will be done on the 
following endpoints (i.e., a separate MMRM will be performed with each of 
these endpoints as the dependent variable): 
o Change from baseline in the QMG score 
o Change from baseline in the MG-ADL scale 
o Change from baseline in the MG-QOL15r survey 
o Change from baseline in the MG Composite  
Treatment, visit, treatment×visit interaction, and Study Portion, will be 
factors in the model and the corresponding baseline score will be a covariate 
(note: Study Portion is a categorical variable referring to the Main Portion 
and Extension Portion). For this analysis, the placebo subjects’ Extension 
Study visit values will use the “matched” visits from the Main Portion. 
Specifically, the EXX visits (see Table 10) for the placebo subjects will map 
to Visit XX of the Main Portion (e.g., the Day E8 visit will map to Day 8 of 
the Main Portion). This has the Visits “matching” relative to the amount of 
time a subject has been on RA101495. For the extension period placebo data, 
the subject’s baseline score (i.e., to be used when estimating change from 
baseline and used in the model as the baseline covariate) will be the Day 84 
score.  
 
The model will be adjusted for repeated measures using a within-subject 
unstructured covariance matrix (note: the covariance matrix structure may be 
simplified if there are convergence issues). The analysis will use the post-
baseline scheduled visits (Day 8, 15, 29, 57, 84/E1, E8, E15, E29, E57, and 
E84).  
 
Based on the MMRM model, the treatment difference of the combined active 
doses versus placebo will be estimated for each of the initial visits using LS 
means (Day 8, 15, 29, 57, and 84) and the LS-Means for the two active dose 
groups will be estimated for Visits: E1, E8, E15, E29, E57, and E84.  
The MMRM model will be analyzed using SAS Proc Mixed, example SAS code for 
this MMRM is provided in the  
 
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Appendix. This analysis will be performed on the mITT population using the 
LOCF Method and Observed Case Method for missing data (as described in 
Section 3.2).  
h. The primary and secondary efficacy endpoint analyses will be performed on 
the mITT and PP population using the LOCF and Observed Case methods for 
the other scheduled assessment time points in the Main Portion. 
3.15.2 Pharmacodynamic Endpoints Analysis 
Pharmacodynamic analyses will be performed on the PD Population.  
The pharmacodynamic endpoints include: 
• Sheep red blood cell (sRBC) lysis assay 
• C5 levels 
Summary statistics will be provided for the values, change from baseline, and percent 
change from baseline at each of the scheduled assessment time points.  
For the Main Portion, the change from baseline for each of these endpoints will be 
assessed by an ANCOVA model with treatment as a factor and the corresponding 
baseline value as a covariate. Each of the active doses will be compared to the 
placebo group based on the ANCOVA model. 
Additionally, the data from the placebo group Extension Portion (i.e., when the 
placebo group subjects are taking 0.1 mg/kg or 0.3 mg/kg RA101495) will be 
combined with the corresponding 0.1 mg/kg or 0.3 mg/kg RA101495 dose group data 
from the Main Portion following the method described in Section 3.4. Summary 
statistics will be provided for the values, change from baseline, and percent change 
from baseline at each of the scheduled assessment time points for this combined data.  
These analyses will be performed on the PD population using observed cases (i.e., no 
censoring or imputation of data). 
3.15.3 Pharmacokinetic Endpoints Analysis 
Pharmacokinetic analyses will be performed on the PK Population.  
The following pharmacokinetic endpoints will be presented in listings and 
summarized in tables. 
• Plasma concentrations of RA101495 and its two major metabolites 
(
) 
• Maximum plasma concentration (Cmax)  
• Time corresponding to Cmax (tmax) 
• Ratio of parent to metabolites (i.e., 2 metabolites). 
 
These analyses will be performed on the PK population using observed cases (i.e., no 
censoring or imputation of data). Note: the PK parameters will be calculated by an 
external vendor and provided to PRA.   
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3.15.4 Exploratory Endpoints Analysis 
For the functional sub-scores of the QMG, MG-ADL, QOL, and Composite scores 
(defined in Section 3.7) the endpoints will be summarized using descriptive statistics 
at each scheduled assessment time point. Additionally, an ANCOVA model, with 
treatment as a factor and corresponding baseline score as a covariate will be 
performed to assess treatment group differences.  This will be performed on the mITT 
population using LOCF. 
The following exploratory endpoints will be summarized using descriptive statistics 
at each scheduled assessment time point in the Main Portion: 
• Mechanistic biomarkers pertinent to MG pathophysiology [e.g., complement 
fixation, complement function, complement pathway proteins, autoantibody 
characterization (titer and immunoglobulin class) and inflammatory markers]  
• Anti-drug antibodies: The number and percentage of subjects with a positive 
confirmatory assay will be summarized for each of the scheduled assessment time 
points. 
Pharmacogenomic analyses (optional) data collected will be presented in a listing.  
3.16 Additional Analyses 
3.16.1 Rescue Therapy 
Subjects requiring rescue therapy over the 12-week Treatment Period is a secondary 
efficacy endpoint, with the analysis described in Section 3.14.2. 
In addition to the secondary efficacy analyses the following analyses will be 
performed for the Main Portion on the mITT Population: 
• For those subjects who receive rescue therapy during the Main Portion, the 
time to rescue therapy will be summarized using descriptive statistics, 
including the number and percentage of subjects receiving rescue therapy, 
and time to rescue therapy. Time to rescue therapy (in days), will be 
calculated as: 
Time to rescue therapy = (Date of Day 1 visit – Date of Rescue Therapy + 1) 
• The frequency and type of rescue medication (Immunoglobulin or Plasma 
Exchange) a subject receives will be summarized. 
These summaries will be provided by dose group and for the 0.1 and 0.3 mg/kg 
dose groups combined.  
For those subjects who receive rescue therapy while on RA101495 (i.e., both in the 
Main Portion and the first 12 weeks of the Extension Portion) the following 
summaries will be performed on the RA101495 Safety population: 
• The number and percentage of subjects receiving rescue therapy 
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• The time from first dose of RA101495 to rescue therapy (summarized for 
those subjects who received rescue therapy) 
• The frequency and type of rescue medication (Immunoglobulin or Plasma 
Exchange) a subject received 
The summaries will be provided by RA10495 dose group and the 0.1 and 0.3 
mg/kg dose groups combined. 
3.17 Interim Analysis 
No interim analysis is planned for the Main Portion of the study. Interim analyses 
during the Extension Portion of the study will be performed.  
3.18 Timing of Primary Analysis 
For the primary analyses of the Main Portion of the study, when all subjects have 
completed the Main Portion of the study, the Main Portion data in the study database 
will be “frozen” and the set of primary, secondary, and a subset of the additional 
efficacy analysis will be performed in addition to a subset of the safety analyses 
corresponding to the Main Portion of the study. 
3.19 Sample Size Considerations 
For the primary efficacy endpoint, change from baseline to Week 12 (Day 84) in 
QMG score, assuming a difference in treatment group means of 4.5, an SD of 5.0, and 
12 subjects per group, the study has approximately 81% power to detect a difference 
between an active and placebo treatment group based on a 1-sided t-test with a 0.10 
type I error rate. 
3.20 Replacement of Subjects 
Subjects who prematurely discontinue participation prior to the Day 84 visit may be 
replaced in order to obtain at least 12 evaluable subjects per treatment arm. 
3.21 Protocol Violations  
Protocol violations will be assessed as major or minor prior to database unblinding, in 
a blinded manner. A listing of protocol violations by treatment group will be 
presented.  
4 References  
Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability 
testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci. 1998;841:769-
772. 
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RA101495-02.201                                                                         Statistical Analysis Plan 
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Benatar M, Sanders DB, Burns TM, Cutter GR, Guptill JT, Baggi F, et al; Task Force 
on MG Study Design of the Medical Scientific Advisory Board of the Myasthenia 
Gravis Foundation of America. Recommendations for myasthenia gravis clinical 
trials. Muscle Nerve. 2012;45(6):909-917. 
Burns, TM, Grouse CK, Conway MR, Sanders DB, and MG Composite and 
MG-QOL 15 study group. Construct and concurrent validation of the MG-QOL 15 in 
the practice setting. Muscle Nerve. 2010;41(2):219-226. 
Burns TM, Sadjadi R, Utsugisawa K, Gwathmey KG, Joshi A, Jones S, et 
al.International clinimetric evaluation of the MG-QOL15, resulting in slight revision 
and subsequent validation of the MG-QOL15r. Muscle Nerve. 2016;54(6):1015-1022. 
Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference 
in myasthenia gravis: outcomes from a randomized trial. Muscle Nerve. 
2014;49(5):661-665. 
Muppidi S, Wolfe GI, Conaway M, Burns TM; MG Composite and MG-QOL15 
study group. MG ADL: still a relevant outcome measure. Muscle Nerve. 
2011;44(5):727-731. 
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;45(6):820-825. 
Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia 
gravis activities of daily living profile. Neurology. 1999;52(7):1487-1489. 
 
 
 
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5 Appendix 1: Sample SAS code for Repeated Measures 
Mixed Models 
The following is the sample code for the MMRM ANCOVA for the Main Portion 
described in Section 3.15.1, sub-section f. Note that this is an example to be used as a 
reference, the actual SAS code may differ from the sample provided below.  
 
** MMRM ANCOVA Code **; 
** Analysis of Main Portion of the Study **; 
proc mixed data=XXXX; 
  class usubjid visit trt(Ref='0'); 
  model y_chg = y_base visit trt trt*visit/s;  
  repeated /subject=usubjid type=UN; 
  lsmeans visit*trt/diff; 
  ods output lsmeans=lsmeans; 
  ods output diffs=diffs; 
  ** Subset to Main Portion, Scheduled Assessment timepoints **; 
  where visit in(8,15, 29, 57, 84);  
run;  
 
** this data step subsets the LS means comparisons to within a 
visit, comparing against trt=0 **; 
data diffs2; 
  set diffs; 
  where _trt=0 and visit=_visit; 
run; 
 
**--------------------------------------------------------------**;  
** MMRM ANCOVA Code                                             **; 
** Analysis of Main and Extension Portion of the Study          **; 
** 1) for subjects randomized to treatment in main portion:     **; 
**   visit_x = visit                                            **; 
** 2) for subjects randomized to placebo in main portion:       **; 
**   visit_x = visit for main portion                           **; 
**   visit_x = corresponding main portion visit for extension   **; 
proc mixed data=simu4; 
  class usubjid visit_x trt(Ref='0'); 
  model y_chg = y_base visit_x trt trt*visit_x/s;  
  repeated /subject=usubjid type=UN; 
  lsmeans visit_x*trt/diff; 
  ods output lsmeans=xlsmeans; 
  ods output diffs=diffs; 
    where visit in(8,15, 29, 57, 84, 91, 98, 112, 140, 167);  
run;  
 
** this data step subsets the LS means comparisons to within a 
visit, comparing against trt=0 **; 
data diffs2; 
  set diffs; 
  where _trt=0 and visit_x=_visit_x; 
run; 
 
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6 Appendix 2: Analyses Including Data After Day E84 
The following are the set of tables to summarize the data collected after Day E84.  
The tables will provide descriptive summary statistics (i.e., no inferential analyses 
will be performed). 
6.1 Additional Analysis Population: Extension Population 
The Extension Population will include all subjects who entered the Extension Period 
of the study as indicated by having a Day E1 visit.  
6.2 Disposition 
The Extension Period Disposition table will be amended to provide the number of 
subjects who completed Week E84 of the study and the reasons for discontinuation. 
6.3 Subject Switching From 0.1 mg/kg to 0.3 mg/kg 
The date a subject in the 0.1 mg/kg group switched to 0.3 mg/kg (i.e., during the 
expansion phase of the study) will be presented in a listing.  
Note: the date that a subject increased from the 0.1 mg/kg dose group to the 0.3 
mg/kg dose group is recorded as “Date subject received first dose of open label study 
drug” in the eCRF form “Open Label Re-consent”. 
6.4 Exposure 
The number of years a patient is on the 0.1 mg/kg dose and 0.3 mg/kg dose group will 
be calculated for each subject using the following algorithm: 
• The beginning of the interval will be the first day the subject begins that dose 
level.  This will one of 3 timepoints:  
o Day 1 of the Main Portion: the subject received this medication in the 
Main Portion) 
o Study Day 84/E1: the subject received placebo in the Main Portion and 
the dose of interest starting 
o The day the subject’s dose increases from 0.1 mg/kg to 0.3 mg/kg: the 
subject was on 0.1 mg/kg and, during the Extension Period, the 
subject’s dose was increased to 0.3 mg/kg. 
 
• The end of the interval will be: 
o The day the subject either discontinues or completes the study  
o For the 0.1 mg/kg dose, the day prior to the subject taking the 0.3 
mg/kg dose 
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The number of years for a subject on zilucoplan will be calculated (for the 0.1 mg/kg 
and 0.3 mg/kg dose groups separately) as: 
Interval = (date of end of Interval – date of beginning of interval)/365.25 
The total number of patient-years for a dose group will be the sum of the individual 
patient-years for that doses group within the corresponding population. This 
information will be presented in the adverse event table  
6.5 Efficacy Endpoints 
Efficacy endpoints will be summarized by the groups listed in Table 16. 
Table 16: Extension Table Groups 
Table Header 
Treatment Group 
Pbo/RA101495  
0.1 mg/kg 
These are the subjects randomized Placebo in the Main 
Portion and randomized to 0.1 mg/kg in the Extension 
Portion 
RA101495/RA101495 
0.1 mg/kg 
 
These are the subjects randomized 0.1 mg/kg in the Main 
Portion and randomized to 0.1 mg/kg in the Extension 
Portion 
Pbo/RA101495  
0.3 mg/kg 
 
These are the subjects randomized Placebo in the Main 
Portion and randomized to 0.3 mg/kg in the Extension 
Portion 
RA101495/RA101495 
0.3 mg/kg 
 
These are the subjects randomized 0.3 mg/kg in the Main 
Portion and randomized to 0.3 mg/kg in the Extension 
Portion 
Total 
These are all subjects in the population.  
Additional information for the efficacy tables: 
• The analysis population for the tables will be the Extension Population 
(defined in Section 6.1) 
• The endpoints will be summarized starting at Week E1 through Week E84 
(i.e., the last scheduled visit for the study) 
• The Observed Case method for the Extension Period, as described in Section 
3.2.2, will be applied.  
• The value and change from baseline values will be summarized. Baseline will 
be derived using the Extension Period definition of Baseline as described in 
Section 3.1.3. 
The efficacy endpoints to be summarized include the primary and secondary change 
from baseline efficacy endpoints (i.e., QMG, MG-ADL, MG-QOL15r, and MG 
Composite).  
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6.6 Safety Endpoints 
6.6.1 Adverse Events 
TEAEs will be summarized across the entire study, excluding TEAEs occurring 
during the Main Portion of the study for those subjects on placebo during the Main 
Portion. Results will be summarized by the dose the subject was on (i.e., 0.1 mg/kg or 
0.3 mg/kg) at the start date of the TEAE as well as “Overall”. 
The AE tables will include: 
• TEAEs by SOC/PT 
• Related TEAEs by SOC/PT 
• Serious TEAEs by SOC/PT 
In addition, an overall summary of TEAEs table will present the following: 
• Any TEAEs 
• Any Grade 2 or Greater, Grade 3 or Greater, and Grade 4 or Greater, TEAEs 
• Any Treatment-Related TEAEs 
• Any Grade 2 or Greater, Grade 3 or Greater, and Grade 4 or Greater, 
Treatment-Related TEAEs 
• Any TEAEs with Outcome of Death 
• Any Serious TEAEs 
• Any Treatment-Related Serious TEAEs 
The AE, SAE, and TEAEs with an outcome of Death listings will be updated to 
include the dose the subject is on at the start of the event. As the subject-years 
exposure will be notably different between the 0.1 mg/kg group and the 0.3 mg/kg 
group a footnote will be provided to provide context to the AE frequencies and 
percentages. The subject-years will be calculated using the method described in 
Section 6.3. 
For each of these AE tables the total number of patient-years for each treatment group 
(and overall) as defined in Section 6.3 will be presented.  
6.6.2 Labs and Vital Signs 
Labs and vital sign endpoints will be summarized in the same manner as the efficacy 
endpoints (defined in Section 6.5). 
 
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