Clinical trial NCT03863080
Conditions: Myasthenia Gravis
Keywords: IMVT-1401
Sponsor: Immunovant Sciences GmbH
Start date: 2019-05-21; Completion date: 2020-12-21
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the current study is to assess safety/tolerability and key pharmacodynamic (PD) effects that are considered to be associated with clinical benefit (reduction of total IgG and anti-AChR-IgG) in Myasthenia Gravis patients following treatment with RVT-1401 (also known as IMVT-1401) compared to placebo.

Detailed description:

Arms: arm 1: RVT-1401 680 mg weekly for 6 weeks + optional open-label extension (RVT-1401, 340 mg every 2 weeks for 6 weeks) arm 2: RVT-1401 340 mg weekly for 6 weeks + optional open-label extension (RVT-1401, 340 mg every 2 weeks for 6 weeks) arm 3: Placebo for 6 weeks + optional open-label extension (RVT-1401, 340 mg every 2 weeks for 6 weeks)
Interventions: intervention 1: RVT-1401 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous administration of RVT-1401 intervention 2: Subcutaneous administration of Placebo

Protocol documents:
Prot_000.pdf: 
 
Immunovant Sciences GmbH Protocol RVT-1401-2002, Version 3.0 
Confidential 
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CLINICAL STUDY PROTOCOL 
Title: 
A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study with an Open-Label Extension of RVT-1401 in 
Myasthenia Gravis Patients 
Sponsor 
Immunovant Sciences GmbH, a Swiss Limited Liability Company, is 
the Sponsor of this study. Immunovant, Inc., an affiliate of 
Immunovant Sciences GmbH, has been engaged by Immunovant 
Sciences GmbH to manage the day-to-day operations of the study. All 
references to “Sponsor” contained herein shall refer to Immunovant, 
Inc., acting pursuant to a services agreement with Immunovant 
Sciences GmbH. 
Compound Name: 
RVT-1401 
Protocol Number 
RVT-1401-2002 
Indication 
Myasthenia Gravis 
Development Phase 
2a 
IND # 
141885 
Version/ 
Effective Date: 
Amendment 2: Version 3.0 
10-APR-2019 
Amendment 1: Version 2.0 
18-JAN-2019 
Original: Version 1.0 
04-DEC-2018  
Immunovant, Inc. 
Study Director 
Telephone:
Email:
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under control of Sponsor, 
and is provided to you in confidence as an investigator, potential investigator or consultant, for review by you, your 
staff, and an applicable Institutional Review Board or Independent Ethics Committee. The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described in the protocol. You 
will not disclose any of the information to others without written authorization from Sponsor, except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 


 
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SPONSOR SIGNATURE PAGE: 
Study title: A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study with an Open-Label Extension of RVT-1401 in Myasthenia Gravis Patients  
 
Protocol Number: 
RVT-1401-2002 
 
This protocol has been approved by Sponsor’s representative. The following signature 
documents this approval. 
Immunovant, Inc. 
 
Date 
 
 




 
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INVESTIGATOR STATEMENT 
• 
I confirm agreement to conduct the study in compliance with the protocol. 
• 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
• 
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations and comply with the study 
protocol. Mechanisms are in place to ensure that site staff receives the appropriate 
information throughout the study. 
 
______________________________________ 
______________________________ 
Principal Investigator Name (Printed) 
 
Signature 
 
______________________________________ 
______________________________ 
Site 
 
 
 
 
 
 
Date 


 
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1. 
TABLE OF CONTENTS 
PAGE 
1. 
TABLE OF CONTENTS ........................................................................................... 5 
2. 
PROTOCOL SUMMARY FOR STUDY RVT-1401-2002 ........................................... 8 
3. 
INTRODUCTION .................................................................................................... 11 
3.1. 
Background ................................................................................................ 11 
3.1.1. 
Myasthenia Gravis ....................................................................... 11 
3.2. 
Rationale .................................................................................................... 12 
3.2.1. 
Study Rationale ........................................................................... 12 
3.2.2. 
Dose rationale ............................................................................. 12 
3.2.3. 
Clinical Experience ...................................................................... 14 
3.2.3.1. 
Safety ......................................................................... 15 
3.2.3.2. 
Pharmacokinetics ....................................................... 15 
3.2.3.3. 
Pharmacodynamic ...................................................... 16 
3.3. 
Benefit: Risk Assessment ........................................................................... 17 
3.3.1. 
Risk Assessment ......................................................................... 17 
4. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 19 
5. 
STUDY DESIGN .................................................................................................... 20 
5.1. 
Overall Design ............................................................................................ 20 
5.2. 
Study Schematics ....................................................................................... 22 
5.3. 
Treatment Arms and Duration ..................................................................... 22 
6. 
PARTICIPANT POPULATION ................................................................................ 23 
6.1. 
Type and Number of Participants ................................................................ 23 
6.2. 
Inclusion Criteria ......................................................................................... 23 
6.3. 
Exclusion Criteria ........................................................................................ 24 
6.4. 
Eligibility for the OLE .................................................................................. 26 
6.5. 
Other Eligibility Criteria Considerations ....................................................... 26 
6.6. 
Screening/Baseline Failures ....................................................................... 26 
6.7. 
Lifestyle Restrictions ................................................................................... 26 
6.7.1. 
Contraception .............................................................................. 26 
6.8. 
Withdrawal Criteria ..................................................................................... 27 
6.8.1. 
Reasons for Withdrawal ............................................................... 27 
6.8.2. 
Participant Withdrawal Procedures .............................................. 28 
6.9. 
Stopping Criteria for Individual Participants ................................................. 28 
6.9.1. 
Liver Chemistry Stopping Criteria ................................................ 28 
6.9.2. 
Criteria for Permanent Discontinuation of Study Treatment 
in Association with Liver Test Abnormalities ................................ 29 
6.9.3. 
QTc Withdrawal Criteria ............................................................... 29 
6.9.4. 
Albumin Monitoring Criteria .......................................................... 30 
6.10. 
Toxicity Management Criteria ..................................................................... 31 
6.10.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and 
Site Reactions) ............................................................................ 31 
6.10.2. 
Other Management Criteria ......................................................... 32 


 
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6.11. 
Participant and Study Completion ............................................................... 32 
7. 
STUDY TREATMENT ............................................................................................ 32 
7.1. 
Investigational Product and Other Study Treatment .................................... 32 
7.2. 
Treatment Assignment ................................................................................ 34 
7.3. 
Blinding ....................................................................................................... 34 
7.4. 
Packaging and Labeling .............................................................................. 34 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 35 
7.6. 
Compliance with Study Treatment Administration ....................................... 35 
7.7. 
Treatment of Study Treatment Overdose .................................................... 36 
7.8. 
Treatment After the End of the Study .......................................................... 36 
7.9. 
Concomitant Medications and Non-Drug Therapies .................................... 37 
7.9.1. 
Permitted Medications and Non-Drug Therapies .......................... 37 
7.9.2. 
Prohibited Medications and Non-Drug Therapies ......................... 37 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 37 
8.1. 
Time and Events Table (12-week follow-up without OLE) ........................... 38 
8.2. 
Time and Events Table (With OLE and 6-week follow-up) .......................... 41 
8.3. 
Screening and Critical Baseline Assessments ............................................ 44 
8.4. 
Study Assessments and Procedures .......................................................... 44 
8.4.1. 
Physical Exams ........................................................................... 44 
8.4.2. 
Vital Signs .................................................................................... 44 
8.4.3. 
Electrocardiogram (ECG) ............................................................. 44 
8.4.4. 
Clinical Safety Laboratory Assessments ...................................... 44 
8.4.5. 
Pharmacokinetics ........................................................................ 46 
8.4.6. 
Anti-Drug Antibody (ADA) and Neutralizing Antibody 
(NAb) ........................................................................................... 46 
8.4.7. 
Pharmacodynamics ..................................................................... 47 
8.4.8. 
Exploratory Biomarkers ................................................................ 47 
8.5. 
Myasthenia Gravis Assessments ................................................................ 48 
8.5.1. 
Myasthenia Gravis Activities of Daily Living (MG-ADL) ................ 48 
8.5.2. 
Quantitative Myasthenia Gravis Score (QMG) ............................. 48 
8.5.3. 
Myasthenia Gravis Composite Score (MGC) ............................... 48 
8.5.4. 
Myasthenia Gravis Quality of Life 15 revised Score (MG-
QOL 15r)...................................................................................... 48 
8.5.5. 
Satisfaction Questionnaire ........................................................... 49 
9. 
DATA MANAGEMENT ........................................................................................... 49 
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ................................. 49 
10.1. 
Sample Size Considerations ....................................................................... 49 
10.2. 
Data Analysis Considerations ..................................................................... 49 
10.2.1. 
Analysis Populations .................................................................... 49 
10.2.2. 
Interim Analysis ........................................................................... 50 
10.3. 
Final Analysis ............................................................................................. 50 
10.3.1. 
Primary Endpoint for Efficacy ....................................................... 51 
10.3.2. 
Secondary Endpoints for Efficacy ................................................ 51 
10.3.3. 
Safety Analyses ........................................................................... 52 
10.3.4. 
Pharmacokinetic Analyses ........................................................... 52 
10.3.5. 
Pharmacodynamic Analyses ........................................................ 52 
10.3.6. 
Other Analyses ............................................................................ 53 
10.3.1. 
OLE and Follow up Analyses ....................................................... 53 


 
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11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAES) ................ 53 
11.1. 
Definition of Adverse Events ....................................................................... 54 
11.2. 
Definition and Reporting of Serious Adverse Events ................................... 54 
11.3. 
Time Period and Frequency for Collecting AE and SAE Information ........... 55 
11.4. 
Method of Detecting and Reporting AEs and SAEs .................................... 56 
11.5. 
Assessing Severity of AEs and SAEs ......................................................... 56 
11.6. 
Assessing Causality of AEs and SAEs ........................................................ 57 
11.7. 
Follow-up of AEs and SAEs ........................................................................ 58 
11.8. 
Regulatory Reporting Requirements for SAEs ............................................ 58 
11.9. 
Overdose .................................................................................................... 58 
12. PREGNANCY REPORTING .................................................................................. 58 
13. RESPONSIBILITIES .............................................................................................. 59 
13.1. 
Principal Investigator Responsibilities ......................................................... 59 
13.1.1. 
Good Clinical Practice (GCP) ....................................................... 59 
13.1.2. 
Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) Approval ........................................................... 59 
13.1.3. 
Informed Consent ........................................................................ 60 
13.1.4. 
Confidentiality .............................................................................. 60 
13.1.5. 
Study Files and Retention of Records .......................................... 61 
13.1.6. 
Electronic Case Report Forms (eCRF) ........................................ 62 
13.1.7. 
Drug Accountability ...................................................................... 62 
13.1.8. 
Inspections .................................................................................. 63 
13.1.9. 
Protocol Compliance .................................................................... 63 
13.2. 
Sponsor Responsibilities ............................................................................. 63 
13.2.1. 
Protocol Modifications .................................................................. 63 
13.2.2. 
Study Report and Publications ..................................................... 63 
13.2.3. 
Posting of Information on Publicly Available Clinical Trial 
Registers ..................................................................................... 63 
13.3. 
Joint Investigator/Sponsor Responsibilities ................................................. 63 
13.3.1. 
Access to Information for Monitoring ............................................ 63 
13.3.2. 
Access to Information for Auditing or Inspections ......................... 64 
13.3.3. 
Study Discontinuation .................................................................. 64 
14. REFERENCES ....................................................................................................... 65 
15. APPENDICES ........................................................................................................ 67 
15.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 67 
15.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments .............................................................................................. 70 
15.3. 
Appendix 3: Protocol Amendment Summary of Changes ............................ 72 
 
 


 
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2. 
PROTOCOL SUMMARY FOR STUDY RVT-1401-2002  
Study Title 
A Phase 2a, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study with an Open-Label Extension of 
RVT-1401 in Myasthenia Gravis Patients 
Objectives 
Primary 
To assess the safety and tolerability of RVT-1401 in AChR 
antibody positive MG patients over a 6-week treatment 
period 
To examine the effects of RVT-1401 on total IgG, IgG 
subclasses (1-4) and anti-AChR-IgG levels 
Secondary 
To examine RVT-1401 PK following repeat doses in 
patients with Myasthenia Gravis (MG) 
To measure anti-RVT-1401 antibodies following repeat 
doses in patients with MG and assess any potential impact 
on PK or PD 
To examine the effects of RVT-1401 on the Quantitative 
Myasthenia Gravis (QMG) score  
To examine the effects of RVT-1401 on the proportion of 
patients with improvement on the QMG score by ≥ 3 points 
from baseline  
To examine the effects of RVT-1401 on Myasthenia Gravis-
Activities of Daily Living score (MG-ADL)  
To examine the effects of RVT-1401 on the proportion of 
participants with an improvement on the MG-ADL Score by 
≥2 points  
To examine the effects of RVT-1401 on the Myasthenia 
Gravis Composite (MGC) score  
To examine the effects of RVT-1401 on the proportion of 
participants with an improvement on the MGC Score by ≥3  
To examine the effects of RVT-1401 on the Myasthenia 
Gravis Quality of Life (MG-QOL15r) score  
Open-Label Extension Objective: 
The objective of the OLE is to evaluate the effect of 
switching to every 2-week dosing regimen of 340 mg RVT-
1401 on all study endpoints. 


 
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Study Phase 
Phase 2a 
Target Population 
Myasthenia Gravis 
Number of Participants 
Planned 
Approximately 21 
Number of Study 
Centers Planned 
Approximately 10-15 
Study Design 
Phase 2a, randomized, double-blind, placebo-controlled 
study, with an open-label extension (OLE) to investigate the 
safety, tolerability, PK, PD, and efficacy of two dosing 
regimens of RVT-1401 
Duration of Treatment 
6 weeks or 12 weeks (3 additional doses for the OLE)  
Criteria for Evaluation 
(Endpoints) 
Primary 
Assessment of safety and tolerability by analysis of adverse 
events (AEs) data and changes from baseline in vital signs, 
clinical laboratory values, and electrocardiograms  
Change from baseline in levels of total IgG and IgG 
subclasses (1-4)  
Change from baseline in levels of anti-AChR-IgG 
Secondary 
PK Parameters of AUC (0-168 h) and maximum 
concentration (Cmax) after first and last dose 
Concentration of RVT-1401 pre-dose (Ctrough)  
Immunogenicity determined by change from pre-dose in 
anti-RVT-1401 antibodies, characterization of any anti-
RVT-1401 to confirm neutralization potential  
Change from baseline in the QMG Score  
Proportion of participants with an improvement on the QMG 
score by ≥ 3 points from baseline  
Change from baseline in the MG-ADL score  
Proportion of participants with an improvement on the MG-
ADL Score by ≥2 points  
Change from baseline in the MGC score  
Proportion of participants with an improvement on the MGC 


 
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Score by ≥3 points  
Change from baseline in the MG-QOL15r score  
 


 
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3. 
INTRODUCTION 
3.1. 
Background 
RVT-1401 is a fully human anti-neonatal Fc receptor (FcRn) monoclonal antibody.  
FcRn is critical to the regulation of Immunoglobulin G (IgG) [Roopenian, 2007 ]. In 
addition to its central role in mediating the transport of IgG within and across cells of 
diverse origin, it also serves to rescue IgG from degradation, thereby prolonging its 
circulating half-life [Roopenian, 2007]. Targeting the FcRn pathway has been shown to 
dramatically reduce circulating IgG, thus supporting its use in the treatment of auto-Ab 
mediated autoimmune diseases.  
3.1.1. 
Myasthenia Gravis 
Myasthenia Gravis (MG) is a chronic autoimmune neuromuscular disease that causes 
weakness and fatigue. The muscles that control eye and eyelid movement are particularly 
susceptible to weakness, but other muscles for chewing, talking, and swallowing are 
frequently involved. Patients with ocular MG often progress to more severe, generalized 
disease with involvement of bulbar, axial, limb, and/or respiratory muscles.   
MG is part of a spectrum of autoimmune diseases in which pathogenic IgG (pIgG) is 
thought to directly cause and/or exacerbate the condition.  MG results from binding of 
autoantibodies to proteins that lead to impaired transmission at the neuromuscular 
junction. Most commonly, in approximately 80% of MG patients, anti-acetylcholine 
receptor (AChR) IgG is detected, and in a smaller subset (approximately 40-50% of 
patients who are seronegative for anti-AChR IgG), anti-muscle-specific kinase receptor 
(MuSK) IgG is detected [Gilhus, 2015]. Recently, autoantibodies against low-density 
lipoprotein related receptor protein 4 (Lrp4) have been described in seronegative MG 
patients with varying frequencies ranging from 2 to 50% [Higuchi, 2011; Zisimopoulou,  
2014; Zhang, 2012; Pevzne, 2012]. The clinical characteristics of Lrp4-MG have yet to 
be fully characterized [Evoli, 2015]. 
The chronic nature of MG requires patients to cope with fluctuating symptoms and often 
maintain treatment with acetylcholinesterase inhibitors, corticosteroids, 
immunosuppressants, plasmapheresis, and/or intravenous immunoglobulin [Sanders, 
2016; Nowak, 2018]. Despite chronic treatment, up to 20% of MG patients can progress 
into myasthenic crisis [Utsugisawa, 2014]. MG has widespread and significant negative 
effects on quality of life including daily activities such as eating, walking, and speaking 
[Nowak, 2018]. Overall, the persistent muscle weakness associated with MG often 
negatively interferes with patients’ ability to engage in daily activities, including 
demands of work, family, social functions, and physical activities [Paul, 2001]. 
Current treatment guidelines recommend pyridostigmine as first line therapy with or 
without concomitant corticosteroids for patients who are anti-AChR-IgG-positive 
[Sanders, 2016]. If corticosteroids are contraindicated, nonsteroidal immunosuppressive 
(IS) agents are used, including azathioprine (AZA), cyclosporine, mycophenolate mofetil, 
methotrexate, and tacrolimus. Despite existing treatment regimens, current methods 
provide variable efficacy. Failure rates for current treatments range from 15–53% 


 
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depending upon the presentation and diagnosis, and up to 20% of patients treated with IS 
agents experience severe side effects [Sanders, 2010]. Thus, there is a need for more 
efficacious and safer therapies.  
 
3.2. 
Rationale 
3.2.1. 
Study Rationale 
RVT-1401 functions by inhibiting the binding of IgG to FcRn. This results in the rapid 
catabolism of IgG via lysosomal degradation. In MG, RVT-1401 treatment is expected to 
lead to a significant reduction in the levels of pIgG such as anti-AChR-IgG, anti-MuSK-
IgG, and anti-Lrp4-IgG that have been identified to drive disease pathology. While this 
initial Ph2a study will focus on anti-AChR IgG positive patients to reduce heterogeneity, 
future studies may also assess the efficacy of anti-FcRn blockade in seronegative 
patients. 
The purpose of the current study is to confirm safety/tolerability and key 
pharmacodynamic (PD) effects that are considered to drive clinical benefit (reduction of 
total IgG and anti-AChR-IgG) in MG patients. A positive correlation between total and 
pIgG reduction and clinical improvement in MG patients has been previously observed 
with another anti-FcRn treatment (ARGX-113). A 6-week open-label extension (OLE) 
has been included to assess transition from weekly dosing regimens for RVT-1401 and 
placebo to a every 2-week dosing regimen (3 additional doses of 340 mg). Results from 
this trial will be used to support progression into a larger and longer study designed to 
confirm clinical efficacy.      
3.2.2. 
Dose rationale 
In MG, RVT-1401 treatment is expected to lead to a significant reduction in the levels of 
pIgG such as anti-AChR-IgG and anti-MuSK-IgG that are considered to be a primary 
driver of disease pathology.  Available evidence suggests that reducing the levels of pIgG 
in MG is associated with clinical benefit. For example, the use of IVIG treatment has 
been shown to reduce AChR autoantibodies by ~30% from baseline and this is associated 
with clinical improvement [Liu, 2010].  Recently, data with another anti-FcRn compound 
(ARGX-113, efgartigimod), reported clinical improvement on the Quantitative 
Myasthenia Gravis (QMG) and Myasthenia Gravis-Activities of Daily Living (MG-ADL) 
scores with an approximate 80% reduction in total IgG and 50% reduction in AChR-IgG 
after once weekly administration for 4 weeks [Howard, 2018].  These data provide a 
target range for potentially therapeutic PD effects; however it is unknown whether there 
is a minimum threshold for pIgG reduction that translates into clinical efficacy. 
RVT-1401 is designed to provide patients with a treatment option that allows home 
administration via subcutaneous (SC) injection. This significantly reduces the burden that 
an IV infusion treatment (e.g., IVIG, Soliris® and other anti-FcRn treatments in 
development) places on patients who will be required to go to an infusion center to 
receive their treatment. 
 


 
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Two dosing regimens of RVT-1401 will be assessed in double-blind phase of this study.  
Both will involve once weekly SC injections: 
• Dosing Regimen A -680 mg weekly for 6 weeks, and  
• Dosing Regimen B - 340 mg weekly for 6 weeks   
Given that there is a practical limit on the volume that can be administered via SC 
injection, these two doses represent what can be administered as a single SC injection 
(340 mg) and two SC injections (680 mg) per week with the current formulation.  
The OLE will involve 1 dosing regimen as a single SC injection: 
• 340 mg every 2 weeks for 6 weeks 
The OLE dose of 340 mg every 2 weeks will allow for the exploration of the effect of 
less frequent dosing of RVT-1401. This dose comprises a less frequent regimen with a 
convenient single SC injection. Since the frequency of dosing will decrease, the drug 
exposure over the dosing interval for subjects who were on active drug will decrease by 
approximately 8- 10 -fold for Regimen A and by 1-2 fold for Regimen B. 
Expected Treatment Effect  
The proposed dosing regimens are expected to provide a sustained total IgG reduction of 
approximately 75-80% and 65-70% for Regimen A and B respectively, following the 
fourth or fifth dose. It is expected that the nadir IgG reduction will occur by the 5th dose 
and be maintained following the sixth dose before rising back to baseline over the next 6 
to 8 weeks. These assumptions are supported by preliminary PD results, shown in  
Figure 1, from the ongoing Phase 1 clinical study RVT-1401-1001 (Section 3.2.3). In 
healthy participants, 4 weekly SC injections of 680 mg of RVT-1401 produced an 
average total IgG percent reduction from baseline of 78%.   
For participants that enter into the OLE, IgG levels will rise over the 2-week interval 
between week 6 and the start of OLE dosing at week 8.  The IgG levels are expected to 
oscillate between decreasing and increasing over the next 3 doses, with trough IgG levels 
expected to rise by 15-25% above the nadir levels achieved during the treatment phase in 
the double-blind part of the study. Subjects who switch to 340 mg every 2 weeks from 
the placebo treatment are expected to achieve an IgG reduction of approximately 35-45% 
after the last OLE dose. Upon completion of OLE dosing, all subject IgG levels are 
expected to return to baseline over the next 6-8 weeks. 
In study RVT-1401-1001, the inter-individual variability in IgG reduction and PK was 
larger in the 340 mg cohort vs. the 680 mg cohort; this difference can be explained by 
lower receptor occupancy in the 340 mg cohort throughout the dosing interval across all 
individuals. It is also noteworthy that, with both doses, the variability in exposure 
decreased with repeat dosing.  This may indicate that full receptor occupancy is not lost 
within the dosing interval, and that with subsequent doses, more receptors are being 
occupied or remain occupied.    


 
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In the repeat dose 340 mg cohort, there were some individuals who did not achieve nadir 
IgG concentration until after the last dose, indicating they may have not reached steady 
state.  In contrast, most subjects in the 680 mg cohort achieved nadir concentration prior 
to the last dose and maintained that response until after the last dose, indicating steady 
state response was achieved. Data from this study will be used to support dose selection 
in future studies.   
 
Figure 1: Mean(+/-SD) Serum IgG Reduction Following Multiple SC Doses of RVT-
1401  
 
 
3.2.3. 
Clinical Experience 
RVT-1401 has been studied in two Phase 1 clinical studies (HL161BKN-001 and RVT-
1401-1001) designed to assess the safety, tolerability, PK, and PD following single 
(intravenous [IV] and SC) and multiple (SC) doses in healthy participants.  As of 
December 14, 2018 RVT-1401 has been administered to 65 healthy participants at the 
following doses: 0.1 mg/kg as a 1-hour intravenous (IV) infusion (n=4), 100 mg as a 1-
hour IV infusion (n=6), 340 mg as a 1-hour IV infusion (n=6), 0.5 mg/kg SC injection 
(n=3), 1.5 mg/kg SC injection (n=6), 5 mg/kg SC (n=6), 340 mg SC injection (n=6), 500 
mg SC injection (n=6), 765 mg SC injection (n=6). Eight participants have received 
repeated 340 mg SC injections weekly for 4 weeks and 8 participants have received 
repeated 680 mg SC injections weekly for 4 weeks 


 
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3.2.3.1. 
Safety 
See Investigator’s Brochure for Details. 
RVT-1401 has been well tolerated with no Grade 3 or 4 adverse events (AEs), and no 
withdrawals due to AEs. There was one SAE (Malpighian carcinoma in left side of the 
neck) considered unrelated to study drug. 
All AEs in subjects receiving RVT-1401 have been reported as mild or moderate. One 
subject who received placebo experienced severe (Grade 3) pain from urinary lithiasis. 
The most frequent AE for both groups was injection site reactions (erythema/ and or 
swelling). Overall, injection site reactions have resolved within a few hours after dosing; 
there were two exceptions of mild swelling (one RVT-1401 and one placebo subject) that 
resolved after 3 and 4 days, respectively. The frequency of injection site reactions was 
not dose-related and similar reactions were observed with placebo. Additionally, injection 
site reactions were not consistently observed following every injection in the repeat dose 
cohorts. 
Preliminary data suggest no subject who has received RVT-1401 had clinically relevant 
changes in laboratory findings, electrocardiograms (ECGs), or vital signs.   
3.2.3.2. 
Pharmacokinetics 
RVT-1401 exhibited non-linear pharmacokinetics (PK) following single SC 
administration across doses ranging from 0.5 mg/kg to 765 mg. The non-linearity is 
consistent with RVT-1401 exhibiting target mediated disposition PK. In addition to 
single dose administration, RVT-1401 has also been administered weekly SC for 4 weeks 
at doses of 340 and 680 mg. The observed mean concentration-time profile following the 
first and last dose were generally similar, rising to peak concentration between 2 and 3 
days after the dose and then declining beginning 4 days after administration up until the 
next dose. The rate of elimination was more rapid following administration of 340 mg 
compared to 680 mg, indicative of target mediated drug disposition. Across both dosing 
cohorts there was accumulation in the exposure measures of Cmax and AUC(0-168). The 
accumulation in Cmax and AUC(0-168) in the 340 mg cohort was 7 and 8.7-fold respectively 
between the first and last dose, and 2.23 and 2.64, respectively in the 680 mg cohort. 
There was large variability in Cmax and AUC(0-168) after the first dose of 340 mg, whereas 
there was less variability following first  SC dose of 680 mg, consistent with what was 
observed in single dose data.  Overall there was reduction in the inter-
individual variability around Cmax and AUC(0-168) after subsequent doses. Following the 
last dose in the 680 mg cohort, the profile shows characteristics of target mediated drug 
disposition, with a linear elimination phase from ~96 hours to 168 hours after the last 
dose, at which time the elimination was very rapid from 168 hours to 336 hours post 
dose.  Exposures increased more than dose proportionally when comparing 
week four of the 340 mg dose to exposures following the 680 mg SC dose.  
 


 
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3.2.3.3. 
Pharmacodynamic 
Following the administration of single SC doses of RVT-1401, total IgG reduction 
increased with increasing dose, with a maximum reduction of 47% observed after a fixed 
dose of 765 mg. The nadir for IgG reduction following single SC dosing occurred 
between days 8-15 in most individuals. IgG serum levels on average returned to within 
90% of baseline by 43 days after drug administration. Albumin levels were also reduced 
from baseline when compared to placebo showing a similar dose related trend. The 
highest reduction occurring following the 765 mg SC dose (average ~14.5%) but were 
not considered to be clinically significant reductions as all patients remained within 
normal limits (3.5 g/dL to 5.5 g/dL) and levels recovered quickly, returning to baseline ~ 
2 weeks after nadir.  
The amount of IgG reduction has also been assessed following weekly SC administration 
of 340 and 680 mg of RVT-1401 or placebo for 4 weeks. There were 8 subjects with data 
out to day 35, that were included in a preliminary PD analysis for the 680 mg cohort and 
7 subjects with data out to day 49 that were included in the analysis for the 340 mg 
cohort. One subject only received 2 doses of 340 mg prior to withdrawing due to personal 
reasons, their data was not included in the preliminary PD analysis. There were 4 placebo 
subjects with data out to day 35 pooled across two cohorts for analysis of PD endpoints. 
Figure 1 presents the mean IgG concentration-time profiles for both weekly SC 
administration of 340 mg and 680 mg doses. Figure 1 shows a reduction in serum IgG as 
a percent of pre-dose across both 340 mg and 680 mg cohorts.  In contrast, the placebo 
group demonstrated minimal changes in serum IgG as a percent of pre-dose. The 
reduction in serum IgG was more rapid following the 680 mg SC compared vs 340 mg 
SC. The median IgG nadir concentration occurred prior to the last dose in the 680 mg 
cohort whereas for 340 mg, it occurred approximately 3 days after the last dose. The 
finding that the 680 mg cohort achieved nadir concentration following the 3rd dose and 
maintained serum IgG reduction after the 4th dose, indicates a maximum response has 
likely been achieved, and that higher doses or more frequent dosing would yield little 
additional benefit. This is consistent with data from other anti-FcRn agents in 
development that have observed a maximum percent reduction in serum IgG from 
baseline of ~ 75-80%.   
Preliminary data following the last dose across both cohorts shows that IgG levels were 
within normal range and within 30% of the baseline value by 5 weeks after the last dose 
(average (SD) IgG concentration was 8.64 (2.73) g/L, and 8.95 (2.03) g/L for the 340 mg 
and 680 mg cohorts, respectively). The return towards baseline indicates the effect is 
reversible.  
The change in serum albumin was also assessed following repeat SC administration of 
340 and 680 mg of RVT-1401 as compared to pooled placebo. Following both single and 
repeat dosing RVT-1401 serum albumin concentrations were reduced in a dose 
dependent fashion, whereas placebo subjects showed little to no change in albumin 
concentrations. While there was a reduction in albumin concentrations following weekly 
dosing of 340 mg of RVT-1401, individual concentrations remained within normal limits 
(>3.5 g/dL) for serum albumin. Following weekly administration of 680 mg of RVT-
1401, all but 1 individual remained above 3.0 g/dL for the duration of dosing and most 


 
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individuals had nadir albumin concentration prior to last dose, indicating that maximum 
albumin reduction had been achieved. In all individuals, albumin levels were within 
normal limits (>3.5 g/dL) within 3-4 weeks of the last dose for the 680 mg cohort. Across 
both cohorts, on average, individuals were within 95% of their baseline concentration 5 
weeks after the last dose, indicating the reversibility of the effect of RVT-1401 on 
albumin. There were no clinical signs or symptoms reported with these transient albumin 
reductions. 
Additional information is available in the current Investigator’s Brochure (IB).  
 
3.3. 
Benefit: Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with RVT-
1401 can be found in the current IB.   
 
3.3.1. 
Risk Assessment 
Potential Risk of 
Clinical Significance 
 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and Stopping Criteria OR 
Management Criteria 
The potential for allergic 
reactions exists following 
administration of any 
protein to human 
participants. 
Participants with history of significant 
allergic reactions are ineligible. 
Participants will be closely monitored for 
reactions for up to 1 hr post-dose before 
they leave the clinic.  
If during the course of study drug 
administration, the participant 
experiences a drug related AE of Grade 3 
(severe) or greater severity, study drug 
administration will be stopped. 
Changes in circulating 
complement 
None 
Serum complement will be monitored 
throughout the study (Section 8.1).  
Abnormal values will be discussed with 
the study medical monitor. 
Sustained 
hypogammaglobulinemia 
The following participants will be 
ineligible: 
-Participants with a total IgG level of 
<6g/L at screening  
-Participant has had their spleen 
removed. 
-Participant has a past medical history of 
primary immunodeficiency, T-cell or 
humoral, including common variable 
immunodeficiency. 
-History of or known infection with human 
Total IgG levels will be monitored 
throughout the study (Section 8.1) by an 
unblinded Medical Monitor.   Transient 
depletion of IgG following administration 
of certain drugs (e.g., corticosteroids) are 
not generally associated with an 
increased risk of infections [Furst, 2008].  
Furthermore, available data from other 
FcRn antagonists in development have 
not reported an increased risk of infection 
in short-term trials similar to RVT-1401-


 
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immunodeficiency virus (HIV), hepatitis B 
virus (HBV), hepatitis C virus (HCV), or 
Mycobacterium tuberculosis. Participants 
must have negative test results for HBV 
surface antigen, HBV core antibody, HCV 
antibody, HIV 1 and 2 antibodies, and a 
negative QuantiFERON®- tuberculin (TB) 
Gold test at Screening. Participants with 
an indeterminate QuantiFERON®-TB 
Gold test result will be allowed one retest; 
if not negative on retesting, the participant 
will be excluded. 
-Absolute neutrophil count <1500 
cells/mm3 
2002. 
Sustained 
hypoalbuminemia 
Investigator discretion  
Serum albumin levels will be monitored 
throughout the study (Section 8.1) by an 
unblinded Medical Monitor.  Treatment of 
hypoalbuminemia will be left to the 
discretion of the investigator and decision 
on dosing discussed with the study 
medical monitor. 
 
 


 
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4. 
OBJECTIVE(S) AND ENDPOINT(S) 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of RVT-
1401 in AChR antibody positive MG patients 
over a 6-week treatment period 
 
 
To examine the effects of RVT-1401 on total 
IgG, IgG subclasses (1-4) and anti-AChR-IgG 
levels 
Assessment of safety and tolerability by 
analysis of AE data and changes from 
baseline in vital signs, clinical laboratory 
values, and electrocardiograms  
 
Change from baseline in levels of total IgG 
and IgG subclasses (1-4)  
 
Change from baseline in levels of anti-AChR-
IgG  
 
 
Secondary 
To examine RVT-1401 PK following repeat 
doses in patients with Myasthenia Gravis 
(MG) 
 
 
 
 
 
To measure anti-RVT-1401 antibodies 
following repeat doses in patients with MG 
and assess any potential impact on PK or PD 
 
 
To examine the effects of RVT-1401 on the 
Quantitative Myasthenia Gravis (QMG) score  
 
To examine the effects of RVT-1401 on the 
proportion of patients with improvement on 
the QMG score by ≥ 3 points from baseline  
 
 
To examine the effects of RVT-1401 on 
Myasthenia Gravis-Activities of Daily Living 
score (MG-ADL)  
 
To examine the effects of RVT-1401 on the 
proportion of participants with an 
improvement on the MG-ADL Score by ≥2 
points  
 
PK Parameters of AUC (0-168 h) and 
maximum concentration (Cmax) after first and 
last dose 
 
Concentration of RVT-1401 pre-dose 
(Ctrough)  
 
 
Immunogenicity determined by change from 
pre-dose in anti-RVT-1401 antibodies, 
characterization of any anti-RVT-1401 to 
confirm neutralization potential  
 
Change from baseline in the QMG Score  
 
 
Proportion of participants with an 
improvement on the QMG score by ≥ 3 points 
from baseline  
 
 
Change from baseline in the MG-ADL score  
 
 
 
Proportion of participants with an 
improvement on the MG-ADL Score by ≥2 
points  
 
 


 
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To examine the effects of RVT-1401 on the 
Myasthenia Gravis Composite (MGC) score  
 
To examine the effects of RVT-1401 on the 
proportion of participants with an 
improvement on the MGC Score by ≥3  
 
To examine the effects of RVT-1401 on the 
Myasthenia Gravis Quality of Life (MG-
QOL15r) score  
 
Change from baseline in the MGC score  
 
 
Proportion of participants with an 
improvement on the MGC Score by ≥3 points  
 
 
Change from baseline in the MG-QOL15r 
score  
 
 
Open-Label Extension Objective: 
The objective of the OLE is to evaluate the effect of switching to a every 2-week dosing 
regimen of 340 mg RVT-1401 on all study endpoints.  
 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a Phase 2a, randomized, double-blind, placebo-controlled study with an OLE 
designed to investigate the safety, tolerability, PK, PD, and efficacy of RVT-1401 (340 
mg/weekly and 680 mg/weekly) vs placebo in AChR antibody positive MG patients. 
Following a 6-week double-blind, placebo-controlled phase, all participants will have the 
option to enter an OLE where they will receive an additional 3 doses of 340 mg RVT-
1401 every 2 weeks for 6 weeks. The study designs are illustrated in Section 5.2.  
Safety, PK, PD, and clinical assessments will be collected throughout the study.  Refer to 
Section 8.1 and 8.2, Time and Events Tables. 
Optional home visits will be offered to collect (at a minimum) blood samples, vital signs, 
and review adverse events and concomitant medications.  


 
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Each participant will participate in the study for up to approximately 21 weeks: a 3-week 
screening period, and a 6-week double-blind, placebo-controlled treatment period.  
Participants who choose not to enroll into the OLE will continue into a 12-week follow-
up period.  Those who choose to enroll into the OLE will receive treatment in a 6-week 
OLE period (3 additional doses, every 2 weeks), and a 6-week follow up period.  The 
study duration is the same whether a participant continues directly into the 12-week 
follow-up period or enrolls into the OLE.  
Randomized, Double-Blind, Placebo-Controlled Phase 
Participants will screen to determine eligibility up to 21 days prior to first dose/baseline 
visit. Once eligibility is confirmed, participants will be randomized on Day 1 to receive 
one of two dose regimens or placebo for weekly SC injections in addition to their 
standard of care therapy for 6 weeks. No dose adjustments of RVT-1401 are allowed 
during the study.  See Section 6.9 for additional information on stopping criteria.   
Following the initial dose at the Baseline Visit (Day 1), study visits will occur at Days 3 
and 5 and then weekly throughout the treatment period.    
After Week 6, if the participant chooses not to enroll into the OLE, they will continue 
with the 12-week follow up period. 
Transition Phase: Option to Enroll into OLE 
Participants will have the option to continue with the follow up period or enroll into the 
OLE (described below) upon completion of the randomized, double-blind, placebo-
controlled phase of the study (Week 6).  To enroll into the OLE, consent must be 
obtained prior to the Week 8 visit. 
The visit schedule will be the same for either option as outlined in Section 5.2; two study 
visits will occur at Days 38 and 40, and then weekly through Week 10 and then every 2 
weeks until Week 18.  
Open-Label Extension 
If the participant is eligible and consents to enroll into the OLE, starting at Week 8 an 
additional 3 doses of 340 mg RVT-1401 will be administered over a 6-week period 
(every 2 weeks) followed by a 6-week follow up period.   


 
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5.2. 
Study Schematics 
Figure 2 
Study Design without OLE 
 
 
Figure 3 
Study Design with OLE 
 
 
5.3. 
Treatment Arms and Duration 
In the double-blind phase of the study, participants will be randomized 1:1:1 to one of the 
three blinded treatments illustrated in Figure 2. 
In the OLE an additional 3 doses over a 6-week period (every 2 weeks) will be 
administered, illustrated in Figure 3. 
 


 
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6. 
PARTICIPANT POPULATION 
6.1. 
Type and Number of Participants 
A sufficient number of participants will be enrolled to achieve approximately 21 
evaluable participants. Enrollment is competitive. 
In order to manage the total study enrollment, the Sponsor may suspend screening and/or 
enrolment at any site or study-wide at any time. 
If participants prematurely discontinue the study, additional replacement participants may 
be enrolled at the discretion of the Sponsor. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
participant safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential. 
To determine participant eligibility at screening, a single repeat of certain tests such as 
laboratory values, vital signs, or ECGs is allowed at the discretion of the Principal 
Investigator. 
 
6.2. 
Inclusion Criteria  
A participant will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Male or female ≥ 18 years of age. 
2. Myasthenia Gravis Foundation of America (MGFA) Class II-IVa and likely not in 
need of a respirator for the duration of the study as judged by the Investigator. 
3. Positive serologic test for anti-AChR antibodies at the screening visit and at least 1 
of the following:  
a. 
History of abnormal neuromuscular transmission test demonstrated by single-
fiber-electromyography or repetitive nerve stimulation OR 
b. History of positive edrophonium chloride test OR 
c. 
Participant has demonstrated improvement in MG signs on oral cholinesterase 
inhibitors as assessed by the treating physician.  
4. QMG score ≥12 at Screening and Baseline.  
5. Stable dose of MG treatment prior to randomization. For participants receiving AZA, 
other non-steroidal immunosuppressive agents, steroids, and/or cholinesterase 
inhibitors as concomitant medications the following conditions will apply: 
a. 
AZA: treatment initiated at least 12 months ago and no dose changes in the last 
6 months before Screening. 


 
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b. Other immunosuppressive treatment (e.g., methotrexate, cyclosporine, 
mycophenolate mofetil, and cyclophosphamide) initiated at least 6 months ago 
and no dose changes in the last 3 months before Screening. 
c. 
Stable dose of steroid treatment at least 6 weeks before Baseline. 
d. Cholinesterase inhibitors: stable dose for >1 week before Screening. Note: 
cholinesterase inhibitors must be held for at least 12 hours consistent with the 
revised manual for the QMG test as recommended by the MGFA, before the 
QMG and MGC assessments.     
6. A female participant is eligible to participate if she is of: 
a. 
Non-childbearing potential defined as pre-menopausal females with a 
documented bilateral tubal ligation, bilateral oophorectomy (removal of the 
ovaries) or hysterectomy; hysteroscopic sterilization, or postmenopausal defined 
as 12 months of spontaneous amenorrhea [in questionable cases a blood sample 
with simultaneous follicle stimulating hormone (FSH) in the post-menopausal 
range is confirmatory].  
b. Child-bearing potential and agrees to use one of the contraception methods 
listed in Section 6.6.1 for an appropriate period of time (as determined by the 
product label or Principal Investigator) prior to the start of dosing to sufficiently 
minimize the risk of pregnancy at that point.  Female participants must agree to 
use contraception until 90 days after the last dose of study treatment. 
7. Male participants must agree to use one of the contraception methods listed in 
Section 6.6.1.  This criterion must be followed from the time of the first dose of 
study treatment until 90 days after the last dose of study treatment. 
8. Willing and capable of giving written informed consent, which includes compliance 
with the requirements and restrictions listed in the consent form. 
 
6.3. 
Exclusion Criteria 
A participant will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Use of rituximab, belimumab, eculizumab or any monoclonal antibody/Fc-fusion 
biologic for immunomodulation within 6 months prior to first dosing.   
2. Use of tacrolimus within 1 week of first dose and throughout the treatment period. 
3. Immunoglobulins given by SC, IV (IVIG), or intramuscular route, or 
plasmapheresis/plasma exchange (PE) within 4 weeks before Screening. 
4. Thymectomy performed < 12 months prior to screening.  
5. Total IgG level <6 g/L (at screening). 
6. Absolute neutrophil count <1500 cells/mm3(at screening). 


 
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7. Participant has any laboratory abnormality (at screening) that, in the opinion of the 
investigator, is clinically significant, has not resolved at baseline, and could 
jeopardize or would compromise the participant's ability to participate in this study. 
8. Have known autoimmune disease other than MG that would interfere with the course 
and conduct of the study (such as uncontrolled thyroid disease). 
9. Medical history of primary immunodeficiency, T-cell or humoral, including common 
variable immunodeficiency. 
10. Have an active infection, a recent serious infection (i.e., requiring injectable 
antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening. 
11. History of or known infection with human immunodeficiency virus (HIV), hepatitis 
B virus (HBV), hepatitis C virus (HCV), or Mycobacterium tuberculosis. 
Participants must have negative test results for HBV surface antigen, HBV core 
antibody, HCV antibody, HIV 1 and 2 antibodies, and a negative QuantiFERON®-
TB Gold test at Screening. Participants with an indeterminate QuantiFERON®-TB 
Gold test result will be allowed one retest; if not negative on retesting, the participant 
will be excluded. 
12. Participant has any clinically significant history of allergic conditions (including 
drug allergies, anaphylactic reactions), that would in the opinion of the Investigator 
or Medical Monitor, contraindicates their participation. 
13. Participant has any medical condition (acute or chronic illness) or psychiatric 
condition that, in the opinion of the investigator, could jeopardize or would 
compromise the participant's ability to participate in this study 
14. Body Mass Index (BMI) at Screening ≥ 35 kg/m2. 
15. Use of investigational drug within 3 months or 5 half-lives of the drug (whichever is 
longer) before Screening.  
16. Currently participating or has participated in another MG clinical study within 28 
days prior to signing the informed consent form. 
17. Participant has received a live vaccination within 8 weeks prior to the Baseline Visit; 
or intends to have a live vaccination during the course of the study or within 7 weeks 
following the final dose of study treatment. 
18. Participant has received a transfusion of any blood or blood products within 60 days 
or donated plasma within 7 days prior to Day baseline. 
19. History of sensitivity to any of the study treatments, or components thereof or a 
history of drug or other allergy that, in the opinion of the Investigator or Medical 
Monitor, contraindicates their participation. 
20. Pregnant or lactating females as determined by positive serum or urine human 
chorionic gonadotropin test at screening or baseline. 
21. Participant has had their spleen removed. 
22. QTcF interval >450 milliseconds for males and >470 milliseconds for females at 
Screening (a single repeat is allowed for eligibility determination).  QTcF >480 msec 


 
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in participants with Bundle Branch Block. 
 
6.4. 
Eligibility for the OLE  
Participants who complete the 6-week, randomized, double-blind treatment phase are 
eligible to participate in the OLE. 
6.5. 
Other Eligibility Criteria Considerations 
To assess any potential impact on participant eligibility with regard to safety, the 
Principal Investigator must refer to the following document(s) for detailed information 
regarding warnings, precautions, contraindications, AEs, and other significant data 
pertaining to the investigational product(s) being used in this study: 
RVT-1401 Investigator’s Brochure 
 
6.6. 
Screening/Baseline Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently randomized.  A minimal set of screen failure information is 
required including demography, screen failure details, eligibility criteria, and any SAEs.  
Screen failure data will be recorded within the electronic Case Report Form (eCRF). 
 
6.7. 
Lifestyle Restrictions 
6.7.1. 
Contraception  
Female participants of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or agree to use a highly effective method of contraception 
(i.e., pregnancy rate of less than 1% per year). 
Abstinence 
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulations methods) and withdrawal are not acceptable methods of contraception. 
Contraceptive Methods with a Failure Rate of <1% 
• Combined hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal).  
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable). 
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label. 


 
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• Male partner sterilization (vasectomy with documentation of azoospermia) prior 
to the female participant's entry into the study, and this male is the sole partner for 
that participant. For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the participant or review of the 
participant's medical history for study eligibility, as obtained via a verbal 
interview with the participant or from the participant’s medical records.  
 
• Female participants and female partners of male study participants using a 
hormonal contraceptive must also use a barrier method (i.e., condom or occlusive 
cap [diaphragm or cervical/vault caps]) and should have been stable on their 
hormonal contraceptive treatment for at least 4 weeks before Screening. 
• Sterilized male participants who have had vasectomy with documented 
azoospermia post procedure can be included.  
• Non-sterilized male participants who are sexually active with a female partner of 
childbearing potential must use effective method of double barrier contraception. 
Male participants practicing true sexual abstinence (when this is in line with the 
preferred and usual lifestyle of the participant) can be included. In addition, male 
participants must be advised not to donate sperm during this period from signing 
of Informed Consent Form (ICF), throughout the duration of the study, and for 90 
days after the last administration of study drug. 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring participants understand how to properly use these methods of contraception. 
Participants must be completely informed of the unknown risks of pregnancy and agree 
not to become pregnant during the time they are participating in this study. If there is any 
question that a participant will not be reliable in the use of appropriate contraceptive 
methods, they should not be entered into the study. 
 
6.8. 
Withdrawal Criteria 
6.8.1. 
Reasons for Withdrawal  
A Principal Investigator may discontinue/withdraw a study participant’s participation in 
the study if any of the following criteria apply: 
• Any clinical AE, laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best 
interest of the participant. 
• Participant pregnancy 
• Significant protocol violation 
• Behavioral or administrative reason 


 
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• Participant request to discontinue/withdraw consent for any reason.  It is 
important to document whether the withdrawal of consent is primarily due to an 
AE, lack of efficacy, or other reason. 
• Discontinuation of the study at the request of the Sponsor, regulatory agency or an 
Institutional Review Board / Independent Ethics Committee 
• Stopping criteria, as noted in Section 6.9 
If a participant meets a withdrawal criterion during treatment, an Early Termination 
visit will be required (Section 6.7.2). 
 
6.8.2. 
Participant Withdrawal Procedures 
If a participant is prematurely discontinued from the study, the Principal Investigator 
must make every effort to perform an Early Termination Visit per Section 8.1 and 
Section 8.2, Time and Events Tables and document the primary reason for withdrawal. 
Should a participant fail to attend the clinic for a required study visit, the site should 
attempt to contact the participant and re-schedule the missed visit as soon as possible.  
The site should also counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study based on previous non-compliance.  In cases where the 
participant does not return for the rescheduled visit or cannot be reached to reschedule the 
missed visit, the site should make every effort to regain contact with the participant (3 
documented telephone calls and if necessary a certified letter to the participant’s last 
known mailing address) so that they can appropriately be withdrawn from the study with 
a primary reason of “Lost to Follow-up”. 
 
6.9. 
Stopping Criteria for Individual Participants 
6.9.1. 
Liver Chemistry Stopping Criteria 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury 
guidelines [FDA, 2009]. 
If the following liver test abnormalities develop, Study Treatment should be withheld 
immediately with appropriate clinical follow-up (including repeat laboratory tests, until a 
participant’s laboratory profile has returned to normal/baseline status), and the event 
reported as a SAE: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)> 8 x 
upper limit of normal (ULN); or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international 
normalized ratio (INR) > 1.5 


 
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• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, 
AST, total bilirubin) is discovered and the laboratory abnormalities resolve to normal or 
baseline values.  The Investigator and sponsor must discuss and agree with any decision 
to rechallenge. 
Rechallenge should not occur when the etiology of the liver test abnormalities is 
considered possibly drug induced. 
 
6.9.2. 
Criteria for Permanent Discontinuation of Study Treatment in 
Association with Liver Test Abnormalities 
Study treatment should be discontinued permanently if all of the following 4 criteria are 
met (i.e., potential severe drug-induced liver injury/Hy’s law case): 
1. Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
2. AST or ALT increases to ≥ 3 x ULN; AND 
3. Alkaline phosphatase value does not reach 2 x ULN; AND 
4. No alternative cause explains the combination of the above laboratory 
abnormalities; important alternative causes include, but are not limited to the 
following: 
• Hepatobiliary tract disease; 
• Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus); 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms; 
• Alcoholic hepatitis; 
• Non-alcoholic steatohepatitis; or 
• Autoimmune hepatitis. 
If an alternative cause for hepatotoxicity is identified, then it should be determined (based 
on the severity of the hepatotoxicity or event) whether Study Treatment should be 
withheld or permanently discontinued as appropriate for the safety of the participant. 
 
6.9.3. 
QTc Withdrawal Criteria 
• 
QTc prolongation defined as QTcF >500 ms, or an increase of QTcF >60 ms above 
baseline on the 12-lead ECG, confirmed (persistent for >5 minutes) on repeated 12-
lead ECGs 
 


 
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6.9.4. 
Albumin Monitoring Criteria 


 
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6.10. 
Toxicity Management Criteria 
6.10.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and Site 
Reactions) 
The severity of each AE will be graded and managed according to the criteria in Table 1. 
Table 1 
Criteria for Determining the Grade/Severity of Adverse Event Terms 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations 
only; intervention not indicated 
2/Moderate 
Limiting age-appropriate instrumental activities of daily living; 
minimal, local, or noninvasive intervention as indicated 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care activities of 
daily living, intervention as indicated 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
 
Injection Site Reactions 
Injection site evaluations will be made by clinical staff following administration of RVT-
1401 and placebo as described below.  Additional details related to the specific injection 
site location will be included within a study specific manual. If an injection site reaction 
is observed, a physician will characterize and document the reaction as an AE. Review of 
the injection site will continue until the AE is resolved. Symptomatic treatment (e.g. 
antihistamines, NSAIDs, IV fluids) may be provided for any injection site reactions based 
on the discretion of the Investigator.  
The injection sites will be monitored for pain, tenderness, erythema and swelling. Each 
injection site reaction will be categorized using the intensity grading scheme presented in 
Table 2. 


 
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Table 2 
Criteria for Determining the Grade/Severity of Injection Site 
Reactions 
Grade 
Criteria 
1/Mild 
Tenderness with or without associated symptoms (e.g., warmth, 
erythema, itching) 
2/Moderate 
Pain; lipodystrophy; edema; phlebitis 
3/Severe or medically significant 
Ulceration or necrosis; severe tissue damage; operative 
intervention indicated 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: 
June 14, 2010). 
 
6.10.2. 
Other Management Criteria 
For an individual study participant, medical monitor notification criteria include, but are 
not limited to: 
• 
Severe signs or symptoms, or significant changes in any of the safety assessments, 
that put the safety of the individual at risk (e.g. laboratory tests or vital signs, etc.) as 
judged by the Investigator.  
 
6.11. 
Participant and Study Completion 
A completed participant is one who has completed all phases of the study including the 
follow-up visits. 
The end of the study is defined as the last participant’s last visit. 
 
7. 
STUDY TREATMENT 
7.1. 
Investigational Product and Other Study Treatment 
The term study treatment is used throughout the protocol to describe RVT-1401 or 
placebo.   
To maintain the study blind within the double-blind phase of the study, all participants 
will receive two injections (2 ml volume each) by an unblinded designee (Section 7.6); 
participants receiving the 680 mg dose will receive two injections of RVT-1401, while 
participants receiving the 340 mg dose will receive one injection with RVT-1401 and one 


 
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placebo injection.  Participants receiving placebo will receive two injections of placebo.  
The blinded syringes will be numbered so that any injection site reaction can be assigned 
to a specific syringe number and medication #.   
The OLE is open-label.  Each participant will receive 3 additional doses of RVT-1401, 
once every 2 weeks, as a single 340 mg injection over a 6-week period. 
Double-Blind: Investigational Product 
Study Treatment Name: 
RVT-1401 
Placebo 
Supplier: 
Dosage formulation: 
Sterile solution for injection.  
Sterile solution for injection.  
Unit dose 
strength(s)/Dosage level(s): 
340 mg: 2mL RVT-1401 in one 
syringe and 2mLs placebo in the 
second syringe for a total of 4 mL 
 
680 mg: 2 mL RVT-1401 in two 
syringes for a total of 4 mL 
2 mL placebo in two 
syringes for a total of 4 mL 
 
 
Route of Administration  
SC injection 
Dosing instructions: 
The detailed methods are indicated in the Pharmacy Manual. 
Participants will be closely monitored for reactions for up to 1 hr 
post-dose before they leave the clinic. 
Dose Preparation 
The preparation procedure and expiry details will be included in 
the Pharmacy manual/product label. 
 
OLE: Investigational Product 
Study Treatment Name: 
RVT-1401 
Supplier: 
Dosage formulation: 
Sterile solution for injection.  
Unit dose 
strength(s)/Dosage level(s): 
340 mg: 2mL RVT-1401 in one syringe  
 
Route of Administration  
SC injection 
Dosing instructions: 
The detailed methods are indicated in the Pharmacy Manual. 
Participants will be closely monitored for reactions for up to 1 hr 
post-dose before they leave the clinic. 
Dose Preparation 
The preparation procedure and expiry details will be included in 
the Pharmacy manual/product label. 
 
 
 


 
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7.2. 
Treatment Assignment 
Randomization within the double-blind phase will occur centrally using an interactive 
web response system (IWRS) using central randomization.  Participants will be assigned 
in accordance with the randomization schedule, prepared prior to the start of the study. 
The OLE is open-label. 
 
7.3. 
Blinding 
This will be a double-blind study. The investigator and study site will also remain blinded 
to the IgG, albumin, total protein, alkaline phosphatase (ALP), and anti-AChR antibody 
data post screening as this could potentially unblind them.  An unblinded Medical 
Monitor will review this lab data on an ongoing basis for safety.  In order to maintain the 
blind of which treatment subjects received during the double-blind phase of the study, 
these labs will continue to be blinded to the investigator and study site in the OLE. 
  The following will apply throughout the study: 
• 
The Investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious medical 
condition when knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the participant as judged by the Investigator. 
Emergency unblinding will be available via the IWRS or via the unblinded 
pharmacist.  
• 
The Investigator should make every effort to first contact the Medical Monitor or 
appropriate study personnel to discuss options before unblinding the participant’s 
treatment assignment.  
• 
If the Medical Monitor is not contacted before the unblinding, the Investigator must 
notify the Sponsor as soon as possible after unblinding.  
• 
The date and reason for the unblinding (the event or condition which led to the 
unblinding) must be fully documented in the eCRF  
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
Investigator or treating physician.   
The Sponsor or their designee may unblind the treatment assignment for any participant 
with a SAE. If the SAE requires that an expedited regulatory report be sent to one or 
more regulatory agencies, a copy of the report, identifying the participant’s treatment 
assignment, may be sent to Investigator in accordance with local regulations. 
 
7.4. 
Packaging and Labeling 
RVT-1401 will be supplied to the study site as a sterile liquid formulation with a nominal 
fill of at least 1 mL in Nuova Ompi 2R clear glass vials with a flip-off cap. The solution 
is clear to slightly yellow, essentially free of visible particles, for SC administration.
 


 
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Placebo will be provided as a sterile liquid formulation with at least a 1 mL fill in Nuova 
Ompi 2R clear glass vials with a flip-off cap. The solution is clear, essentially free of 
visible particles, for SC administration.
 
Doses will be prepared by the unblinded pharmacist or designee with a label that includes 
at a minimum the study number, participant number, medication number and vial 
number. Doses are administered to participants by pre-identified unblinded clinic staff or 
designee.  
See Pharmacy Manual for exact instructions on dose preparation. 
All labels will meet all local applicable requirements and Annex 13 of Good 
Manufacturing Practices: Manufacture of investigational medicinal products (July 2010) 
and/or other local regulations as applicable. 
 
7.5. 
Preparation/Handling/Storage/Accountability 
A description of the methods and materials required for preparation will be detailed in the 
pharmacy manual. 
• 
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may prepare, handle, supply or administer study treatment.  All 
study treatments must be stored in a secure environmentally controlled and 
monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the Investigator and authorized site staff.  
• 
For the double-blind phase of the study, the Unblinded Pharmacist or designee is 
responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).   
• 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  In the case of unintentional 
occupational exposure notify the unblinded monitor, Medical Monitor and/or the 
Sponsor study contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
Investigator, where this is required by local laws, or is available upon request from 
the Sponsor. 
 
7.6. 
Compliance with Study Treatment Administration 
For the double-blind phase of the study only, the individual dose for a participant is 
prepared by an unblinded Pharmacist, licensed Pharmacy Technician, or designee. The 


 
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preparation of the dose will be reviewed and confirmed by a second unblinded member of 
the study site staff.  
For the double-blind phase of the study only, the IP will be administered by an unblinded 
designee. For the double-blind phase and the OLE, the date and time of each dose 
administered along with the location of each injection identified by syringe number, will 
be recorded in the source documents.  The location/syringe number and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff 
(blinded to study treatment) other than the person administering the study drug.  
 
7.7. 
Treatment of Study Treatment Overdose 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose the Investigator or treating physician should: 
• contact the Medical Monitor immediately, 
• closely monitor the participant for AEs/SAEs and laboratory abnormalities. 
• obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis) 
• document the quantity of the excess dose as well as the duration of the overdosing 
in the eCRF 
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
 
7.8. 
Treatment After the End of the Study 
Participants will not receive any additional treatment with the study treatment from the 
Sponsor after completion of the study because the long-term safety and efficacy of RVT-
1401 have not been established. 
The Principal Investigator is responsible for ensuring that consideration has been given to 
the post-study care of the participant’s medical condition, whether or not the Sponsor is 
providing specific post-study treatment. 
 


 
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7.9. 
Concomitant Medications and Non-Drug Therapies 
7.9.1. 
Permitted Medications and Non-Drug Therapies 
Any concomitant medication should be recorded in the study records, including the doses 
administered, the dates and times of administration and the reason for administration. 
Refer to Section 6.2 and Section 6.3 in the study inclusion and exclusion criteria for 
permitted standard of care MG treatments. 
7.9.2. 
Prohibited Medications and Non-Drug Therapies 
Refer to the exclusion criteria (Section 6.3) and the SRM for a list of prohibited 
medications. 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Tables, are essential and required for study conduct. 
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Tables, Section 8.1 and 
Section 8.2.  
The following points must be noted:  
• 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form.  
• 
The total blood volume collected will be specified within the ICF. 
 


 
 
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8.1. 
Time and Events Table (12-week follow-up without OLE) 
 
Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6  
 (Days) 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 21 
Days 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window 
(days) 
 
 
 
+1 
day 
 
+1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 
days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead 
Electrocardiogram2 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test3 
(females) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
QuantiFERON®-TB 
Gold 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis2 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Blood chemistry 
and hematology2 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Serum complement 
(CH50, C3)2 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 


 
 
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Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6  
 (Days) 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 21 
Days 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window 
(days) 
 
 
 
+1 
day 
 
+1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 
days 
 
Immunoglobulins 
(IgM, IgA)2 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
X 
X 
RVT-1401 PK 
sampling2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Total IgG2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobins  
(IgG subclasses)2 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
Anti- RVT-
1401antibody2, 4 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Nab Assessment2 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
anti-AChR 
antibody2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug administration 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Injection site 
reactions5 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
MG-ADL6, 7 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Quantitative 
Myasthenia Gravis 
(QMG) Score6, 7 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 


 
 
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Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6  
 (Days) 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 21 
Days 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window 
(days) 
 
 
 
+1 
day 
 
+1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 
days 
 
Myasthenia Gravis 
Composite (MGC) 
Score6, 7 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Myasthenia Gravis 
Quality of Life (MG-
QOL15r) Score6, 7 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
Satisfaction 
Questionnaire  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Screening can take place over multiple days to ensure participants withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
2. 
Vitals, ECG and blood draws for safety, PK, and PD assessment will be collected pre-dose on dosing days where specified. 
3. 
Pregnancy tests will be collected pre-dose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening, week 18, and early withdrawal. 
4. 
Participants positive for anti- RVT-1401 antibody at Week 18 will be requested to return at approximately 6, 9, and 12 months post-dose for additional samples or until their result is no longer positive. However, for 
purposes of safety follow-up and database lock participation ends at the Week 18 visit.  
5. 
Local injection site reactions will be assessed at approximately 10 minutes post dose. 
6. 
MG assessments will be assessed pre-dose when collected on dosing days 
7. 
Subjects should be instructed to withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
 
 
 






 
 
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Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6  
 (Days) 
 
OLE and Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 21 
Days 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window 
(days) 
 
 
 
+1 
day 
 
+1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 
days 
 
Myasthenia Gravis 
Composite (MGC) 
Score 8,9 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Myasthenia Gravis 
Quality of Life (MG-
QOL15r) Score 8,9 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
Satisfaction 
Questionnaire  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Screening can take place over multiple days to ensure participants withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
2. 
Consent for enrollment into the OLE must occur prior to Week 8. 
3. 
Participants who complete the 6- week, randomized, double-blind treatment phase are eligible to participate in the OLE  
4. 
Vitals, ECG and blood draws for safety, PK, and PD assessment will be collected pre-dose on dosing days where specified. 
5. 
Pregnancy tests will be collected pre-dose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening, week 18, and early withdrawal. 
6. 
Participants positive for anti- RVT-1401 antibody at Week 18 will be requested to return at approximately 6, 9, and 12 months post-dose for additional samples or until their result is no longer positive. However, for 
purposes of safety follow-up and database lock participation ends at the Week 18 visit.  
7. 
Local injection site reactions will be assessed at approximately 10 minutes post dose. 
8. 
MG assessments will be assessed pre-dose when collected on dosing days.  
9. 
Subjects should be instructed to withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
 
 


 
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8.3. 
Screening and Critical Baseline Assessments 
Screening assessments are outlined in the Time and Events Table, (Section 8.1). The 
following demographic parameters will be captured: year and month of birth, sex, race 
and ethnicity. 
Medical/medication history will be assessed as related to the inclusion/exclusion criteria 
listed in Section 6. 
Written informed consent must be obtained prior to performance of any study related 
procedures. Screening can take place over multiple days. In particular, the protocol 
requirement to withhold cholinesterase inhibitors for at least 12 hours prior to the QMG 
and MGC assessments may require participants to return on a separate day during the 
screening period to ensure they sign an informed consent form prior to withholding this 
treatment.  
 
8.4. 
Study Assessments and Procedures 
8.4.1. 
Physical Exams 
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems and skin. Height 
will also be measured and recorded at screening only and weight at screening and 
baseline only.   
A brief physical examination will include, at a minimum, assessments of the skin, 
Respiratory, Cardiovascular system, and abdomen (liver and spleen). 
 
8.4.2. 
Vital Signs 
Vital signs will be measured in semi-supine position and will include temperature, 
systolic and diastolic blood pressure and pulse rate.  
 
8.4.3. 
Electrocardiogram (ECG) 
ECGs will be measured in semi-supine position. 
Twelve-lead ECGs will be obtained during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.  
Refer to Section 6.8.3 for QTcF criteria and additional QTcF readings that may be 
necessary. 
 
8.4.4. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments must be conducted in accordance with the 
SRM or Laboratory Manual, and Protocol Time and Events Tables (Section 8.1 and 


 
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Section 8.2).   Laboratory requisition forms must be completed, and samples must be 
clearly labelled with the participant number, protocol number, site/center number, and 
visit date.   Details for the preparation and shipment of samples will be provided by the 
laboratory and are detailed in the SRM or the laboratory manual.  Reference ranges for all 
safety parameters will be provided to the site by the laboratory responsible for the 
assessments. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification) the results must be recorded.   
Hematology, clinical chemistry, urinalysis and additional parameters to be tested by 
central laboratory are listed below: 
Hematology 
Platelet Count  
RBC Indices: 
Automated WBC Differential: 
Red Blood Cell (RBC)Count 
Mean corpuscular 
volume (MCV) 
Neutrophils 
White Blood Cell (WBC) Count (absolute)  
Mean corpuscular 
hemoglobin (MCH) 
Lymphocytes 
Reticulocyte Count 
Mean corpuscular 
hemoglobin 
concentration 
(MCHC) 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
Clinical Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
AST (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose fasting 
[on Day 1 
(baseline) and 
Week 7 only] 
Total carbon dioxide 
(CO2 ) 
Gamma glutamyltransferase 
(GGT) 
Albumin 
Sodium 
Calcium (corrected) 
Alkaline phosphatase (ALP) 
Total Protein 
Serum 
complement 
(CH50, C3) 
Immunoglobulin M 
(IgM) 
Immunoglobulin A 
(IgA) 
 
Immunoglobulin G 
(IgG) 
 
 
 
Since changes in ALP, total protein and albumin level can potentially unblind the 
investigator to which dose the participant has been randomized to; values for ALP, total 
protein, and albumin levels will be blinded to the site.  An unblinded Medical Monitor 
will review this lab data on an ongoing basis for safety.   


 
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NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Appendix 2: Liver Safety Required Actions and Follow up Assessments.  
Routine Urinalysis 
Specific gravity, pH 
glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other tests 
QuantiFERON®-TB Gold 
Viral Serology [HIV1/HIV2, Hepatitis B (HBsAg), Hepatitis B (Core antibody), Hepatitis C (Hep C 
antibody] 
FSH (as needed for confirmation of postmenopausal status) 
Pregnancy Tests:  serum test at screening, Week 18, and early withdrawal and urine dipstick pre-
dose at other timepoints. Positive urine tests should be confirmed with a serum test. 
 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
Principal Investigator, the etiology should be identified, if possible and the Sponsor 
notified. 
 
8.4.5. 
Pharmacokinetics 
Blood samples for PK analysis of RVT-1401 will be collected at the time points indicated 
in Section 8.1 and 8.2, Time and Events Tables.  The actual date and time of each blood 
sample collection will be recorded.     
Processing, storage and shipping procedures are provided in the SRM or lab manual. 
Serum analysis will be performed under the control of the Sponsor.  Concentrations of 
RVT-1401 will be determined in serum samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site. 
 
8.4.6. 
Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) 
Blood samples for ADA and NAb analysis will be collected at the time points indicated 
in Section 8.1 and 8.2, Time and Events Tables.  The actual date and time of each blood 
sample collection will be recorded.   
Processing, storage and shipping procedures are provided in the SRM or lab manual. 
ADA analysis will be performed under the control of the Sponsor.  Anti-RVT-1401 
antibody titers will be determined in serum samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site.  If Anti-


 
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RVT-1401 antibody titers are detected, they will be further characterized using a 
validated cell based Nab assay 
8.4.7. 
Pharmacodynamics 
Blood samples for PD analysis will be collected at times indicated in the Time and 
Events Tables (Section 8.1 and 8.2).   
Pharmacodynamic Markers 
Total IgG, and differentiation by class: 
IgG subclasses (IgG1, 2, 3, and 4)  
 
Anti-AChR antibody levels 
The actual date and time of each blood sample collection will be recorded. These samples 
may be used for the analysis of exploratory biomarkers. Samples will be collected, 
labelled, stored, and shipped as detailed in the SRM or lab manual. 
8.4.8. 
Exploratory Biomarkers 


 
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8.5. 
Myasthenia Gravis Assessments 
8.5.1. 
Myasthenia Gravis Activities of Daily Living (MG-ADL) 
The MG-ADL is an 8-item, patient reported questionnaire that assesses MG symptoms 
and their effects on activities of daily living. The scale has been validated and shown to 
correlate with the QMG scale and newer MG outcome scales such as the MGC and MG-
QOL15r [Wolfe, 1999, Muppidi, 2011].  
Participants are asked to rate each item on a scale of 0-3.  The MG-ADL score is 
calculated by totalling the rating for each of the 8 items.  The scale takes approximately 
2-3 min to complete and can be administered by the physician or trained clinic personnel 
or study coordinator.  Details can be found within the SRM or study specific manual. 
8.5.2. 
Quantitative Myasthenia Gravis Score (QMG) 
The QMG score was developed as a tool to assess MG disease severity and the pattern of 
deficits based on quantitative testing of affected muscle groups [Barohn, 1998].  The 
scale is comprised of 13 test items that are graded on a scale of 0-3.  The total sum across 
all 13 items represents the QMG Score.  The test takes approximately 30 minutes to 
perform and can be administered by a trained physician, research coordinator or clinical 
evaluator who has been trained for this study.  Details can be found within the SRM or 
study specific manual. 
8.5.3. 
Myasthenia Gravis Composite Score (MGC) 
The MGC was developed by selecting the best performing items from 3 commonly used 
MG-specific scales (QMG, MG manual muscle test, and MG-ADL) and is comprised of 
10 functional domains: 3 ocular, 3 bulbar, 1 respiratory, 1 neck, and two limb items 
[Burns, 2008].  The scale measures symptoms and signs of MG in these domains 
incorporating both physician and patient-reported test items. The MGC takes 
approximately 5 min to complete and can be administered by a trained physician, 
research coordinator or clinical evaluator.  Details can be found within the SRM or study 
specific manual. 
8.5.4. 
Myasthenia Gravis Quality of Life 15 revised Score (MG-QOL 15r) 
The MG-QOL15r is a patient-reported scale designed to assess how their MG affects 
different aspects related to quality of life.  There are 15 items that are graded on a scale of 
0-2; the total across all 15 items represents the MG-QOL15r score. The survey takes 
approximately 2 minutes to complete by the participant.  Details can be found within the 
SRM or study specific manual. 


 
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8.5.5. 
 Satisfaction Questionnaire   
A brief survey asking participants for feedback on their experience with the SC injections 
during the course of the study will be completed at the end of the treatment period.  The 
survey will take less than 2 min to complete by the participant. 
 
9. 
DATA MANAGEMENT 
For this study, participant data will be entered into a Sponsor-approved electronic 
database and combined with data provided from other sources (e.g., safety laboratory, PK 
and PD vendor, etc.) in validated datasets then transmitted electronically to the Sponsor 
or designee.   
Management of clinical data will be performed in accordance with applicable Sponsor 
approved standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data. 
Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and the World Health Organization 
Drug Dictionary Enhanced (WHO-DDE), respectively.   
The Principal Investigator will retain original source documents and the Sponsor will 
receive eCRF-required data as electronic datasets. Participant initials will not be collected 
or transmitted to the Sponsor. 
 
10. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
10.1. 
Sample Size Considerations 
The sample size for this study was not determined using statistical methods.  The sample 
size was chosen based on clinical and recruitment considerations.  However, the sample 
size of 14 active and 7 placebo participants will allow the study to show a 33% difference 
between either active arm and the placebo arm, assuming 90% power, equal standard 
deviations of 20 and an alpha of 0.05 using a two-sided z-test for the primary endpoint of 
percentage change from baseline in IgG at Week 7.  
10.2. 
Data Analysis Considerations 
10.2.1. 
Analysis Populations 
Intention-To-Treat (ITT) Population 
All enrolled participants who take at least one dose of study medication will be included 
in the ITT population.  Participants will be summarized by randomized treatment group. 
This will be the population for all PD parameters. 


 
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Safety Population 
All participants who enroll in the study and receive at least one dose of study treatment 
will be included in the Safety Population.  Participants will be summarized by actual 
treatment group. 
This will be the population for the safety analyses, as well as for presentation and 
summarization of baseline/demographic characteristics. 
Pharmacokinetic Population 
The PK Population will include all participants who undergo plasma PK sampling and 
have evaluable concentration-time data for analysis. 
Pharmacodynamic Population  
The PD population will include all participants who have baseline measure, along with a 
post baseline measure and receive at least one dose of study treatment. 
Open-Label Extension Population  
The OLE population will include all participants who enroll in the OLE and receive at 
least one dose of study treatment in the OLE. 
12-Week Follow up Population 
The 12-Week Follow up Population will include all participants who receive at least one 
dose of study treatment in Part 1 and decline participation in the OLE but continue with 
the 12-week follow up period.  
 
10.2.2. 
Interim Analysis 
An interim analysis will occur after the last subject completes the Week 7 visit of the 
study.  All endpoints will be evaluated for this analysis.  A final analysis will occur when 
the last subject completes or discontinues the study.  Since this analysis is occurring at 
the end of the double-blind treatment phase, no adjustments of the alpha level are 
necessary.  This analysis will serve as the primary analysis and a second analysis will 
occur, summarizing the endpoints after the treatment-free phase. 
10.3. 
Final Analysis  
Final analysis will be performed after the completion of the study and the database is 
locked. 
Data will be listed and summarized.  Treatment will be assigned based on the dosing 
schedule and included in the data listings.  Listings will be sorted by participant, day, and 
time; summaries will be presented by treatment, day, and time.  


 
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Unless stated otherwise, descriptive summaries for continuous variables will include n, 
mean, standard deviation (SD), median, first and third quartiles, minimum, and 
maximum.  The geometric mean with associated 95% confidence interval (CI), and the 
between-participant CV (%CVb) for PK parameters only will also be included.  For 
categorical variables, n and percent will be used as summary statistics. Baseline is the last 
available assessment prior to time of the first dose unless it is specified otherwise.  If 
there are multiple assessments collected on the same scheduled time, the average of these 
assessments will be used.  For tabulated safety summaries, only the scheduled 
assessments will be included in the summary tables. 
Version 9.4 or higher of the SAS system will be used to analyze the data as well as to 
generate tables, figures, and listings. 
Complete details will be documented in the Statistical Analysis Plan (SAP), which will 
be signed off prior to the lock of the study database. 
 
10.3.1. 
Primary Endpoint for Efficacy 
The primary endpoint will be defined as the percentage change from Baseline in the IgG 
parameter at Week 7.  The endpoint will be summarized using a 6-number summary 
including the sample size, mean, standard deviation, median, minimum and maximum 
values.  Treatment group comparisons between the two active (separately) to the placebo 
arm will be performed using an Analysis of Covariance model with treatment and 
baseline value in the model.  An alpha of 0.05 will be used to determine statistical 
significance. 
10.3.2. 
Secondary Endpoints for Efficacy 
The secondary endpoints for efficacy are Immunogenicity determined by percentage 
change from Baseline in anti-RVT-1401 antibodies and characterization of any anti-
RVT-1401 antibodies to confirm neutralization potential at Week 7.   
For each of the continuous secondary endpoints, the actual value, change from baseline 
and percentage change from baseline for all secondary endpoints will be summarized by 
visit and treatment group using the n, mean, SD, median, first and third quartiles, 
minimum, and maximum values.  The comparison of the active arms (separately) to the 
placebo arm will be performed using an Analysis of Covariance model with treatment 
and baseline value in the model.  An alpha of 0.05 will be used to determine statistical 
significance.  If deemed appropriate, the two active arms may be combined and compared 
to placebo to evaluate any treatment effect. 
For categorical secondary endpoints, the number of participants who meet the endpoint 
and the percentage will be summarized.  The percentage will be calculated using those 
participants who had a value at the time point.  Statistical testing may be performed 
between the two treatments using a Fishers Exact Test.  If deemed appropriate, the two 
active arms may be combined and compared to placebo to evaluate any treatment effect. 


 
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10.3.3. 
Safety Analyses 
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, 
vital signs measurements, and ECG readings at various time points during the study, and 
by the documentation of AEs.  
AE verbatim text will be coded and classified by body system and preferred (coded) term 
using the MedDRA.  All AEs, both serious and non-serious will be listed.  AE summaries 
by study part and treatment group, of the number and percent of participants reporting 
each event at least once will be generated. 
Clinical chemistry, hematology, and urinalysis values will be listed for each participant 
and flagged high or low relative to the normal range where appropriate.  Descriptive 
summary statistics will be created by study part, treatment and assessment time. 
Other safety data will be summarized descriptively by treatment and time. Details will be 
provided in the SAP. 
10.3.4. 
Pharmacokinetic Analyses 
Serum compound concentration-time data will be analyzed by non-compartmental 
methods with Phoenix WinNonlin or other PK software programs.  Calculations will be 
based on the actual sampling times recorded during the study.  From the plasma 
concentration-time data, the following primary PK parameters will be determined (if 
possible):  
AUC(0-t), Cmax, tmax, Ctrough  
 
Additional PK parameters may be calculated.  PK data will be presented in graphical and 
tabular form and will be summarized descriptively.   
10.3.5. 
Pharmacodynamic Analyses 
All participants in the ITT population will be included in the summaries of PD data.  The 
actual value, change from baseline and percentage change from baseline for all PD 
parameters will be summarized by visit and treatment group using the n, mean, SD, 
median, first and third quartiles, minimum, and maximum values.  Statistical testing may 
be performed between the two treatment groups using mixed models.  Details will be 
provided in the Statistical Analysis Plan.   
Serum IgG, IgG subclass (1-4), and anti-AChR levels will be summarized as both raw 
values as well as percent change from baseline (intra-participant assessment). Additional 
PK/PD and PD/PD relationships may be evaluated.  PD data will be presented in 
graphical and tabular form and will be summarized descriptively.   
The comparison of the active arms (separately) to the placebo arm will be performed 
using an Analysis of Covariance model with treatment and baseline value in the model.  
An alpha of 0.05 will be used to determine statistical significance. 


 
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10.3.6. 
Other Analyses 
 
10.3.1. 
OLE and Follow up Analyses 
Data listings and summaries will be provided separately for the OLE and 12-Week 
Follow up Populations. Descriptive Analyses will be presented by randomized treatment 
assignment from the double-blind treatment period and overall.  Baseline will be 
specified in the Statistical Analysis Plan.  If there are multiple assessments collected on 
the same scheduled time, the average of these assessments will be used.  Only the 
scheduled assessments will be included in the summary tables.  All OLE and follow up 
analyses will be based on the OLE and 12-Week Follow up Populations, respectively.  
Ad hoc statistical analyses such as two sample t-test or Chi-Square test, may be 
performed for the changes or shifts at weeks 8, 10, and 12 separately.  The significance 
will be evaluated at a 0.05 two-sided level for informational purposes only. 
 
11. 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE 
EVENTS (SAES) 
The Principal Investigator or site staff is responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.  All SAEs must be reported to 
the Sponsor within 24 hours of awareness of the event (Section 11.2). 
Once former study participants have completed the study, the Principal Investigator is not 
obligated to actively seek AEs or SAEs. However, if the Principal Investigator learns of 
any SAE, including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event reasonably related to the investigational product or 
study participation, the Principal Investigator must promptly notify the Sponsor. 
 


 
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11.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a participant or clinical investigation 
participant, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. 
Events meeting the definition of an AE include but are not limited to: 
• Any clinically significant, new or worsened, abnormal laboratory test results 
(hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., 
ECGs, radiological scans, vital signs measurements). Clinical significance is 
determined based on the medical and scientific judgement of the Investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including an 
increase in frequency and/or intensity of the condition. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction (e.g. with 
medications or food). 
• Signs, symptoms, or the clinical sequelae of a overdose of either investigational 
product or a concomitant medication (overdose without an AE should be reported 
as a protocol deviation). 
Events that do not meet the definition of an AE include: 
• Anticipated day-to-day fluctuations of pre-existing condition(s), including the 
disease under study, that do not represent a clinically significant exacerbation or 
worsening. 
• Abnormal or worsening laboratory, imaging, or other safety findings that are not 
clinically significant. 
• Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
11.2. 
Definition and Reporting of Serious Adverse Events 
Serious adverse events must be marked as a SAE within the AE eCRF form, which will 
send an immediate auto notification to 
and 
the Medical Monitor.  
If the eCRF is not available, the site must email 
and the Medical Monitor within 24 hours 
of the study site personnel’s knowledge of the event.  
A SAE is any untoward medical occurrence that, at any dose: 


 
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• 
Results in death 
• 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization 
Hospitalization planned prior to signing the informed consent is not considered an SAE.  
Surgeries and other interventions that were under consideration prior to signing the 
informed consent are not considered an SAE if the underlying condition has not changed 
from baseline. 
“Hospitalization” includes admission to the hospital of any duration.  It does not include 
emergency room visits. Complications that occur during hospitalization are AEs and are 
SAEs if they prolong hospitalization or fulfill any other serious criteria. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
• 
Results in disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may jeopardize the subject or may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definition. Examples of such events are allergic bronchospasm, blood dyscrasias or 
convulsions where treatment prevents the need for hospitalization. 
The following should always be considered serious:  invasive or malignant cancers, and 
development of drug dependency or drug abuse. 
  
11.3. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
AEs will be collected from the time of informed consent until the follow-up contact, 
at the timepoints specified in the Section 8.1 and 8.2, Time and Events Tables. 
• 
Medical occurrences that begin prior to any study procedure but after obtaining 
informed consent may be recorded on the Medical History/Current Medical 
Conditions section of the eCRF. 
• 
All SAEs will be recorded and reported to the Sponsor within 24 hours of site 
awareness. 
• 
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to investigational 


 
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product will be recorded from the time a participant consents to participate in the 
study up to and including any follow-up contact.  
• 
Once former study participants have completed the study, the Principal Investigator 
is not obligated to actively seek AEs or SAEs. However, if the Principal Investigator 
learns of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event reasonably related to the 
investigational product or study participation, the Principal Investigator must 
promptly notify the Sponsor. 
 
11.4. 
Method of Detecting and Reporting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  Appropriate questions include: 
• 
“How are you feeling?”  
• 
“Have you had any (other) medical problems since your last visit/contact?”  
• 
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact? 
All AEs and SAEs should be promptly recorded in the eCRF, completing all fields for 
which data is available.  When known, the diagnosis should be entered as the event term 
in the eCRF, rather than individual symptoms.  When the diagnosis is unclear, key 
symptoms may be entered, and the investigator should obtain appropriate tests to 
establish a diagnosis, if possible.  Discharge summaries should be requested for all 
hospitalizations. 
For SAEs, the eCRF will send an auto notification to 
and the Medical Monitor when the form is 
saved.  Each SAE should be assigned a causality at the time of entry, as this is required to 
determine regulatory reporting. Follow-up information regarding the SAE, including 
hospital discharge summary, should be emailed to 
 
11.5. 
Assessing Severity of AEs and SAEs 
Severity describes the intensity of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical 
significance, such as a severe headache.  This is not the same as “serious,” which is based 
on participant/event outcome or action taken.  
The Investigator must determine the severity of each AE according to the following 
criteria:  


 
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Criteria for Determining the Grade/Severity of Adverse Event Terms  
Grade  
Criteria  
1/Mild  
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated  
2/Moderate  
Minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily 
living  
3/Severe or medically 
significant  
Not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living  
4/Life-threatening  
Life threatening consequences; urgent intervention 
indicated  
5/Death  
Death related to adverse event  
  
Adverse event severity should be recorded in the appropriate section of the AE eCRF and 
in the participant’s source documents. 
 
11.6. 
Assessing Causality of AEs and SAEs 
Regulatory authorities require that both investigator and sponsor assess whether there is a 
reasonable possibility that the study treatment caused each AE.  This assessment requires 
careful medical consideration of each event in relationship to the timing of drug 
administration, the presence of other factors which may have caused the event 
(underlying illness, concomitant medication, complications, exposure to other toxins or 
allergens, environmental factors, etc.), and the effects of stopping and/or restarting the 
study treatment.  The following definitions are to be used for the relationship of the AE  
to Study Treatment: 
The investigator will assess the causality of each reported AE as follows: 
 
• 
Probably related: an AE occurring at a reasonable time following administration of a 
drug, where other causes are unlikely, there is evidence to suggest that the drug 
caused the event, and/or where the event recurs after reintroduction of the drug 
(without other explanation for the recurrence). 
• 
Possibly related: an AE occurring at a reasonable time following administration of a 
drug and for which there is a reasonable possibility that the drug caused the event, 
e.g. there is some evidence to suggest a causal relationship.  
• 
Not related: an AE with poor or no relationship to the timing of drug administration, 
or where another cause such as underlying disease, complications, or other 
medications reasonably explains the event, or where the event does not recur after 
continued administration or reintroduction of the drug for an adequate period. 
 


 
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11.7. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Principal Investigator is required to proactively 
follow each event at subsequent visits/contacts until the event resolves.  All SAEs and 
AEs will be followed until resolution, or until the condition stabilizes or until the 
participant is lost to follow-up. Where necessary, repeated laboratory testing should be 
requested to confirm resolution. Ongoing AEs where no further information is likely to 
be available may be closed after consultation between the Sponsor and Medical Monitor. 
11.8. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of SAEs/adverse event of special 
interest (AESIs) is essential so that legal obligations and ethical responsibilities towards 
the safety of subjects and the safety of a product under clinical investigation are met. 
 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. The 
Sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC and Investigator. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and are forwarded to the 
Investigators in accordance with local regulations. 
 
The Investigator who receives an Investigator safety report describing a SAE(s)/AESI(s) 
or other specific safety information (e.g., summary or listing of SAEs) from the Sponsor 
will file it with the IB and will notify the IRB/IEC, as appropriate according to local 
requirements. 
 
11.9. 
Overdose 
Overdose is less likely in a study where the drug is administered within a clinical unit by  
a healthcare provider.  If there are no symptoms of an overdose, it may be recorded as a 
protocol deviation.  Overdose with symptoms should be recorded as an AE or SAE, as 
appropriate. 
 
12. 
PREGNANCY REPORTING 
All female participants will be tested for pregnancy prior to study drug dosing. 
Participants testing positive for pregnancy will be ineligible for study participation.  
Any pregnancies in a subject, or the partner of a subject, between the time of informed 
consent and study termination must be reported to the Sponsor within 24 hours of 
learning of the pregnancy. Information on the status and health of the mother, the 
pregnancy and its outcome, and the child will be recorded on the form provided. In case 
of a partner pregnancy, the partner of the study subject will be asked to sign a partner 


 
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pregnancy consent form in order to collect pregnancy and outcome information. 
Information on the status of the mother and child will be forwarded to the Sponsor.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any premature termination of the pregnancy will be reported. 
 
13. 
RESPONSIBILITIES 
13.1. 
Principal Investigator Responsibilities 
13.1.1. 
Good Clinical Practice (GCP) 
The Principal Investigator will ensure that this study is conducted in accordance with the 
principles of the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, 
Hong Kong, and South Africa), International Conference on Harmonisation (ICH) 
guidelines, or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the study participant.  For studies 
conducted under a United States IND, the Principal Investigator will ensure that the basic 
principles of “Good Clinical Practice,” as outlined in 21 Code of Federal Regulations 
(CFR 312), subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 
1998, and 21 CFR, part 56, 1998, are adhered to.  These standards are consistent with the 
requirements of the European Community Directive 2001/20/EC. 
Since this is a “covered” clinical trial, the Principal Investigator will ensure that 21 CFR, 
Part 54, 1998, is adhered to; a “covered” clinical trial is any “study of a drug or device in 
humans submitted in a marketing application or reclassification petition participant to this 
part that the applicant or FDA relies on to establish that the product is effective 
(including studies that show equivalence to an effective product) or that make a 
significant contribution to the demonstration of safety.”  This requires that Principal 
Investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the Sponsor, or proprietary interests in the drug being 
studied.  This documentation must be provided before participation of the Principal 
Investigator and any sub-investigator.  The Principal Investigator and sub-investigator 
agree to notify the Sponsor of any change reportable interests during the study and for 
one year following completion of the study. Study completion is defined as the date that 
the last participant has completed the protocol defined activities. 
13.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval 
This protocol and any accompanying material to be provided to the participant (such as 
informed consent form, advertisements, participant information sheets, or descriptions of 
the study used to obtain informed consent) will be submitted by the Principal Investigator 
to an IRB or IEC.  Approval from the IRB or IEC must be obtained before starting the 
study and should be documented in a letter to the Principal Investigator specifying the 
protocol number, protocol version, protocol date, documents reviewed, and date on which 
the committee met and granted the approval. 


 
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Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC on an 
annual basis or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
procedures established by the IRB/IEC. 
 
13.1.3. 
Informed Consent 
The Principal Investigator or designee is responsible for obtaining written informed 
consent from each individual participating in this study after adequate explanation of the 
aims, methods, objectives, and potential hazards of the study and before undertaking any 
study-related procedures. The Principal Investigator must utilize an IRB or IEC-approved 
consent form for documenting written informed consent. Each informed consent will be 
appropriately signed and dated by the participant and the person obtaining consent.  
Participants must be re-consented to continue their participation in the study if a protocol 
amendment is made that substantially alters the study design or the potential risks or 
burden to the participant. 
 
13.1.4. 
Confidentiality 
The Principal Investigator must assure that participants’ anonymity will be strictly 
maintained and that their identities are protected from unauthorized parties.  Only 
participant number (i.e., not names) and month and year of birth (as allowed) should be 
recorded on any form or biological sample submitted to the Sponsor, IRB or IEC, or 
laboratory. The Principal Investigator must keep a screening log showing codes, names, 
and addresses for all participants screened and for all participants enrolled in the trial. 
The Principal Investigator must keep a screening log showing codes, names, and 
addresses for all participants screened and for all participants enrolled in the trial. 
The Principal Investigator agrees that all information received from the Sponsor, 
including but not limited to the IB, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of the Sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to 
any third party (except employees or agents directly involved in the conduct of the study 
or as required by law) without prior written consent from the Sponsor. The Principal 
Investigator further agrees to take all reasonable precautions to prevent the disclosure by 
any employee or agent of the study site to any third party or otherwise into the public 
domain. 
 


 
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13.1.5. 
Study Files and Retention of Records 
The Principal Investigator must maintain adequate and accurate records to enable the 
conduct of the study to be fully documented and the study data to be subsequently 
verified.  These documents should be classified into at least the following two categories: 
(1) Investigator’s study file, and (2) participant clinical source documents. 
The Investigator’s study file will contain the IB, protocol/amendments, eCRF and query 
forms, IRB or IEC and governmental approval with correspondence, informed consent, 
drug records, staff curriculum vitae and authorization and training forms, and other 
appropriate documents and correspondence. 
The required source data should include the following for each participant: 
• participant identification (name, month and year of birth, gender); 
• documentation that participant meets eligibility criteria, i.e., history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion 
criteria); 
• participation in trial (including trial number); 
• trial discussed and date of informed consent; 
• dates of all visits; 
• documentation that protocol specific procedures were performed; 
• results of efficacy parameters, as required by the protocol; 
• start and end date (including dose regimen) of trial medication (preferably drug 
dispensing and return should be documented as well); 
• record of all AEs and other safety parameters (start and end date, and preferably 
including causality and intensity); 
• concomitant medication (including start and end date, dose if relevant; dose 
changes should be motivated); 
• date of trial completion and reason for early discontinuation, if applicable. 
All clinical study documents must be retained by the Principal Investigator until at least 2 
years after the last approval of a marketing application in an ICH region (i.e., United 
States, Europe, or Japan) and until there are no pending or contemplated marketing 
applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and 
regulatory authorities have been notified.  The Principal Investigator may be required to 
retain documents longer if required by applicable regulatory requirements, by local 


 
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regulations, or by an agreement with the Sponsor.  The Principal Investigator must notify 
the Sponsor before destroying any clinical study records. 
Should the Principal Investigator wish to assign the study records to another party or 
move them to another location, the Sponsor must be notified in advance. 
If the Principal Investigator cannot guarantee this archiving requirement at the study site 
for any or all of the documents, special arrangements must be made between the Principal 
Investigator and the Sponsor to store these in sealed containers outside of the site so that 
they can be returned sealed to the Principal Investigator in case of a regulatory audit.  
When source documents are required for the continued care of the participant, 
appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the 
Sponsor for a period up to 10 years for purposes of this study. 
 
13.1.6. 
Electronic Case Report Forms (eCRF) 
For each participant enrolled, an eCRF must be completed and signed by the Principal 
Investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection.  This also applies to records for those participants who fail to complete the 
study (even during the screening period if an eCRF was initiated).  If a participant 
withdraws from the study, the reason must be noted on the eCRF.  If a participant is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome. 
 
13.1.7. 
Drug Accountability 
The Principal Investigator or designee (i.e., pharmacist) is responsible for ensuring 
adequate accountability of all used and unused investigational product including placebo.  
This includes acknowledgment of receipt of each shipment of study product (quantity and 
condition), participant dispensing records, and returned or destroyed study product.  
Dispensing records will document quantities received from the Sponsor and quantities 
dispensed to participants, including lot number, date dispensed, participant identifier 
number, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies 
with the Sponsor requirements.  Drug may be returned or destroyed on an ongoing basis 
during the study as appropriate.  At the end of the study, following final drug inventory 
reconciliation by the monitor, the study site will dispose of and/or destroy all unused 
investigational medicinal product supplies, including empty containers, according to 
these procedures.  If the site cannot meet the Sponsor’s requirements for disposal, 
arrangements will be made between the site and the Sponsor or its representative for 
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All drug supplies and associated documentation will be periodically reviewed and 
verified by the study monitor over the course of the study. 
 
13.1.8. 
Inspections 
The Principal Investigator should understand that source documents for this trial should 
be made available to appropriately qualified personnel from the Sponsor or its 
representatives, to IRBs or IECs, or to regulatory authority or health authority inspectors. 
 
13.1.9. 
Protocol Compliance 
The Principal Investigator is responsible for ensuring the study is conducted in 
accordance with the procedures and evaluations described in this protocol. 
 
13.2. 
Sponsor Responsibilities 
13.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study 
participants, may be made only by the Sponsor. 
13.2.2. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies).  The 
Sponsor will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated 
report may be prepared in certain cases. 
 
13.2.3. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of participants begins.  Results will be posted as required. 
 
13.3. 
Joint Investigator/Sponsor Responsibilities 
13.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have 
direct access to the Principal Investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on them.  The monitor should have 
access to any participant records needed to verify the entries on the eCRFs.  The Principal 


 
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Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
 
13.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the Sponsor may conduct inspections or 
audits of the clinical study.  If the Principal Investigator is notified of an inspection by a 
regulatory authority the Principal Investigator agrees to notify the Sponsor medical 
monitor immediately.  The Principal Investigator agrees to provide to representatives of a 
regulatory agency or the Sponsor access to records, facilities, and personnel for the 
effective conduct of any inspection or audit. 
 
13.3.3. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be 
necessary, the Sponsor will arrange discontinuation procedures and notify the appropriate 
regulatory authority (ies), IRBs, and IECs.  In terminating the study, the Sponsor and the 
Principal Investigator will assure that adequate consideration is given to the protection of 
the participants’ interests. 


 
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14. 
REFERENCES 
Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan W. Reliability testing of 
the quantitative myasthenia gravis score. Ann NY Acad Sci 1998; 841:769-72. 
Burns TM, Conaway MR, Cutter GR, Sanders DB; Muscle Study Group. Construction of 
an efficient evaluative instrument for myasthenia gravis: the MG composite. Muscle 
Nerve. 2008 Dec;38(6):1553-62. 
Evoli A, Iorio R. Characteristics of myasthenia gravis with antibodies to muscle-specific 
kinase and low-density lipoprotein-related receptor protein 4. Clinical and Experimental 
Neuroimmunology. 2015;6:40-48. 
FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, 2009. 
Furst, DE. Serum Immunoglobulins and Risk of Infection: How Low Can You Go? 2008 
Elsevier Inc. Semin Arthritis Rheum 39:18-29 
Gilhus NE, Vershuuren JJ. Myasthenia gravis: subgroup classification and therapeutic 
strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. 
Hendrikx J, Haanen J, Voest E, Schellens J, Huitema A, Beijnen J.  Fixed Dosing of 
Monoclonal Antibodies in Oncology. The Oncologist 2017; 22:1212-1221 
Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density 
lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol. 2011 
Feb;69(2):418-22. 
Howard JF, Argenx. A double-blind placebo-controlled study to evaluate the safety and 
efficacy of FcRn-antagonist efgartigimod (ARGX-113) in generalized myasthenia gravis. 
American Academy of Neurology (AAN) Annual Meeting, 24 Apr 2018, Los Angeles, 
CA. 
Liu JF, Wang WX, Xue J, Zhao C-B, You H-Z, Lu J-H, Gu Y. Comparing the 
Autoantibody Levels and Clinical Efficacy of Double Filtration Plasmapheresis, 
Immunoadsorption, and Intravenous Immunoglobulin for the Treatment of Late-onset 
Myasthenia Gravis. Ther Apher Dial. 2010;14(2)153-160. 
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 
Nov;44(5):727-31 
Nowak RJ. Myasthenia Gravis: Challenges and Burdens of Disease. Neurology Reviews 
(suppl). 2018 Mar. 


 
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https://www.mdedge.com/neurologyreviews/article/161081/myasthenia-gravis-
challenges-and-burdens-disease. Accessed 10 May 2018. 
Paul RH, Nash JM, Cohen RA, Gilchrist JM, Goldstein JM. Quality of Life and Well-
Being of Patients with Myasthenia Gravis. Muscle Nerve. 2001;24:512-516. 
Pevzner A, Schoser B, Peters K, Cosma NC, Karakatsani A, Schalke B, Melms A, 
Kröger S. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia 
gravis. 2012 Mar;259(3):427-35. 
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev 
Immunol. 2007 Sep;7(9):715-25. 
Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. 
Autoimmunity. 2010;45(5-6):428-435. 
Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, Kuntz N, Massey JM, 
Melms A, Murai H, Nicolle M, Palace J, Richman DP, Verschuuren J, Narayanaswami P. 
International consensus guidance for management of myasthenia gravis. Neurology. 2016 
Jul 26;87(4):419-25. 
Utsugisawa K, Suzuki S, Nagane Y, Masuda M, Murai H, Imai T, Tsuda E, Konno S, 
Nakane S, Suzuki Y, Fujihara K, Suzuki N. Health-related quality of life and treatment 
targets in myasthenia gravis. Muscle Nerve. 2014;50:493-500. 
Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis 
activities of daily living profile. Neurology. 1999 Apr 22;52(7):1487-9 
Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, Xiong WC, Lisak 
RP, Tzartos SJ, Mei L. Autoantibodies to lipoprotein-related protein 4 in patients with 
double-seronegative myasthenia gravis. Arch Neurol. 2012 Apr;69(4):445-51. 
Zisimopoulou P, Evangelakou P, Tzartos J, Lazaridis K, Zouvelou V, Mantegazza R, 
Antozzi C, Andreetta F, Evoli A, Deymeer F, Saruhan-Direskeneli G, Durmus H, 
Brenner T, Vaknin A, Berrih-Aknin S, Frenkian Cuvelier M, Stojkovic T, DeBaets M, 
Losen M, Martinez-Martinez P, Kleopa KA, Zamba-Papanicolaou E, Kyriakides T, 
Kostera-Pruszczyk A, Szczudlik P, Szyluk B, Lavrnic D, Basta I, Peric S, Tallaksen C, 
Maniaol A, Tzartos SJ. A comprehensive analysis of the epidemiology and clinical 
characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. 2014 Aug;52:139-45. 


 
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15. 
APPENDICES 
15.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
AChR 
Anti-acetylcholine receptor 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC (0-t) 
Area under the concentration-time curve from time zero to 
time 
AUC (0-168) 
Area under the concentration-time curve from time zero to 
168 hours 
AZA 
Azathioprine  
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence intervals 
Cmax 
Maximum concentration 
CO2 
Carbon dioxide 
CPK 
Serum creatine phosphokinase 
Cτ 
Concentration at end of dosing interval 
CV 
Cardiovascular 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FcRn 
fully human anti-neonatal FC receptor 
FDA 
U.S. food and drug administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
IEC 
Independent ethics committee  
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational new drug 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 


 
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IS 
Immunosuppressive 
ITT 
Intent to treat 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MG 
Myasthenia Gravis 
MG-ADL 
Myasthenia Gravis-Activities of Daily Living  
MGC 
Myasthenia Gravis Composite 
MGFA 
Myasthenia Gravis Foundation of America 
MG-QOL15r 
Myasthenia Gravis Quality of Life  
MedDRA 
Medical dictionary for regulatory activities 
MSDS 
Material safety data sheet 
MuSK 
Muscle-specific kinase receptor  
NAb 
Neutralizing Antibody 
NSAID 
Non-steroidal anti-inflammatory agents 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PE 
Plasma exchange 
pIgG 
Pathogenic IgG  
PIS 
Post-Intervention Status  
PK 
Pharmacokinetic 
QMG 
Quantitative Myasthenia Gravis  
RBC 
Red blood cell 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SRM 
Study reference manual 
SUSAR 
Suspected unexpected serious adverse reactions  
t1/2 
Elimination half-life 
TB 
Tuberculosis 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO-DDE 
World health organization drug dictionary enhanced 


 
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Trademark Information 
Trademarks of Immunovant Sciences 
GmbH 
 
Trademarks not owned by Immunovant 
Sciences GmbH 
 
 
WinNonlin 
 
 
SAS 
 
 
FlowJo 
 
 
nSolver 
 


 
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15.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments 
Liver chemistry stopping criteria have been designed to assure participant safety and to 
evaluate liver event etiology (in alignment with the FDA Drug-induced Liver Injury: 
Premarketing Clinical Evaluation). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Liver Safety Process 
The procedures listed below are to be followed if a participant has ALT, bilirubin and/or 
INR elevations that meet the definition of a SAE (as defined in Section 11): 
• 
Notify the medical monitor within 24 hours of learning of the abnormality to confirm 
follow-up. 
• 
Complete the liver event case report forms.  
• 
Upon completion of the safety follow-up withdraw the participant from the study 
unless further safety follow up is required. 
• 
Make every reasonable attempt to have participants return to the clinic within 24 
hours for repeat liver chemistries, additional testing, and close monitoring (with 
specialist or hepatology consultation recommended). 
• 
Monitor participants twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
• Obtain viral hepatitis serology including: 
• 
Hepatitis A IgM antibody. 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM).  
• 
Hepatitis C ribonucleic acid (RNA).   
• 
Cytomegalovirus IgM antibody. 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing). 
• 
Hepatitis E IgM antibody. 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Assess eosinophilia 
• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
on the AE eCRF. 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
eCRF. 


 
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• Record alcohol use on the Liver Events eCRF. 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in participants with definite or likely acetaminophen use in 
the preceding week [James, 2009]. NOTE: not required in China Liver imaging 
(ultrasound, magnetic resonance, or computerized tomography) to evaluate liver 
disease. 
The Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests are 
performed. 
 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 


 
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SAP_001.pdf: 
CONFIDENTIAL
Page 1 of 51
29 July 2020
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2a, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study with an Open-Label Extension of 
RVT-1401 in Myasthenia Gravis Patients
Name of Test Drug:
RVT-1401
Study Number:
RVT-1401-2002
Protocol Version:
Amendment 2 (Version 3.0)
Protocol Date:
10-Apr-2019
CRF Version:
Version 5.0
CRF Date:
15-May-2020
Analysis Plan Version:
Version 2.0 (Final)
Analysis Plan Date:
28-Jul-2020
Analysis Plan History:
                                             
Version
Date
Final 1.0
20Aug2019
This original version was not used for analyses
Final 2.0 (Final)
28-Jul2020
This version was completed prior to any unblinding so it 
is considered the original version for analyses


CONFIDENTIAL
Page 2 of 51
29 July 2020
APPROVAL
Upon review of this document, including the table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are 
acceptable.
Signature
Date
_______________________________________________
_______________
_______________________________________________
                                     
_______________
CONFIDENTIAL AND PROPRIETARY INFORMATION
33'
33'
33'
33'
33'
33'


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29 July 2020 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ................................................................................................................................ 4 
1. 
INTRODUCTION ......................................................................................................................................... 7 
1.1. 
Study Objectives ............................................................................................................................... 7 
1.2. 
Study Design ..................................................................................................................................... 8 
1.3. 
Sample Size and Power ................................................................................................................... 17 
2. 
IMPACT OF COVID-19 ............................................................................................................................. 18 
3. 
TYPE OF PLANNED ANALYSIS ............................................................................................................. 19 
4. 
BLINDING .................................................................................................................................................. 20 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ..................................................................... 21 
5.1. 
Analysis Populations ....................................................................................................................... 21 
5.2. 
Baseline ........................................................................................................................................... 22 
5.3. 
Subject Groups ................................................................................................................................ 22 
5.4. 
Multiple Comparisons ..................................................................................................................... 22 
5.5. 
Missing Data ................................................................................................................................... 23 
6. 
SUBJECT DISPOSITION ........................................................................................................................... 25 
6.1. 
Disposition of Subjects ................................................................................................................... 25 
6.2. 
Extent of Exposure .......................................................................................................................... 25 
6.2.1. 
Duration of Exposure to Study Drug ............................................................................. 25 
6.2.2. 
Adherence with Study Drug Regimen ........................................................................... 26 
6.2.3. 
Satisfaction with Study Drug Regimen ......................................................................... 26 
6.3. 
Protocol Deviations ......................................................................................................................... 26 
7. 
BASELINE DATA ...................................................................................................................................... 27 
7.1. 
Demographics and Baseline Characteristics ................................................................................... 27 
7.2. 
Medical History .............................................................................................................................. 27 
8. 
ESTIMAND SPECIFICATION .................................................................................................................. 27 
8.1. 
The Treatment Condition ................................................................................................................ 27 
8.2. 
The Population of Interest ............................................................................................................... 28 
8.3. 
The Variable of Interest .................................................................................................................. 28 
8.4. 
The Population-level Summary....................................................................................................... 28 
9. 
EFFICACY ANALYSES ............................................................................................................................ 29 
9.1. 
Definition of the Primary Efficacy Endpoint .................................................................................. 29 
9.2. 
Statistical Hypotheses for the Efficacy Endpoints .......................................................................... 29 
9.3. 
Analysis of the Primary Efficacy Endpoint ..................................................................................... 30 
9.4. 
Secondary Efficacy Endpoints ........................................................................................................ 31 
9.4.1. 
Definition of Secondary Efficacy Endpoints ................................................................. 31 
9.4.2. 
Analysis Methods for Secondary Efficacy Endpoints ................................................... 33 
9.5. 
Exploratory Analyses ...................................................................................................................... 33 
9.5.1. 
Duration of Response of Each Clinical Scale through Week 7 ..................................... 33 
9.5.2. 
Time to Response of Each Scale through Week 7 ........................................................ 34 
9.5.3. 
Relationship Between Change from Baseline on Clinical Scores and 
Total IgG and Anti-AChR Antibody ............................................................................. 34 
10. SAFETY ANALYSES................................................................................................................................. 35 
10.1. 
Adverse Events ............................................................................................................................... 35 


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29 July 2020 
10.1.1. 
Adverse Event Dictionary ............................................................................................. 35 
10.1.2. 
Adverse Event Severity ................................................................................................. 35 
10.1.3. 
Relationship of Adverse Events to Study Drug ............................................................. 35 
10.1.4. 
Serious Adverse Events ................................................................................................. 35 
10.1.5. 
Treatment-Emergent Adverse Events ........................................................................... 36 
10.1.5.1. 
Definition of Treatment-Emergent ........................................................... 36 
10.1.5.2. 
Incomplete Dates ..................................................................................... 36 
10.1.6. 
Summaries of Adverse Events ...................................................................................... 37 
10.1.7. 
Injection Site Reactions ................................................................................................. 38 
10.2. 
Laboratory Evaluations ................................................................................................................... 38 
10.3. 
Vital Signs ....................................................................................................................................... 41 
10.4. 
Concomitant Medications ............................................................................................................... 41 
10.5. 
Electrocardiogram Results .............................................................................................................. 42 
10.6. 
Other Safety Data ............................................................................................................................ 42 
11. PHARMACOKINETIC ANALYSES ......................................................................................................... 44 
12. PHARMACODYNAMIC ANALYSES ...................................................................................................... 46 
13. IMMUNOGENICITY ANALYSIS ............................................................................................................. 47 
14. CHANGES FROM ANALYSES AS DESCRIBED IN THE PROTOCOL ................................................ 48 
15. REFERENCES ............................................................................................................................................ 49 
16. SOFTWARE ................................................................................................................................................ 51 
 


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 5 of 51 
29 July 2020 
LIST OF ABBREVIATIONS 
 
AChR 
Anti-acetylcholine receptor 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC0-t 
Area under the concentration-time curve from time zero to time 
BLQ 
 Below the limit of quantitation 
CI 
Confidence interval 
Cmax 
Maximum serum concentration 
Cτ 
Concentration at end of dosing interval 
Ctrough 
Concentration at end of dosing interval 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
ITT 
Intent to treat 
LOCF 
Last observation carried forward 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov Chain Monte Carlo 
MG 
Myasthenia Gravis 
MG-ADL 
Myasthenia Gravis-Activities of Daily Living 
MGC 
Myasthenia Gravis Composite 
MGFA 
Myasthenia Gravis Foundation of America 
MG-QOL 
Myasthenia Gravis Quality of Life 
MI 
Multiple Imputation 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred term 
Q1 
First quartile 
Q3 
Third quartile 
QMG 
Quantitative Myasthenia Gravis 
SAE 
Serious adverse event 


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 6 of 51 
29 July 2020 
SAF 
Safety 
SOC 
System organ class 
TLFs 
Tables, listings and figures 
tmax 
Time to maximum serum concentration 
WHO 
World Health Organization 


Immunovant
Statistical Analysis Plan
RVT-1401-2002
CONFIDENTIAL
Page 7 of 51
29 July 2020
1.
INTRODUCTION
Study Objectives
Primary Study Objectives
x
To assess the safety and tolerability of RVT-
1401 in anti-acetylcholine receptor (AChR)
antibody-positive myasthenia gravis (MG)
patients over a 6-week treatment period
x
To examine the effects of RVT-1401 on total 
immunoglobulin G (IgG), IgG subclasses (1-4) 
and anti-AChR-IgG levels
Secondary Study 
Objectives
x
To examine RVT-1401 pharmacokinetics (PK)
following repeat doses in patients with MG 
x
To measure anti-RVT-1401 antibodies following 
repeat doses in patients with MG and assess any 
potential impact on PK or pharmacodynamics 
(PD)
x
To examine the effects of RVT-1401 on the 
Quantitative Myasthenia Gravis (QMG) score
x
To examine the effects of RVT-1401 on the 
proportion of patients with improvement on the 
QMG score by ≥3 points from baseline
x
To examine the effects of RVT-1401 on 
Myasthenia Gravis-Activities of Daily Living 
(MG-ADL) score 
x
To examine the effects of RVT-1401 on the 
proportion of participants with an improvement 
on the MG-ADL score by ≥2 points
x
To examine the effects of RVT-1401 on the 
Myasthenia Gravis Composite (MGC) score
x
To examine the effects of RVT-1401 on the 
proportion of participants with an improvement 
on the MGC score by ≥3
x
To examine the effects of RVT-1401 on the 
Myasthenia Gravis Quality of Life (MG-
QOL15r) score


Immunovant
Statistical Analysis Plan
RVT-1401-2002
CONFIDENTIAL
Page 8 of 51
29 July 2020
Exploratory Study 
Objectives
Open-Label Extension 
Objective
x
To evaluate the effect of switching to an every 2-
week dosing regimen of 340 mg RVT-1401 on 
all study endpoints
Study Design
Design Configuration and 
Subject Population
This is a Phase 2a, randomized, double-blind, placebo-
controlled study with an open-label extension (OLE) to 
investigate the safety, tolerability, PK, PD, and efficacy of 
2 dosing regimens of RVT-1401 in AChR antibody-
positive MG patients.
Treatment Groups
x
RVT-1401 680 mg/week
x
RVT-1401 340 mg/week
x
Placebo
Key Eligibility Criteria
x
Myasthenia Gravis Foundation of America (MGFA) 
Class II-IVa and likely not in need of a respirator for 
the duration of the study as judged by the Investigator
x
Positive serologic test for anti-AChR antibodies at the 
screening visit and at least 1 of the following:
a.
History of abnormal neuromuscular transmission 
test demonstrated by single-fiber-
electromyography or repetitive nerve stimulation 
OR
b. History of positive edrophonium chloride test OR
c.
Participant has demonstrated improvement in MG 
signs on oral cholinesterase inhibitors as assessed 
by the treating physician.
x
QMG score ≥12 at Screening and Baseline
x
Stable dose of MG treatment prior to randomization. 
For participants receiving azathioprine, other non-
PPD


Immunovant
Statistical Analysis Plan
RVT-1401-2002
CONFIDENTIAL
Page 9 of 51
29 July 2020
steroidal immunosuppressive agents, steroids, and/or 
cholinesterase inhibitors as concomitant medications 
the following conditions will apply:
a.
Azathioprine: treatment initiated at least 
12 months ago and no dose changes in the last 
6 months before Screening
b. Other immunosuppressive treatment (e.g., 
methotrexate, cyclosporine, mycophenolate 
mofetil, and cyclophosphamide) initiated at least 
6 months ago and no dose changes in the last 
3 months before Screening
c.
Stable dose of steroid treatment at least 6 weeks 
before Baseline
d. Cholinesterase inhibitors: stable dose for >1 week 
before Screening. Note: cholinesterase inhibitors 
must be held for at least 12 hours consistent with 
the revised manual for the QMG test as 
recommended by the MGFA, before the QMG and 
MGC assessments
Study Periods/Phases
x
3-week screening period
x
6-week treatment period
x
12-week follow-up period or 6-week OLE period
and a 6-week follow-up period
Figure 1. Study Design for Subjects Who do not Participate in the Open-Label 
Extension


Immunovant
Statistical Analysis Plan
RVT-1401-2002
CONFIDENTIAL
Page 10 of 51
29 July 2020
Figure 2. Study Design for Subjects Who Participate in the Open-Label Extension
Schedule of Assessments
Following the initial dose at the Baseline Visit (Day 1), study visits will occur at Days 3 and 
5 and then weekly throughout the 6-week treatment period. Following the final dose at 
Week 6, two study visits will occur at Days 38 and 40, and then weekly through Week 10 
and then every 2 weeks until Week 18.
Randomization
Participants will be randomized to RVT-1401 680 mg/week, RVT-1401 
340 mg/week or placebo according to a 1:1:1 ratio.
Study 
Duration
Each participant will participate in the study for up to approximately 
21 weeks, including a 3-week screening period, and a 6-week double-
blind, placebo-controlled treatment period. Participants who choose not 
to enroll in the OLE will proceed to a 12-week follow-up period. Those 
who choose to enroll into the OLE will receive treatment in a 6-week 
OLE period (3 additional doses of 340 mg RVT-1401, every 2 weeks), 
followed by a 6-week follow-up period.


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 11 of 51 
29 July 2020 
Schedule of Assessments: 12-Week Follow-Up Without Open-Label Extension 
 
Screening1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
 
Treatment Period 
Week 6 
(Days) 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
 
Within 21 
Days 
 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
 
Day 
38 
 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window 
(days) 
 
 
+1 
day 
+1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead 
electrocardiogram2 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test3 
(females) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
QuantiFERON®-
TB Gold 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis2 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Blood chemistry 
and hematology2 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Serum 
complement 
(CH50, C3)2 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Immunoglobulins 
(IgM, IgA)2 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
X 
X 
RVT-1401 PK 
sampling2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 12 of 51 
29 July 2020 
 
Screening1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
 
Treatment Period 
Week 6 
(Days) 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
 
Within 21 
Days 
 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
 
Day 
38 
 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window 
(days) 
 
 
+1 
day 
+1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
 
Total IgG2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobins  
(IgG subclasses)2 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
Anti- RVT-
1401antibody2, 4 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Nab Assessment2 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Anti-AChR 
antibody2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug 
administration 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Injection site 
reactions5 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
MG-ADL6, 7 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Quantitative 
Myasthenia Gravis 
(QMG) Score6, 7 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Myasthenia Gravis 
Composite (MGC) 
Score6, 7 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Myasthenia Gravis 
Quality of Life 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
PPD


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 13 of 51 
29 July 2020 
 
Screening1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
 
Treatment Period 
Week 6 
(Days) 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
 
Within 21 
Days 
 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
 
Day 
38 
 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window 
(days) 
 
 
+1 
day 
+1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
 
(MG-QOL15r) 
Score6, 7 
Participant 
Satisfaction 
Questionnaire  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Screening can take place over multiple days to ensure participants withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
2. 
Vitals, ECG and blood draws for safety, PK, and PD assessment will be collected pre-dose on dosing days where specified. 
3. 
Pregnancy tests will be collected pre-dose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening, week 18, and early withdrawal. 
4. 
Participants positive for anti- RVT-1401 antibody at Week 18 will be requested to return at approximately 6, 9, and 12 months post-dose for additional samples or until their result is no longer positive. However, for 
purposes of safety follow-up and database lock, participation ends at the Week 18 visit.  
5. 
Local injection site reactions will be assessed at approximately 10 minutes post dose. 
6. 
MG assessments will be assessed pre-dose when collected on dosing days 
7. 
Subjects should be instructed to withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
 


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 14 of 51 
29 July 2020 
Schedule of Assessments: Open-Label Extension and 6-Week Follow-Up 
 
Screening
1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
OLE and Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
 
Within 21 
Days 
 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
 
Day 
38 
 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window (days) 
 
 
 
+1 
day 
 
+1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 
days 
 
Informed consent 
X2→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→→ 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead 
electrocardiogram3 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test4,5 
(females) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
 
X 
X 
QuantiFERON®-TB 
Gold 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis4 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Blood chemistry 
and hematology4 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Serum complement 
(CH50, C3)4 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Immunoglobulins 
(IgM, IgA)4 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
X 
X 
RVT-1401 PK 
sampling4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
Total IgG4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 15 of 51 
29 July 2020 
 
Screening
1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
OLE and Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
 
Within 21 
Days 
 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
 
Day 
38 
 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window (days) 
 
 
 
+1 
day 
 
+1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 
days 
 
Immunoglobins  
(IgG subclasses)3 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
Anti- RVT-
1401antibody4,6 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Nab Assessment4 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
anti-AChR 
antibody3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug administration 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
Injection site 
reactions7 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
MG-ADL 8,9 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Quantitative 
Myasthenia Gravis 
(QMG) Score 8,9 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Myasthenia Gravis 
Composite (MGC) 
Score 7,8 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X 
Myasthenia Gravis 
Quality of Life (MG-
QOL15r) Score 8,9 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
Participant 
Satisfaction 
Questionnaire  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PPD


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
Page 16 of 51 
29 July 2020 
 
Screening
1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
OLE and Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
 
Within 21 
Days 
 
Day 1 
(Baseline) 
 
Day 
3 
 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
 
Day 
38 
 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
 
Time Window (days) 
 
 
 
+1 
day 
 
+1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+1 
day 
+1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 
days 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Screening can take place over multiple days to ensure participants withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
2. 
Consent for enrolment into the OLE needs to occur prior to Week 8. 
3. 
Participants who complete the 6- week, randomized, double-blind treatment phase are eligible to participate in the OLE  
4. 
Vitals, ECG and blood draws for safety, PK, and PD assessment will be collected pre-dose on dosing days where specified. 
5. 
Pregnancy tests will be collected pre-dose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening, week 18, and early withdrawal. 
6. 
Participants positive for anti- RVT-1401 antibody at Week 18 will be requested to return at approximately 6, 9, and 12 months post-dose for additional samples or until their result is no longer positive. However, for 
purposes of safety follow-up and database lock participation ends at the Week 18 visit.  
7. 
Local injection site reactions will be assessed at approximately 10 minutes post dose. 
8. 
MG assessments will be assessed pre-dose when collected on dosing days.  
9. 
Subjects should be instructed to withhold cholinesterase inhibitors for at least 12 hours prior to the QMG and MGC assessments. 
 


Immunovant
Statistical Analysis Plan
RVT-1401-2002
CONFIDENTIAL
Page 17 of 51
29 July 2020
Sample Size and Power
Planned Sample Size and Power 
Statement
A sufficient number of participants will be enrolled 
to achieve approximately 21 evaluable participants. 
The sample size for this study was not determined 
using statistical methods. The sample size was 
chosen based on clinical and recruitment 
considerations. 
However, the sample size of 14 active and 7 placebo 
participants will allow the study to show a 33% 
difference between either active arm and the 
placebo arm, assuming 90% power, equal standard 
deviations of 20 and an alpha of 0.05 using a 
2-sided z-test for the primary endpoint of percentage 
change from baseline in IgG at Week 7.


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2. 
IMPACT OF COVID-19 
In accordance with FDA guidance,  Statistical Considerations for Clinical Trials During the 
COVID-19 Public Health Emergency:  Guidance for Industry (CDER, CBER, June 2020), 
this SAP is updated to reflect the evaluation by the Immunovant team and agreements as to 
accommodation of issues related to COVID-19. 
 
An interim analysis after 15 patients have completed Week 7 has been introduced, due to 
barriers to recruitment and data gathering following site closures. An IAP has been 
developed to support such an analysis, should it be done. 
 
During blind data review meetings (BDRM), which are done consistent with ICH E9, it was 
discovered that one subject had a missing Week 7 visit, although there had been no study 
withdrawals. This subject could not attend the Week 7 visit due to the closure of the site due 
to COVID-19. Assessments that could be done remotely were done remotely. 
 
The statistical impact was evaluated by the team with the following convention agreed: 
1. This subject did not withdraw from the study, and the statistics will not represent this 
patient as a withdrawal. 
2. This subject did not miss a visit. The missing data resulting from the site closure is 
not missing for reasons typical for clinical studies, and the missing data should be not 
handled in the typical way in the analysis. 
3. The assessments that could be done remotely were done remotely, and those values 
will be used as the Week 7 assessment values. Other values used for analysis will be 
the latest values obtained prior to the first dose of open-label treatment. 
 
In this case, hard-coding is permitted for programming. 
 
 
 


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3. 
TYPE OF PLANNED ANALYSIS AND ALPHA 
ALLOCATION 
Per protocol, an interim analysis will occur after the last subject completes the Week 7 visit 
of the study. All efficacy endpoints will be evaluated for this analysis. It is noted that the 
planned interim/primary analysis is the final analysis of the complete dataset from the 
double-blind treatment period. The database is interim due to the follow-up period, in which 
safety data will continue to accrue and be updated.  
Due to COVID-19 impact on the study, an interim analysis may be done after 15 subjects 
have completed Week 7, although the study is continuing. An interim analysis plan (IAP) 
will guide any interim analysis that is done. The IAP will document disclosure and 
safeguards to protect the integrity of the ongoing study. 
A final analysis will occur when the last subject completes or discontinues the study and the 
database is locked. 
An additional analysis of the anti-RVT-1401 antibody data will be performed if any subjects 
require follow-up testing. This analysis will focus solely on the antibody data and does not 
require any alpha correction. The CSR will be amended with this additional analysis if it is 
necessary. 
Alpha is controlled through the conditional sequencing of hypotheses. No other adjustment 
for multiplicity is needed. The interim analysis, if done, will be executed for administrative 
purposes due to business needs in response to circumstances precipitated by COVID-19 
issues. Alpha is allocated for the interim analysis of 0.0001, which is considered to be 
negligible; consequently, the final analysis has alpha = 0.05 preserved.  
 


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4. 
BLINDING 
At the time of the finalization of this SAP, no unblinding of any kind has occurred. It is noted 
that the only unblinded personnel for the study are documented in planning documents. 
Immunovant supports strong process and has standard operating procedures (SOPs) 
consistent with written regulatory guidance and standard conventions to protect the blinding 
of this study.  
 
Selected laboratory analytes that may reveal the treatment for individual subjects are 
conveyed and stored in protected spaces with controlled access to safeguard further the 
treatment given to specific subjects.  
 
There are four sources of unblinding or potential unblinding for this study: 
1. The randomization scheme, which was created by and is managed by contracted 
statisticians and personnel not otherwise involved in operational execution of the 
study and not involved with site activities. 
2. The concentration values, which are conveyed and stored in controlled places, 
consistent with other companies. 
3. The clinical trial material (CTM) to be assigned by computerized systems and 
dispensed by site personnel, which are managed by individuals not involved in 
operational execution of the study related to site activities, 
4. Selected laboratory analytes, including IgG and albumin, which are known to be 
reduced with this compound, which are conveyed and stored in controlled-access 
space. 
 
At the time of this SAP development, no one involved in the development of the SAP and no 
one involved in the query process is unblinded from any of these sources. 


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5.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Data will be listed and summarized. Listings will be sorted by treatment, participant, day, and 
time and include both scheduled and unscheduled visits; table summaries will be presented 
by treatment include placebo, RVT-1401 340 mg, RVT-1401 680 mg, combined RVT-1401 
group, and by scheduled visit.
Open label extension period will start from the date of the first OLE dose for each subject. 
Unless otherwise specified, data collected during OLE period will be included in the same
listings, tables, and figures with data collected during double-blind period.
Unless stated otherwise, descriptive summaries for continuous variables will include n, mean, 
standard deviation (SD), median, first and third quartiles (Q1, Q3), minimum, and maximum. 
The geometric mean with associated 95% confidence interval (CI) and the between-
participant coefficient of variation (CV) (%CVb) for PK parameters only will also be 
included. For categorical variables, n and percent will be used as summary statistics. Baseline 
is the last available assessment prior to time of the first dose unless it is specified otherwise. 
If there are multiple assessments collected on the same scheduled time, the average of these 
assessments will be used. For tabulated safety summaries, only the scheduled assessments 
will be included in the summary tables.
In general, summary statistics for raw variables will be displayed as follows: minimaand 
maxima will be displayed to the same number of decimal places as the raw data. Means, 
medians, and quartiles will be presented to 1 more decimal place than the raw data ; standard 
deviations will be presented to 2 more decimal places than the raw data.
The numbers of decimal places for summary statistics of derived variables (i.e., variables that are 
not measured by the study site but are calculated for analysis based on other measured variables) 
will be determined on a case by case basis.
Analysis Populations
In accordance with guidance from the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Statistical 
Principles for Clinical Trials E9 (1998), the following analysis populations will be used for 
all statistical analyses:
x
The full analysis set (FAS) includes all randomized subjects who receive at least 
one dose of randomized study medication with at least one valid post-treatment 
value. The FAS is used for all efficacy analyses.  
x
The per-protocol set (PPS) includes all FAS subjects who do not have significant 
protocol violations, where a significant protocol violation is one that has the 
potential to affect analysis conclusions.  Final determinations of significant 
protocol violations will be made at the final blinded data review meeting in 
accordance with guidance from ICH E9 (Statistical Principles).
x
The safety analysis set (SAF) includes all subjects who received at least one dose 
of study medication. The SAF is used for all safety analyses.


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x
The Pharmacokinetic (PK) analysis set includes all subjects who undergo PK 
sampling and have evaluable concentration-time data for analysis.
x
The Pharmacodynamic (PD) analysis set includes all subjects who received at least 
1 dose of study medication and have a baseline PD measurement and at least 1 
post-baseline PD measurement.
x
The Open-label Extension (OLE) analysis set includes all subjects who enroll in 
the OLE study phase and receive at least 1 dose of study medication in the OLE. 
The OLE subjects will be summarized by actual treatment in the double-blind 
treatment period for safety and PK analyses and by randomized treatment assigned 
in the double-blind treatment period for other analyses based on the OLE 
population.
Solely to understand the influence of dropouts on study conclusions, the FAS will be 
partitioned into completers and dropouts. 
Efficacy analysis will be done as randomized.  Safety analysis will be done as treated. In the 
event the administered dose level is not consistent throughout the double-blinded period, the
as treated arm will be determined by the highest dose level received during the double-
blinded treatment period.
A summary of the number and percent of subjects in each analysis set will be provided by 
treatment group and in total. Analysis based on a 12-week Follow-up analysis set may be 
provided depending on the number of subjects who choose not to enroll in the OLE study 
phase.
Baseline 
Baseline is defined as the last non-missing value prior to the date (time) of first dose of study 
drug unless otherwise specified. If there are multiple assessments collected on the same 
scheduled date and time, the average of these values will be used.
For the OLE, baseline is defined as the last non-missing value prior to the date (time) of first 
dose of study drug in the OLE.
Subject Groups
For analyses based on the SAF analysis set or the PK analysis set, subjects will be grouped 
for analyses according to the actual treatment received. For all other analyses, subjects will 
be grouped for analyses according to randomized treatment assignment from the double-
blind treatment period.
Multiple Comparisons
Adjustments for multiple comparisons for the primary efficacy endpoints list in Section 9.2
will be performed using a fixed, sequential testing procedure. The order of the testing 
sequence is specified in Section 9.2. The first test in the sequence will be performed at a 
significance level of 0.05. If that test is significant, then the second test in the sequence will 
be performed at a significance level of 0.05, and so on. Testing will stop when a 
non-significant test occurs in order to maintain a family-wise error rate of alpha=0.05.


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There will be no adjustments for multiple comparisons for the secondary efficacy or OLE 
endpoints.
Missing Data 
In general, values for missing data will not be imputed, except as noted.
If there are no missing data, other than COVID-19-related missing values (which are handled 
as described previously in this SAP), or if there is a single subject with missing data, the 
following missing data conventions are deemed unnecessary. For a single subject, the latest 
available value will be used as the response value of interest.
In the event that more than one subject has missing data, the following missing data 
methodologies will be followed:
For the primary endpoints, missing values for post-baseline assessments will be imputed 
using the method of multiple imputation (MI). As a sensitivity analysis, last observation after 
baseline carried forward (LOCF) will be used to impute the missing value.
Post-baseline values that are missing will be imputed for each primary efficacy endpoint
using the Markov Chain Monte Carlo (MCMC) method. Ten copies of the dataset with a 
monotonic missing pattern will be generated using the monotone data augmentation method, 
to impute the amount of missing data that is required to make the missing data pattern 
monotone before applying the multiple imputation algorithm. This method uses a non-
informative Jeffery’s prior to derive the posterior mode from the expectation-maximization 
algorithm as starting values for the MCMC method. For each of the 10 monotonic missing 
pattern datasets, an additional 10 datasets will be imputed to replace missing values at 
scheduled visits for a total of 100 datasets. These datasets will be generated using a 
monotone regression-based multiple imputation model. For subjects with complete data up to 
a particular visit, a multiple regression model will be fit that includes the outcome at that visit 
as the dependent variable and outcomes at previous visits, treatment group, baseline age, 
gender, time from disease onset, concomitant medications and duration of use, and baseline 
outcome as independent variables. Using these regression models, a missing value for a 
subject at a particular visit will be imputed as a draw from the predictive distribution given 
the outcomes at previous visits (some possibly imputed), the treatment group, age, gender, 
time from disease onset, concomitant medications and duration of use, and the baseline 
value. 
The SAS MI procedure (ie PROC MI) will be used. The ROUND option will be used to 
round the imputed values to the same precision as the observed values and the minimum 
value for imputed will be specified as zero to avoid negative values. The seed to be used for 
generating the monotonic missing pattern datasets will be 0518, the seed to be used for the
regression-based MI will be 0519. The analysis of covariance (ANCOVA) or rank analysis, 
and the mixed model repeated measures (MMRM) will be performed separately for each of 
the 100 complete analysis data sets, and the results will be combined into one multiple 


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imputation inference (estimated treatment effect and associated confidence interval and p 
value), using PROC MIANLALYZE. 
Missing individual items or questions from the QMG scale, MGC scale, the MG-ADL 
questionnaire, and the MG-QOL15r scale will be imputed using the method of LOCF if no 
more than 2 questions are missing for QMG scale, MGC scale and MG-QOL15r scale, or no 
more than 1 question in MG-ADL questionnaire is missing. Otherwise, the individual score 
and the corresponding total score will be treated as missing. 


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6.
SUBJECT DISPOSITION
Disposition of Subjects
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, randomized, included in each analysis set, and the 
number and percent of subjects:
x
Completing the 6-week double-blind treatment period, 
x
Completing the 12-week post-treatment follow-up period, and 
x
Not completing the study (with summary of reasons for not completing the study)
The denominator for the percentages of subjects in each category will be the number of 
subjects in the full analysis set.
Additionally, a summary of disposition will be provided for the OLE by randomized 
treatment assignment from the double-blind treatment period. This summary will present the 
number and percent of subjects:
x
Completing the 6-week OLE treatment period,
x
Completing the 6-week OLE follow-up period, and 
x
Not completing the OLE
The denominator for the percentages of subjects in each category will be the number of 
subjects in the OLE analysis set.
No inferential statistics will be generated. Data listings of reasons for study discontinuation
and reasons for OLE discontinuation will be provided. 
Extent of Exposure
6.2.1.
Duration of Exposure to Study Drug
Duration of exposure to study drug will be defined as (last dose date – first dose date + 1), 
regardless of temporary interruptions in study drug administration, and will be expressed in 
days. Duration of exposure to study drug will be summarized using descriptive statistics 
(sample size, mean, standard deviation, median, Q1, Q3, minimum and maximum) and as the 
number and percent of subjects exposed at each week.
Summaries will be provided separately for the 6-week double-blind treatment period and the 
6-week OLE treatment period by treatment group for the SAF analysis set and the OLE 
analysis set, respectively. No inferential statistics will be generated. 


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6.2.2.
Adherence with Study Drug Regimen
Adherence to study drug will be defined as the number of doses received divided by the 
number of doses planned. Adherence will be calculated separately for the 6-week double-
blind treatment period and the 6-week OLE treatment period.
Descriptive statistics for adherence (sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum) along with the number and percent of subjects belonging to 
adherence categories (e.g., <80%, 80% - 90%) will be provided by treatment group for the 
SAF analysis population and the OLE analysis population, respectively. No inferential 
statistics will be provided.
6.2.3.
Satisfaction with Study Drug Regimen
For each item listed in the first question ("In this study, how bothered have you been by the 
following:") of the treatment satisfaction questionnaire, the number and percentage of 
subjects who responded "quite a bit bothered" or "severely bothered" will be summarized. 
Likewise, for each item listed in the second question ("Regarding the weekly injections, 
please rate how satisfied you were with the following:"), the number and percentage of 
subjects who responded "not at all satisfied," "a little satisfied," or "moderately satisfied" will 
be summarized.
All responses to the treatment satisfaction questionnaire will be listed.
Protocol Deviations
Major protocol deviations that could potentially affect the efficacy or safety conclusions of 
the study will be identified prior to database lock and unblinding. Major protocol deviations 
may include, but are not limited to:
x
Randomly assigned subjects who did not satisfy selected inclusion and exclusion 
criteria;
x
Randomly assigned subjects who developed withdrawal criteria during the study but 
were not withdrawn;
x
Subjects who received the wrong treatment or incorrect dose;
x
Subjects who received an excluded concomitant treatment;
A listing of all protocol deviations including the deviation designation (major or minor), 
category, whether it is significant deviation led to an exclusion of a subject from the PP set 
will be presented in a data listing.  
Major protocol deviations will be summarized by deviation category and treatment group.
This ongoing clinical study coincides with the coronavirus disease 2019 (COVID-19) global 
pandemic. Any protocol deviations specifically due to COVID-19 will be summarized 
separately.


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7.
BASELINE DATA
Demographics and Baseline Characteristics
Subject demographic data (e.g., age, sex, race, and ethnicity) and baseline characteristics 
(e.g., QMG, MG-ADL, MGC, and MG-QOL15r scores, treatments for disease, time since 
thymectomy, and time from MG onset) will be summarized by treatment group and overall 
using descriptive statistics (sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum) for continuous data and by the number and percent of subjects for 
categorical data. The summaries of demographic and baseline characteristics data will be 
provided for the SAF analysis set. No inferential statistics will be generated. The time from 
MG onset will be calculated by using (The date of randomization – The start date of the MG 
collected in the CRF medical history form + 1) / 365. Refer Section 8.4 algorithms for the 
missing or incomplete MG start date.
Additionally, a summary of demographic and baseline characteristics data will be provided 
for subjects who enrolled in the OLE.
Medical History
Medical history will be listed.
8. ESTIMAND SPECIFICATION
This SAP is constructed to conform to regulatory guidance. In particular, this section is 
included as recommended by ICH E9 (R1) Addendum on estimands and sensitivity analysis 
in clinical trials to the guideline on statistical principles for clinical trials (30 August 2017)
and the update November 2019. The scientific question of interest evaluates the potential 
superiority of RVT-1401 over placebo in the treatment of MG in subjects who meet protocol 
eligibility criteria. 
In accordance with ICH E9 Addendum, the specification of the estimand is included in this 
SAP with the 4 attributes detailed in ICH E9 Addendum, Section A.3.1.
In accordance with guidance from the ICH E9 (R1) Addendum on Estimands and Sensitivity 
Analysis in Clinical Trials to the Guideline to Statistical Principles tor Clinical Trials (2018), 
the characterization of the estimand includes the following attributes.
The Treatment Condition
Blind data review considerations of intercurrent events revealed the potential that infections 
experienced by some subjects could affect the efficacy scales in important ways, rendering 
the responses to questionnaire data uninterpretable for protocol purposes. 


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The Population of Interest
The population of interest includes qualified subjects who meet eligibility criteria specified in 
the protocol and who have at least one valid post-baseline measure of IgG.
The Variable of Interest
For this study, the primary endpoint is IgG level and anti-AChR-IgG with co-primary 
importance on treatment responsiveness (whether or not subjects are treatment responders) 
evaluated based on clinical endpoints.
The Population-level Summary
The population-level summary for this study includes the mean percent change in IgG of 
patients in the FAS who received RVT-1401 (combined) versus placebo followed by 
estimates of subjects receiving each dose. Response data from efficacy questionnaires will 
include mean changes, mean percent changes, and responder analysis as defined under 
variables of analysis.


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9.
EFFICACY ANALYSES
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoints include:
x
Percentage change from baseline in total IgG at Week 7.
Supportive variables to the primary efficacy laboratory variable are:
x
Percentage change from baseline in IgG1 at Week 7
x
Percentage change from baseline in IgG2 at Week 7
x
Percentage change from baseline in IgG3 at Week 7
x
Percentage change from baseline in IgG4 at Week 7
x
Percentage change from baseline in anti-AChR-IgG level at Week 7
Percentage change from baseline will be calculated as:
%∆ = ൤100 x ൬Week 7 - Baseline
Baseline
൰൨
Statistical Hypotheses for the Efficacy Endpoints
The efficacy endpoint hypotheses will be tested in the order below. 
1. H0: μ11 = μ1p vs. HA: μ11 ≠ μ1p, where μ11 = LSmean of %ΔTotal IgG for RVT-1401 680 
mg/wk or RVT 340 mg/wk and μ1p = LSmean of %ΔTotal IgG for placebo
Supportive superiority on percent change in IgG is evaluated:
x
H01: The percent change from baseline in Total IgG after 6 weeks of treatment for 
the group treated with RVT-1401 680 mg/wk is equal to that of the placebo group.
x
H11: The percent change from baseline in IgG after 6 weeks of treatment for the 
group treated with RVT-1401 680 mg/wk is not equal to that of the placebo group.
Supportive superiority on percent change in IgG is evaluated: 
x
H02: The percent change from baseline in IgG after 6 weeks of treatment for the 
group treated with RVT-1401 340 mg/wk is equal to that of the placebo group.
x
H12: The percent change from baseline in IgG after 6 weeks of treatment for the 
group treated with RVT-1401 340 mg/wk is not equal to that of the placebo group.


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Superiority on percent change in anti-AChR-IgG level is evaluated:
x
H03: The percent change from baseline in anti-AChR-IgG after 6 weeks of 
treatment for the group treated with RVT-1401 680 mg/wk is equal to that of the 
placebo group.
x
H13: The percent change from baseline in anti-AChR-IgG after 6 weeks of 
treatment for the group treated with RVT-1401 680 mg/wk is not equal to that of 
the placebo group.
evaluation continues:
x
H04: The percent change from baseline in anti-AChR-IgG after 6 weeks of 
treatment for the group treated with RVT-1401 340 mg/wk is equal to that of the 
placebo group.
x
H14: The percent change from baseline in anti-AChR-IgG after 6 weeks of 
treatment for the group treated with RVT-1401 340 mg/wk is not equal to that of 
the placebo group.
Conditional on the p-value being less than alpha, testing continues:
Superiority on change in MG-ADL is evaluated:
x
H05: The percent change from baseline in MG-ADL after 6 weeks of treatment for 
the group treated with RVT-1401 680 mg/wk or RVT 340 mg//wk is equal to that 
of the placebo group.
x
H15: The percent change from baseline in MG-ADL after 6 weeks of treatment for 
the group treated with RVT-1401 680 mg/wk or RVT-1401 340 mg/wk is not 
equal to that of the placebo group.
Conditional on the p-value being less than alpha, testing continues:
x
H06: The proportion of responders on MG-ADL after 6 weeks of treatment for the 
group treated with RVT-1401 680 or 340 mg/wk is equal to that of the placebo 
group.
x
H16: The proportion of responders on MG-ADL after 6 weeks of treatment for the 
group treated with RVT-1401 680 or 340 mg/wk is not equal to that of the placebo 
group.
Analysis of the Primary Efficacy Endpoint
The primary efficacy endpoints will be summarized descriptively (sample size, mean, 
standard deviation, median, Q1, Q3, minimum and maximum). Efficacy analysis will be 
done on the FAS subjects consistent with ICH E9 principles. 


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The primary hypothesis test analysis will use the intent-to-treat methodology and a main-
effects model for ANCOVA, with adjustment for baseline levels.  If 2 or more subjects have 
missing Week 7 data, missing data will be predicted using MI methodology. 
For sensitivity analysis, interaction terms of site by treatment group will be examined.  In the 
event of a significant interaction term, the impact on analysis conclusion will be examined.  
The primary analysis model will not include interaction terms.  Assumptions underlying 
ANCOVA will be examined.  If assumptions of ANCOVA are unwarranted and the validity 
of the ANCOVA becomes questionable, rank analogues will be advanced as the primary 
analysis. Missing data will be managed using MI methods.
The primary analysis on treatment responders will use Fisher’s exact test supported by 
logistic regression with baseline measure as covariables.
The primary analysis will be conducted using the FAS following the intent-to-treat (ITT) 
principle.
Descriptive summaries will be produced for the actual values, change from baseline and 
percent change from baseline by treatment group and visit.
Longitudinal data analyses will be used to support the primary analysis utilizing a mixed 
model repeated measures (MMRM) methodology with treatment, baseline as covariate, time, 
treatment-by-time interaction as fixed effects, and subject as a random effect.
For completeness, an observed cases analysis will be done by visit in which no data are 
excluded, no data are imputed, and no data are represented at times other than when they 
were observed. As an alternative for handling missing data according to the rules of the 
primary analysis, a sensitivity analysis will be done using LOCF.
For statistical analyses, 95% confidence intervals will be produced for the least squares 
means (LSM) in each treatment group and combined treatment group, as well as the LSM 
differences as compared to placebo.  For MMRM and ANCOVA, two-sided p-values will be 
displayed for the comparison against placebo. 
To ensure robustness of analysis conclusions against parametric assumptions, rank analogues 
will be executed as sensitivity analysis.  If the PPS differs from the FAS by more than 10%, 
the analyses will be replicated on the PPS.  If the PPS and the FAS do not differ by more 
than 10%, analysis may not be done on the PPS.  Final judgments will be made at the blinded
data review meeting in accordance with ICH E9.
All analyses will be done using the intent-to-treat (ITT) principle. 
Secondary Efficacy Endpoints
9.4.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include:
x
Change from baseline in the MG-ADL score by visit through Week 7


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x 
Achievement of MG-ADL response of 2 points or more at Week 7 
x 
Change from baseline in the QMG score by visit through Week 7 
x 
Achievement of QMG improvement with an improvement from baseline on the 
QMG score by ≥3 points at Week 7 
x 
Achievement of MGC improvement with an improvement from baseline on the 
MGC score by ≥3 points at Week 7 
x 
Change from baseline in the MGC score by visit through Week 7 
x 
Change from baseline in the MG-QOL15r score by visit through Week 7 
x 
Durability of MG-ADL response as evaluated by proportion of assessments by 
Week 7 with change showing improvement of 2 or more points. 
x 
Durability of QMG response as evaluated by proportion of assessments by Week 7 
with change showing improvement of 3 or more points. 
x 
Durability of MGC score as evaluated by proportion of assessments by Week 7 
with change showing improvement of 3 or more points. 
x 
Achievement of improvement by meeting at least one of the following criteria: 
x 
Achievement of improvement of at least 2 points on MG-ADL 
x 
Achievement of improvement of at least 3 points on QMG 
x 
Achievement of improvement of at least 3 points on MGC 
x 
Achievement of improvement by meeting at least two of the following criteria: 
x 
Achievement of improvement of at least 2 points on MG-ADL 
x 
Achievement of improvement of at least 3 points on QMG 
x 
Achievement of improvement of at least 3 points on MGC 
x 
Achievement of improvement by meeting all three of the following criteria: 
x 
Achievement of improvement of at least 2 points on MG-ADL 
x 
Achievement of improvement of at least 3 points on QMG 
x 
Achievement of improvement of at least 3 points on MGC 
The QMG scale is comprised of 13 items that are graded on a scale of 0 to 3. The sum across 
all 13 items represents the QMG score which will range from 0 to 39. 
The MGC scale is a patient reported scale comprised of 10 items that are rated on a scale 
ranging from 0 to 9 depending on the item. The sum across all 10 items represents the total 
MGC score which will range from 0 to 50. 
The MG-ADL is a patient reported questionnaire comprised of 8 items that are rated on a 
scale of 0 to 3. The sum across all 8 items represents the MG-ADL score which will range 
from 0 to 24. 


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The MG-QOL15r is a patient-reported scale comprised of 15 items that are graded on a scale 
of 0 to 2. The sum across all 15 items represents the MG-QOL15r score which will range 
from 0 to 30.
Missing individual items or questions from the QMG scale, MGC scale, the MG-ADL 
questionnaire, and the MG-QOL15r scale will be imputed using the method of LOCF if no 
more than 2 questions are missing for QMG scale, MGC scale, and MG-QOL15r scale or no 
more than 1 question is missing for the MG-ADL questionnaire. Otherwise, will take the 
total score for the given scale as missing.
9.4.2.
Analysis Methods for Secondary Efficacy Endpoints
Total MG-ADL, QMG, MGC, and MG-QoL15r score and each of the component scores will 
be summarized descriptively (sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum) by treatment group and analyzed using ANCOVA model with 
treatment as a fixed factor and baseline value as a covariate. Least-squares means and 95% 
CIs will be calculated and provided for each treatment group. The least-squares means will 
be compared using a t-test.  
Number and proportion of subjects with a ≥2-, ≥3-, ≥4-, ≥5-, ≥6-, ≥7-, or ≥8-point 
improvement in total MG-ADL, QMG, and MGC score at all timepoints will be summarized
descriptively by treatment group. The percentage will be calculated using those participants 
who had a value at the time point. Fisher’s exact test will be used to compare each active 
dose regimen to placebo. A logistic regression with treatment as the main effect and the 
baseline value as a covariate will be used for comparing the proportion of responders
between the treatment groups. The odds ratio and corresponding 2-sided 95% Wald 
confidence interval will be provided.
There will be no adjustments for multiple comparisons for secondary endpoints. An alpha 
level of 0.05 will determine statistical significance. Analyses of secondary efficacy endpoints 
will be provided for the FAS.
Exploratory Analyses
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10.
SAFETY ANALYSES
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a participant or clinical 
investigation participant, temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the
use of a medicinal product.
Adverse events summaries will be constructed displaying AEs in decreasing order of 
frequency under the combined RVT-1401 group according to the numbers of subjects 
reporting the AE (not the number of events).
A listing will be constructed that includes the subject identification, the dose group, TEAEs, 
MedDRA terms, seriousness, severity, causality related to study medication, elapsed time to 
onset, duration, and outcome. 
10.1.1.
Adverse Event Dictionary
AE verbatim text will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA version 21.1). System organ class (SOC), high level group term, high level term, 
preferred term (PT), and lower level term will be attached to the clinical database.
10.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life threatening) or Grade 5 (death) according to toxicity criteria 
specified in the study protocol. The severity grade of events for which the investigator did 
not record severity will be categorized as “missing” for tabular summaries and data listings
and will be considered the least severe for the purposes of sorting for data presentation.
10.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator answers “Probably Related” or “Possibly 
Related” to the question “Is there a reasonable possibility that the study treatment caused or 
contributed to the adverse event?” Adverse events for which the investigator did not record 
relationship to study drug will be considered related to study drug. Data listings will show 
relationship as missing.
10.1.4.
Serious Adverse Events
Serious adverse events (SAEs) are those identified in the clinical database as such. The 
clinical database will be reconciled with the SAE database before database lock.


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10.1.5. 
Treatment-Emergent Adverse Events 
10.1.5.1. 
Definition of Treatment-Emergent 
Adverse events will be classified by study part according to the following: 
x 
Pre-treatment: AEs that either started prior to the date of the first dose of study 
drug or had no recorded start date and the stop date is prior to the first dose of 
study drug. 
x 
Treatment-emergent: AEs that either started on or after the date of the first dose of 
study drug and on or before the date of 6 weeks (42 days) post the last dose of 
study drug or had no recorded start date and the stop date is not before the first 
dose of study drug. 
x 
Post-treatment: AEs that started after the date of 6 weeks (42 days) post the last 
dose of study drug. 
x 
OLE treatment-emergent: AEs that either started on or after the date of the first 
dose of study drug in the OLE. 
10.1.5.2. 
Incomplete Dates 
The following algorithms will be applied to missing and incomplete start and stop dates: 
Start Dates:  
If the day portion of the start date is missing, then the start date will be estimated to be equal 
to the date of first dose of study drug, provided the start month and year are the same as the 
first dose of study drug and the stop date is either after the first dose of study drug or 
completely missing. Otherwise, the missing day portion will be estimated as “01.”  
If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first dose of study drug, provided the start year is the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the event will be assumed to start on the first day of 
the given year (e.g., ??-???-2013 is estimated as 01-JAN-2013).  
If the start date is completely missing and the stop date is either after the first dose of study 
drug or completely missing, the start date will be estimated to be the first day of study drug 
dosing. Otherwise, the start date will be estimated to be the first day of the same year as the 
stop date.  
Stop Dates:  
If only the day of the stop date is unknown, the day will be assumed to be the last of the 
month (e.g., ??-JAN-2013 will be treated as 31-JAN-2013).  
If both the day and month of the stop date are unknown, the stop date will be assumed to be 
last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013).  


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If the stop date is completely missing, and the stop date will be imputed using the last known 
date on the study. 
10.1.6. 
Summaries of Adverse Events 
All AE summaries will be provided separately for the double-blind treatment period and the 
follow-up period as well as the OLE treatment period and OLE follow-up period. Double-
blind treatment period AE summaries will present treatment-emergent AEs which occurred 
before study drug administration during OLE study period or before the primary lock date, 
whichever comes first. Follow-up period AE summaries will present post-treatment AEs, 
OLE treatment period AE summaries will present OLE treatment-emergent AEs which occur 
before or on week 12 visit and OLE follow-up period AE summaries will present OLE post-
treatment AEs. Pre-treatment AEs will be listed. 
Overall summaries of treatment-emergent AEs by treatment group will be provided to 
include the number and percentage of subjects who: 
1. Had any AE, 
2. Had any Grade 3 or higher AE, 
3. Had any treatment-related AE,  
4. Had any Grade 3 or higher treatment-related AE,  
5. Had any SAE,  
6. Had any treatment-related SAE,  
7. Permanently discontinued from study drug due to an AE, and  
8. Died. 
Summaries (number and percent of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group for the following: 
x 
All AEs, 
x 
All Grade 3 or higher AEs, 
x 
All treatment-related AEs, 
x 
All Grade 3 or higher treatment-related AEs, 
x 
All SAEs,  
x 
All treatment-related SAEs, 
x 
All AEs that leading to permanently discontinued from study drug.  
Multiple events will be counted once only per subject in each summary. For data 
presentation, SOC will be ordered alphabetically, with PT sorted by decreasing frequency in 


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the combined RVT-1401 column. Treatment period and follow-up period AE summaries will 
be provided for the SAF analysis population. Open-label extension AE summaries will be 
provided for the OLE analysis population. Whole study AE summaries include the double 
blinded period, OLE period and follow up will be provided for below 3 tables:
x
Overall summaries of treatment-Emergent AEs
x
Treatment-emergent AEs by SOC and PT
x
Serious treatment-emergent AEs by SOC and PT
In addition to the by-treatment AE summaries, data listings will be provided for the 
following:
x
Pre-treatment AEs
x
Treatment-emergent AEs
x
Post-treatment AEs
x
OLE treatment-emergent AEs
x
SAEs
x
Liver events
x
AEs leading to discontinuation or interruption of study drug
x
Deaths
x
Grades 2-4 albumin events
10.1.7.
Injection Site Reactions
Injection site reactions will be summarized (number and percentage of subjects) by symptom 
and toxicity grade and provided by treatment group. Multiple events will be counted once 
only per subject in each summary. Additionally, a summary of the number of subjects who 
experienced at least 1 injection site reaction during the study and at each visit will be 
provided for the SAF analysis population. No inferential statistics will be generated. Injection 
site reactions will also be listed.
Laboratory Evaluations
Descriptive statistics (sample size, mean, standard deviation, median, Q1, Q3, minimum and 
maximum) of baseline, post-baseline, and change from baseline central laboratory values 
collected for each laboratory parameter will be provided by treatment group for all scheduled 
visits. If result contains ‘<’, then the result for continuous summaries will be the value 
divided by 2, and if the result contains ‘>’ then the result for continuous summaries will be 
the value plus 0.01 for analysis. The listings will display the value as collected.


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Hematology, clinical chemistry, urinalysis and additional parameters to be tested by central 
laboratory are listed below: 
 
Hematology 
Platelet count  
Red Blood Cell Indices: 
Automated White Blood 
Cell Differential: 
Red blood cell count 
Mean corpuscular volume  Neutrophils 
White blood cell count 
(absolute)  
Mean corpuscular 
hemoglobin  
Lymphocytes 
Reticulocyte count 
Mean corpuscular 
hemoglobin concentration 
 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
Clinical Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
AST (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose fasting 
[on Day 1 
(baseline) and 
Week 7 only] 
Total carbon dioxide 
(CO2 ) 
Gamma glutamyl 
transferase (GGT) 
Albumin* 
Sodium 
Calcium (corrected) 
Alkaline phosphatase 
(ALP) 
Total Protein 
Serum 
complement 
(CH50, C3) 
Immunoglobulin M 
(IgM) 
Immunoglobulin A 
(IgA) 
Immunoglobulin 
G 
(IgG) 
Routine Urinalysis 
Specific gravity, pH 
Glucose, protein, blood, and ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other tests 
QuantiFERON®-TB Gold 
Viral Serology [HIV1/HIV2, hepatitis B (HBsAg), hepatitis B (core antibody), hepatitis 
C (Hep C antibody] 
Follicle-stimulating hormone (as needed for confirmation of postmenopausal status) 
Pregnancy tests: serum test at screening, Week 18, and early withdrawal and urine 
dipstick pre-dose at other time points. Positive urine tests should be confirmed with a 
serum test. 
* Albumin collected from central lab will be graded to Grade 1 to 3 by CTCAE version 5.0. 


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Additionally, summaries (number and percentage of subjects) of shifts from baseline central 
laboratory value (low, normal, or high) to post-baseline value (low, normal, or high) at each 
scheduled post-baseline visit for each parameter will be provided by treatment group. 
Albumin from central laboratory will be graded according to CTCAE v5.0 as below. The 
highest CTCAE grade for each visit will be summarized using a shift table to assess changes 
from baseline. Grading of albumin will only be based on the following numeric values, (note 
this may lead to a discrepancy with the protocol-defined Grade 2 event since the protocol 
also involves signs/symptoms attributable to hypoalbuminemia and not just on the lab value): 
Grade 1 
Grade 2 
Grade 3 
<LLN - 3 g/dL; 
 <LLN - 30 g/L 
<3 - 2 g/dL;  
<30 - 20 g/L 
<2 g/dL;  
<20 g/L 
Central and local laboratory clinical chemistry, hematology, and urinalysis values will be 
listed and flagged high or low relative to the normal range where appropriate. Summaries of 
laboratory data will be provided for the SAF analysis population. No inferential statistics will 
be generated. 
Because “exacerbations” of pre-existing abnormalities in laboratory analytes are examined 
using clinical judgment and are reported as TEAEs, additional analysis on treatment-
emergent abnormal values is limited to subjects with values that are normal prior to dosing 
and abnormal after dosing.  
Adverse events of special interest also treatment-emergent abnormal values TEAVs in 
laboratory parameters related to liver function tests, specifically ALT, AST, bilirubin, and 
ALK. 
Potentially clinically significant values in laboratory analytes will be examined in accordance 
with the table of values or changes of potential clinical significance in this SAP. Proportions 
of subjects in each treatment group who meet the criteria will be analyzed.  
Laboratory data will be summarized by Baseline and change from Baseline to each scheduled 
assessment time with descriptive statistics.  
Liver function tests have additional monitoring for this study. 
To explore the potential for drug-induced liver injury consistent with Guidance for Industry 
“Drug-induced liver injury: premarketing clinical evaluation” (CDER, CBER, July 2009), 
subjects will be summarized and listed who meet the following criteria: 
1. Elevations in either AST or ALT of at least 3-times the upper limit of normal, and 
2. An accompanying abnormal bilirubin.   
Additionally, a summary and listing will be examined for subjects with elevations in either 
AST or ALT of at least 3-times the upper limit of normal, regardless of bilirubin. 
 


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Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, temperature, weight,
and height) will be summarized descriptively. Descriptive statistics (sample size, mean, 
standard deviation, median, Q1, Q3, minimum and maximum) of baseline, post-baseline, and 
change from baseline values for each parameter will be provided by treatment group for all 
scheduled time points. Summaries of vital sign data will be provided for the SAF analysis 
set. No inferential statistics will be generated. Vital sign values will also be listed. 
Concomitant Medications
Concomitant medication verbatim terms on case report forms will be mapped to Anatomical 
Therapeutic Chemical (ATC) Class and Preferred Names using the World Health 
Organization (WHO) Drug Dictionary version 01Sep2018. Concomitant medications will be 
summarized (number and percentage of subjects) by ATC class and preferred name and 
provided by treatment group. Multiple medications (by preferred name) will be counted once 
only per subject. The summary will be sorted alphabetically by ATC class and then by 
decreasing total frequency within preferred names. Additionally, a summary of the frequency 
of IVIG/PLEX rescue medications will be provided. Summaries of concomitant and rescue 
medications will be provided for the SAF analysis population. No inferential statistics will be 
generated.
Concomitant medications will be defined as medications that started or were ongoing on or 
after the date of the first dose of study drug. Prior medications will be defined as medications 
that stopped prior to the first dose of study drug. All medications will be listed along with a 
flag to indicate whether the medication was a prior medication or a concomitant medication.
Concomitant and rescue medications will be summarized separately for the OLE.
Concomitant medications in the OLE will be defined as medications that started or were 
ongoing on or after the date of the first dose of study drug in the OLE. Summaries of 
concomitant and rescue medications in the OLE will be provided for the OLE analysis 
population.
The following algorithms will be applied to missing and incomplete start and stop dates:
Start Dates: 
If the day portion of the start date is missing, then the start date will be estimated to be equal 
to the date of first dose of study drug, provided the start month and year are the same as the 
first dose of study drug and the stop date is either after the first dose of study drug or 
completely missing. Otherwise, the missing day portion will be estimated as “01.” 
If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first dose of study drug, provided the start year is the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the event will be assumed to start on the first day of 
the given year (e.g., ??-???-2013 is estimated as 01-JAN-2013). 
If the start date is completely missing and the stop date is either after the first dose of study 
drug or completely missing, the start date will be estimated to be the first day of study drug 


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dosing. Otherwise, the start date will be estimated to be the first day of the same year as the 
stop date. 
Stop Dates: 
If only the day of the stop date is unknown, the day will be assumed to be the last of the 
month (e.g., ??-JAN-2013 will be treated as 31-JAN-2013). 
If both the day and month of the stop date are unknown, the stop date will be assumed to be 
last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013). 
If the stop date is completely missing, and the stop date will be imputed using the last known 
date on the study.
Electrocardiogram Results
Electrocardiogram (ECG) results (heart rate, PR, QRS, QT, and corrected QT interval by 
Fredericia (QTcF) will be summarized descriptively. Descriptive statistics (sample size, 
mean, standard deviation, median, Q1, Q3, minimum and maximum) of baseline, post-
baseline, and change from baseline values for each parameter will be provided by treatment 
group for all scheduled time points. 
Additionally, summaries (number and percentage of subjects) of shifts in the investigator’s 
ECG assessment from baseline (normal, abnormal and clinically significant, or abnormal but 
not clinically significant) to post-baseline (normal, abnormal and clinically significant, or 
abnormal but not clinically significant) at each scheduled post-baseline visit will be provided 
by treatment group.
Summaries of ECG data will be provided for the SAF analysis set. No inferential statistics 
will be generated. ECG data will also be listed.
Corrections to QT intervals will be made by Fridercia’s method. Categorical analysis will be 
done consistent with ICH E14, “Clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs” (October 2005). Subjects will be 
categorized and summarized according to:
x
Absolute QTc interval prolongation:
o
QTc interval > 450
o
QTc interval > 480
o
QTc interval > 500
x
Change from baseline in QTc interval:
o
QTc interval increases from baseline > 30
o
QTc interval increases from baseline > 60
Other Safety Data
Data listings will be provided for the following:


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x 
Eligibility criteria 
x 
Procedures 
x 
Physical examination 
x 
Pregnancy test 
x 
Liver imaging 
x 
Liver biopsy 
x 
Receptor occupancy 
x 
Pro-inflammatory biomarker multiplex 
x 
Gene expression 
x 
Immunoglobulins (IgM, IgA) 
x 
Serum complement 
x 
Viral serology 
x 
QuantiFERON-TB Gold 
 


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11. 
PHARMACOKINETIC ANALYSES 
Serum concentration data will be summarized descriptively for each nominal time point. 
Individual serum concentration-time plots will be presented on linear and semi-log scales. 
The PK analysis will be divided into 2 sections: primary analysis and OLE analysis, where 
the OLE analysis will contain individuals in the OLE population only. For descriptive 
statistics and mean figures, concentrations that are below the limit of quantitation (BLQ) will 
be treated as zero, except when an individual BLQ falls between 2 quantifiable values, in 
which case it will be treated as missing data and will be excluded from the mean profile.  
Serum RVT-1401 concentration-time data will be analyzed by non-compartmental analysis 
(NCA), using actual sampling times recorded during study. The pharmacokinetic analysis 
and generation of tables, listings, and figures will be performed using a validated installation 
of Phoenix WinNonlin® version 8.1 and above (Certara, Princeton, NJ, USA) as part of a 21 
CFR Part 11 compliant database system (Phoenix Knowledgebase Server “PKS”) and all the 
analysis will be stored on the PKS, with an audit trail for all the steps capturing the changes 
needed for the completion of the analysis and generation of the tables, listings, and figures. 
The primary analysis of PK will be conducted on the Pharmacokinetic (PK) population, 
which includes all subjects who had both a pre-dose and at least 1 analyzable post-dose PK 
sample. The primary pharmacokinetic parameters to be calculated are area under the 
concentration-time curve from time zero to time AUC0-t, maximum serum concentration 
(Cmax), concentration at end of dosing interval (Ctrough), and time to maximum serum 
concentration (tmax) after the first and last dose on Week 1 and Week 6, respectively. The 
Cmax,, tmax, AUC0-t  will be estimated using linear-up log-down method, as data permits. 
Additionally, Ctrough will be determined for every dosing interval (Week 2, Week 3, Week 4, 
and Week 5), where PK samples taken within 8 hours before the next dose administration 
will be considered for reporting. Additional PK parameters (e.g. accumulation ratio for both 
Cmax and/or AUC (0-t) between Week 1 and Week 6) may be calculated if data permits. 
Pharmacokinetic (PK) parameters (AUC0-t, Cmax, Ctrough and tmax) will be summarized 
descriptively as follows: 
x 
Serum concentration data: sample size, number and percentage BLQ, mean, 
standard deviation, CV, median, minimum and maximum 
x 
AUC0-t, Ctrough and Cmax: sample size, mean, standard deviation, CV, geometric 
mean, geometric CV, median, minimum and maximum 
x 
tmax: sample size, median, minimum and maximum 
Summaries of PK parameters and serum concentration data will be provided for the PK 
analysis population. No inferential statistics will be generated. Individual and summary PK 
parameter and serum concentration data will also be listed. 
For summary tables, the descriptive statistics will be rounded to 1 more digit than the 
individual values for the arithmetic mean, SD, median and geometric mean, and to the same 
number of digits for the minimum and maximum values. The tmax will be reported using the 
median and range up to 2 decimal points in listing and summary tables. The number of non-


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missing observations (n) will be reported as an integer number. The CV% and geometric 
CV% will be reported as a percentage of the integer number. 
For individual plots, the time course of RVT-1401 serum concentration profile will be 
presented as 1 plot per graph and as composite plots (consisting of overlaid profiles for all 
subjects with the same dose as connected lines). The graphical output will be presented in 
both linear and semi-log scales. Actual sampling times will be used for individual plots. For 
mean plots for each dose group, the arithmetic mean of RVT-1401 serum concentration time 
profiles will be presented in linear and semi-log graphs. Linear mean plots will be presented 
with their upper SD bars. Scheduled (nominal) sampling times will be used for mean plots. 


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12. 
PHARMACODYNAMIC ANALYSES 
Pharmacodynamic endpoints (total IgG, IgG1, IgG2, IgG3, IgG4, and anti-AChR-IgG level) 
will be summarized descriptively and analyzed using an ANCOVA model. Descriptive 
statistics (sample size, mean, standard deviation, median, Q1, Q3, minimum and maximum) 
of baseline, post-baseline, change from baseline, and percentage change from baseline values 
for each PD endpoint will be provided by treatment group for all scheduled visits.  
The ANCOVA model with treatment as a fixed factor, and baseline value as covariate will be 
used to produce least-squares means and 95% CIs for each treatment group at each scheduled 
visit. For each scheduled visit, the least-squares means will be compared using a t-test. Line 
plots of the least squares means and 95% CIs by visit will also be provided. 
There will be no adjustments for multiple comparisons of PD endpoints. An alpha level of 
0.05 will determine statistical significance. Analyses of PD endpoints will be provided for 
the PD analysis population. 
 
 


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13. 
IMMUNOGENICITY ANALYSIS 
Immunogenicity analysis will be based on the safety population and the presence of anti-drug 
antibodies (ADAs) will be determined using the 3-tiered approach: screening, confirmation, 
and titration. All samples will be brought through the tier 1 screening assay to determine the 
potential presence of anti RVT-1401 antibody. All samples determined potentially positive 
will be analyzed in the tier 2 confirmation assay where presence of anti-RVT-1401 will be 
confirmed – the therapeutic antibody will be used to compete with the analytical responses of 
ADA to assess specificity of screened positive samples. After ADA confirmation, all samples 
that were confirmed positive for ADA will be analyzed in the tier 3 assay in order to 
characterized and determine antibody titers. Titration results will characterize the magnitude 
of the ADA response during the confirmatory assay. 
Interpretation of the result will first be performed with a descriptive count of the 
immunogenicity assessment with a summary of ADA titer confirmed positive and a summary 
of immunogenicity rate by anti-RVT-1401 from confirmatory assay across all doses. 
Comparison will be performed between active and placebo treatment descriptively. 
Optional analysis on ADA incidence and PK parameter descriptive presentation in ADA 
negative and positive confirmed subjects might be performed. 


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14. 
CHANGES FROM ANALYSES AS DESCRIBED IN THE 
PROTOCOL 
x 
The definition of PP population was not included in the protocol but was defined 
as follows: 
The PP analysis population includes all subjects who were randomized and received at least 
one 1 dose of study medication and had no major protocol deviations. Subjects will be 
summarized by randomized treatment for analyses based on the PP population. 
x 
Below definition of 12-Week Follow-up Population was defined in the protocol 
but was not included the SAP. 
The 12-Week Follow-up Population will include all participants who receive at least one 
dose of study treatment and decline participation in the OLE but continue with the 12-week 
follow-up period (ie, the non-OLE participants). 
x 
The analysis populations defined in the SAP are not consistent with the protocol 
Section 10.2.1; the definitions in SAP were updated to comply with ICH E9. 
 


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15. 
REFERENCES 
1. Richardson, H.R. (1970, July). Recursive regression when the least-squares estimate 
is not asymptotically efficient. SIAM Jr on App Math, Vol. 19, No 1.  
2. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations 
for clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
4. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles 
for clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
5. ICH. (2005, October). ICH Harmonized tripartite guideline: Clinical evaluation of 
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic 
drugs (E14). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
6. European Medicines Agency. (2007, October). Guidance “Reflection Paper on 
Methodological Issues In Confirmatory Clinical Trials Planned With An Adaptive 
Design.” 
7. CDER and CBER. (2009, July). Guidance for industry: Drug-induced liver injury: 
premarketing clinical evaluation. 
8. CDER and CBER (2010, February). FDA draft guidance Adaptive Design for 
Clinical Trials for Drugs and Biologics. 
9. National Research Council. (2010). The prevention and treatment of missing data in 
clinical trials. Panel on Handling Missing Data in Clinical Trials. Committee on 
National Statistics, Division of Behavioral and Social Sciences and Education. 
Washington, DC: The National Academies Press. 


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10. CDER and CBER. (2012, December). Draft guidance for industry “Enrichment 
strategies for clinical trials to support approval of human drugs and biological 
products.” 
11. Permutt, T. (2013, April 30). DIA/FDA Statistics Forum 2013, Session Topic: 
Missing Data. Bethesda, MD. 
12. ICH. (2018, February 28). ICH Harmonized tripartite guideline: ICH E9 (R1) 
Addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
statistical principles for clinical trials (E9 addendum). International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. 
13. U.S. Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER). Guidance for Industry: E9 
Statistical Principles for Clinical Trials. Federal Register. September 16, 1998 (63 FR 
49583). 
14. U.S Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER). Guidance for Industry: E14 
Clinical Evaluation of QT/QTc Interval Prolongation and Pro-arrhythmic Potential 
for Non-Antiarrhythmic Drugs. Federal Register, October 19, 2005. 
 
 
 


Immunovant 
Statistical Analysis Plan 
RVT-1401-2002 
 
 
 
 
 
CONFIDENTIAL 
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29 July 2020 
16. 
SOFTWARE 
SAS Software Version 9.4 or higher. SAS Institute Inc., Cary, NC, USA. 
WinNonLin Version 6 or higher