Clinical trial NCT03938545
Conditions: Graves' Ophthalmopathy (GO)
Keywords: IMVT-1401 Graves' Orbitopathy Thyroid Eye Disease
Sponsor: Immunovant Sciences GmbH
Start date: 2019-07-23; Completion date: 2021-04-15
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the current study is to assess the efficacy and safety/tolerability of three dose regimens of RVT-1401 in the treatment of active, moderate to severe GO participants. In addition, the study is designed to characterize the effect of RVT-1401 exposure on reduction in anti-TSHR IgG

Detailed description:

Arms: arm 1: Regimen A= RVT-1401 680 mg weekly for 12 weeks arm 2: Regimen B= RVT-1401 340 mg weekly for 12 weeks arm 3: Regimen C= RVT-1401 255 mg weekly for 12 weeks arm 4: for 12 weeks
Interventions: intervention 1: RVT-1401 (Administered via subcutaneous injection) intervention 2: Placebo (Administered via subcutaneous injection)
Intervention descriptions: intervention 1: RVT-1401 is a fully human anti-neonatal Fc receptor (FcRn) monoclonal antibody. intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
Immunovant Sciences GmbH Protocol RVT-1401-2001, Amendment 02: Version 3.0 
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CLINICAL STUDY PROTOCOL 
Title: 
ASCEND GO 2: A Phase 2b, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study of RVT-1401 for the Treatment of Patients 
with Active, Moderate to Severe Graves’ Ophthalmopathy 
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-1401-2001 
Indication 
Graves’ Ophthalmopathy 
Development Phase 
2b 
Regulatory #s 
IND: 141988 
CTA: 226455 
EUDRA CTA: 2018-004676-35 
Version/ 
Effective Date: 
Amendment 02: Version 3.0 
09-AUG-2019 
Amendment 01: Version 2.0 
12-FEB-2019 
Original: Version 1.0 
14-DEC-2018  
Immunovant, Inc. 
Study Director 
, 
 
Telephone: 
 
Email: 
 
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Immunovant Sciences GmbH Protocol RVT-1401-2001, Amendment 02: Version 3.0 
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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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MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Medical Monitor/SAE Contact Information: 
 
Role 
Contact 
Day Time Phone Number and 
email address 
After-hours 
Phone/Cell/ 
Pager 
Number 
Primary 
Medical 
Monitor  
 
 
Office: 
 
 
 
Cell:  
 
SAE 
contact  
information  
   
 
 
Study Sponsor: 
Immunovant Sciences GmbH Registered Address: 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Immunovant, Inc. Address: 
320 W. 37th St. 
New York, NY 10018 
USA 
 
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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 ........................................................................................... 6 
2. 
PROTOCOL SUMMARY FOR STUDY RVT-1401-2001 ........................................... 9 
3. 
INTRODUCTION .................................................................................................... 12 
3.1. 
Background ................................................................................................ 12 
3.1.1. 
Graves’ Ophthalmopathy ............................................................. 12 
3.2. 
Rationale .................................................................................................... 13 
3.2.1. 
Study Rationale ........................................................................... 13 
3.2.2. 
Dose Rationale ............................................................................ 13 
3.2.3. 
Clinical Experience ...................................................................... 15 
3.2.3.1. 
Safety ......................................................................... 15 
3.2.3.2. 
Pharmacokinetics ....................................................... 16 
3.2.3.3. 
Pharmacodynamic ...................................................... 16 
3.3. 
Benefit: Risk Assessment ........................................................................... 18 
3.3.1. 
Risk Assessment ......................................................................... 18 
4. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 20 
5. 
STUDY DESIGN .................................................................................................... 22 
5.1. 
Overall Design ............................................................................................ 22 
5.2. 
Study Schematic ......................................................................................... 23 
5.3. 
Treatment Arms and Duration ..................................................................... 23 
6. 
PARTICIPANT POPULATION ................................................................................ 23 
6.1. 
Type and Number of Participants ................................................................ 23 
6.2. 
Inclusion Criteria ......................................................................................... 24 
6.3. 
Exclusion Criteria ........................................................................................ 25 
6.4. 
Other Eligibility Criteria Considerations ....................................................... 27 
6.5. 
Screening/Baseline Failures ....................................................................... 27 
6.6. 
Lifestyle Restrictions ................................................................................... 27 
6.6.1. 
Contraception .............................................................................. 27 
6.7. 
Withdrawal Criteria ..................................................................................... 29 
6.7.1. 
Reasons for Withdrawal ............................................................... 29 
6.7.2. 
Participant Withdrawal Procedures .............................................. 29 
6.8. 
Stopping Criteria for Individual Participants ................................................. 30 
6.8.1. 
Liver Chemistry Stopping Criteria ................................................ 30 
6.8.2. 
Criteria for Permanent Discontinuation of Study Treatment 
in Association with Liver Test Abnormalities ................................ 30 
6.8.3. 
QTc Withdrawal Criteria ............................................................... 31 
6.8.4. 
Albumin Monitoring Criteria .......................................................... 31 
6.8.5. 
Other Individual Stopping Criteria ................................................ 31 
6.9. 
Toxicity Management Criteria ..................................................................... 32 
6.9.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and 
Injection Site Reactions) .............................................................. 32 
6.9.2. 
Other Management Criteria ......................................................... 33 


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6.10. 
Participant and Study Completion ............................................................... 33 
7. 
STUDY TREATMENT ............................................................................................ 34 
7.1. 
Investigational Product ................................................................................ 34 
7.2. 
Treatment Assignment ................................................................................ 34 
7.3. 
Blinding ....................................................................................................... 34 
7.4. 
Packaging and Labeling .............................................................................. 35 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 36 
7.6. 
Compliance with Study Treatment Administration ....................................... 36 
7.7. 
Treatment of Study Treatment Overdose .................................................... 36 
7.8. 
Treatment After the End of the Study .......................................................... 37 
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 ..................................................... 38 
8.1. 
Time and Events Table ............................................................................... 39 
8.2. 
Screening and Critical Baseline Assessments ............................................ 43 
8.3. 
Study Assessments and Procedures .......................................................... 43 
8.3.1. 
Physical Exams ........................................................................... 43 
8.3.2. 
Ophthalmic Exams ....................................................................... 43 
8.3.3. 
Vital Signs .................................................................................... 44 
8.3.4. 
Electrocardiogram (ECG) ............................................................. 44 
8.3.5. 
Clinical Safety Laboratory Assessments ...................................... 44 
8.3.6. 
Pharmacokinetics ........................................................................ 46 
8.3.7. 
Anti-Drug Antibody (ADA) and Neutralizing Antibody 
(NAb) ........................................................................................... 46 
8.3.8. 
Pharmacodynamics ..................................................................... 47 
8.3.9. 
Exploratory Biomarkers ................................................................ 47 
8.4. 
Graves’ Ophthalmopathy Assessments ...................................................... 47 
8.4.1. 
Clinical Activity Score (CAS) ........................................................ 47 
8.4.2. 
Lid Retraction .............................................................................. 48 
8.4.3. 
Proptosis...................................................................................... 48 
8.4.4. 
Motility ......................................................................................... 48 
8.4.5. 
GO-Quality Of Life (GO-QOL) ...................................................... 48 
8.4.6. 
External Photographs (For participating sites only) ...................... 48 
8.4.7. 
Orbital CT Scan (For participating sites only) ............................... 48 
8.4.8. 
Gorman Score for Diplopia .......................................................... 49 
8.4.9. 
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 ..................................................................... 50 
10.2.1. 
Analysis Populations .................................................................... 50 
10.3. 
Final Analysis ............................................................................................. 50 
10.3.1. 
Primary Efficacy Endpoint ............................................................ 51 
10.3.2. 
Secondary Efficacy Endpoints ..................................................... 51 
10.3.3. 
Safety Analyses ........................................................................... 52 
10.3.4. 
Pharmacokinetic Analyses ........................................................... 52 
10.3.5. 
Pharmacodynamic Analyses ........................................................ 53 


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10.3.6. 
Other Analyses ............................................................................ 53 
11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAES) ................ 54 
11.1. 
Definition of Adverse Events ....................................................................... 54 
11.2. 
Definition and Reporting of Serious Adverse Events ................................... 55 
11.3. 
Time Period and Frequency for Collecting AE and SAE Information ........... 56 
11.4. 
Method of Detecting and Reporting AEs and SAEs .................................... 56 
11.5. 
Assessing Severity of AEs and SAEs ......................................................... 57 
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 .................................................................................................... 59 
12. PREGNANCY REPORTING .................................................................................. 59 
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 ........................................................... 60 
13.1.3. 
Informed Consent ........................................................................ 60 
13.1.4. 
Confidentiality .............................................................................. 61 
13.1.5. 
Study Files and Retention of Records .......................................... 61 
13.1.6. 
Electronic Case Report Forms (eCRF) ........................................ 62 
13.1.7. 
Drug Accountability ...................................................................... 63 
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 ..................................................................................... 64 
13.3. 
Joint Investigator/Sponsor Responsibilities ................................................. 64 
13.3.1. 
Access to Information for Monitoring ............................................ 64 
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-1401-2001  
Study Title 
A Phase 2b, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study of RVT-1401 for the 
Treatment of Patients with Active, Moderate to Severe 
Graves’ Ophthalmopathy 
Objectives 
Primary 
To examine the effects of RVT-1401 versus placebo 
on proptosis responder rate at week 13  
 
To assess the safety and tolerability of RVT-1401 in 
patients with active, moderate to severe GO 
Secondary 
To examine the effect of RVT-1401 versus placebo on 
proptosis responder rate at weeks 2, 3, 4, 5, 6, 8, 10, 
12, 14, 16, and 20 
To examine the effect of RVT-1401 versus placebo on 
proportion of patients with a CAS score of 0 or 1 
To examine the effect of RVT-1401 versus placebo on 
mean change from baseline in proptosis 
To examine the effect of RVT-1401 versus placebo on 
mean change from baseline in CAS  
To examine the effect of RVT-1401 versus placebo on 
overall ophthalmic improvement 
To examine the effect of RVT-1401 versus placebo on 
diplopia 
To examine the effect of RVT-1401 versus placebo on 
the Graves’ Ophthalmopathy Quality of Life (GO-QOL) 
score in the visual functioning and appearance 
subscales 
To assess the change in serum levels of anti-TSHR 
antibodies and total IgG & IgG subclasses (1-4) 
To examine RVT-1401 PK following repeated doses in 
patients with active, moderate to severe GO 
To measure anti-RVT-1401 antibodies following 
repeated doses in patients with moderate to severe 


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active GO 
Study Phase 
Phase 2b 
Target Population 
Graves’ Ophthalmopathy 
Number of 
Participants Planned 
Approximately 77 participants 
Number of Study 
Centers Planned 
Approximately 20 centers 
Study Design 
Randomized, double-blind, placebo-controlled study to 
investigate the efficacy, safety and tolerability of RVT-
1401 in GO patients 
Duration of Treatment 
12 weeks 
Criteria for Evaluation 
(Endpoints) 
Primary 
Proptosis responder rate (defined as percentage with 
≥2 mm reduction in study eye without deterioration (≥2 
mm increase) in fellow eye).   
Assessment of safety and tolerability by analysis of 
adverse event (AE) data and changes from baseline in 
vital signs, ECGs, and clinical laboratory values 
Secondary 
Proportion of participants with CAS of 0 or 1  
Change from baseline in proptosis  
Change from baseline in CAS  
Proportion of patients with overall ophthalmic 
improvement defined as when at least two of the 
following outcome measures improves in one eye, 
without worsening in any of these measures in either 
eye: 
• Reduction in proptosis by at least 2 mm; 
• Improvement of ≥ 8 degrees in motility in any 
duction or improvement in diplopia 
(disappearance or change in degree); 
• Improvement in CAS by at least 2 points 


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Change from baseline in the Gorman Score for 
Diplopia  
Change from baseline in the GO-QOL visual 
functioning and appearance subscale scores 
Change from baseline in levels of anti-TSHR 
antibodies  
Change from baseline in levels of total IgG and IgG 
subclasses (1-4)  
Concentration of RVT-1401 pre-dose (Ctrough) 
Immunogenicity determined by number of participants 
with treatment-emergent positive anti-RVT-1401 
antibodies 
 


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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. RVT-1401 functions by inhibiting the binding of IgG to 
FcRn, resulting in the rapid catabolism of IgG via lysosomal degradation. 
3.1.1. 
Graves’ Ophthalmopathy 
Graves’ disease is characterized by hyperthyroidism with concomitant low levels of 
thyroid stimulating hormone (TSH).  Specifically, the hyperthyroidism is caused by 
antibodies that bind to and are agonists at the TSH receptors (TSHR) in the thyroid 
[Smith, 2017].  TSH receptors are also located in non-thyroid tissues including dermal 
fibroblasts, orbital fibroblasts, and adipocytes. Upregulation of TSHR in these tissues is 
believed to be responsible for Graves’ dermopathy (pretibial myxedema) and Graves’ 
ophthalmopathy (GO) associated with Graves’ disease [Bahn, 2010].   
In addition to pathogenic autoantibodies directed at TSHR, IgG that activate insulin-like 
growth factor receptor (IGF-1R) signalling in patients with Graves’ disease has also been 
suggested as contributing to GO [Pritchard, 2003]. Studies investigating this pathway 
have led to the discovery that the IGF-1R and TSHR form a receptor complex where 
IGF-1R can augment the signalling of TSHR [Tsui, 2008].  A recent clinical trial 
assessing the efficacy of teprotumumab, an IGF-1R inhibitory monoclonal antibody 
(MAb) in patients with active, moderate-to severe GO demonstrated positive clinical 
benefit lending support to the role of this pathway [Smith, 2017].   
The exact nature of the interaction between IGF-1R and TSHR continues to be 
investigated.  Some data suggest synergistic activation of hyaluronan secretion with 
simultaneous activation of TSHR and IGF-1R, and that the effects of TSHR stimulating 
antibodies are only partially blocked by an IGF-1R antagonist while it can be completely 
blocked with a TSHR antagonist [Krieger, 2015].  These data indicate that both TSHR 
and IGF-1R play a critical role in the pathogenesis of GO.   
GO is characterized by enlarged extraocular muscles and an increased volume of orbital 
fat.  In severe cases, this can lead to diplopia and/or loss of vision.  The disease passes 
through several phases; from the onset, the first phase involves worsening of symptoms 
and signs in the active/inflammatory phase.  This is followed by gradual improvement in 
the inflammatory signs and congestive symptoms until eventually no further changes 
occur.  It is in the final stable (inactive) state where abnormalities in both function and 
appearance may persist indefinitely.  Therefore, treatments should be aimed at the active 
phase of GO to ideally prevent the occurrence of permanent changes.   


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RVT-1401 will reduce levels of all pathogenic IgG, while teprotumumab is limited to 
preventing signalling through IGF-1R. Thus, RVT-1401 is hypothesized to be more 
effective than teprotumumab for the treatment of GO due to a broader effect on multiple 
targets important in the pathophysiology of this disease.  In addition, RVT-1401 is 
expected to have effects on both ocular and thyroid manifestations of Graves’ disease.  
No other anti-FcRn compounds are currently in clinical development for the treatment of 
GO, giving RVT-1401 the potential to be first-in-class with broader application using a 
convenient subcutaneous (SC) mode of administration. 
 
3.2. 
Rationale 
3.2.1. 
Study Rationale 
The purpose of the current study is to assess the efficacy and safety/tolerability of three 
dose regimens of RVT-1401 in the treatment of active, moderate to severe GO patients. 
In addition, the study is designed to characterize RVT-1401 exposure to reduction in anti-
TSHR IgG.      
3.2.2. 
Dose Rationale 
An autoimmune response against the TSHR plays a major role in the development of GO. 
This is supported by studies that have shown elevated TSHR expression in the orbital 
tissues from patients with GO as well as the fact that anti-TSHR IgG antibodies are 
detectable in the majority of patients with GO [Starkey, 2003; Bahn, 1998; Wakelkamp, 
2003; Bahn, 2010].  Anti-TSHR antibody serum levels have also been shown to be 
directly associated with GO clinical features and have prognostic value such that patients 
with persistently high TSHR titers have a greater risk of severe disease course and 
outcome [Lytton, 2010; Ponto, 2011; Eckstein, 2006].  In GO, RVT-1401 treatment is 
expected to lead to a reduction in the levels of pIgG such as anti-TSHR antibodies and 
thus provide therapeutic benefit to these patients. 
RVT-1401 is designed to provide patients with a treatment option that can allow home 
administration via SC injection. This significantly reduces the burden that an IV infusion 
treatment (e.g., teprotumumab) places on patients who will be required to go to an 
infusion center to receive their treatment. 
Three dosing regimens of RVT-1401 will be assessed in this study. All dosing regimens 
will involve once weekly SC injections: 
• Dosing Regimen A - 680 mg weekly for 12 weeks  
• Dosing Regimen B - 340 mg weekly for 12 weeks   
• Dosing Regimen C - 255 mg weekly for 12 weeks 
Given that there is a practical limit on the volume that can be administered via SC 
injection, the two higher 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.  


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As it is unknown how much IgG reduction is needed to show clinical benefit, three 
dosing regimens are proposed to explore the relationship between IgG reduction and 
clinical effect compared to placebo. The 680 mg/weekly dose will provide the maximum 
reduction in total IgG and is thus expected to have the greatest potential for 
demonstrating maximum clinical benefit.  The other two RVT-1401 doses (340 
mg/weekly and 255/weekly) will allow characterization of clinical benefit at lower 
doses.    
The proposed weekly doses are expected to provide an average total IgG reduction of 
approximately 75-80%, 65-70%, and 45-55% for 680 mg, 340 mg, and 255 mg 
respectively, by the fourth or fifth dose. It is predicted that the nadir IgG reduction will be 
achieved by the 3rd-5th dose (depending on dose studied) and maintained following the 
remaining doses before rising back to baseline over the next 6 to 8 weeks after stopping 
treatment.  
These assumptions are supported by preliminary PD results, shown in Figure 1, of 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%.  
 
Figure 1: 
Serum IgG (Mean +/-SD) Reduction Following Multiple Doses of RVT-
1401 (Study RVT-1401-1001) 
 
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 


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within the dosing interval, and that with subsequent doses, more receptors are being 
occupied or remain occupied. 
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. These data will be used to support dose selection in future 
studies. 
Since a weekly 340 mg and 680 mg dose of RVT-1401 produce a significant reduction in 
total serum IgG levels, which in GO patients would also include anti-TSHR IgG, it is 
expected that RVT-1401 treatment will provide therapeutic benefit to these patients. As it 
is unknown to what extent reduction of anti-TSHR IgG is needed to translate into clinical 
efficacy, this trial has been designed to assess multiple dosing regimens to further assess 
a minimum effective dose. 
 
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 (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 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. 
3.2.3.1. 
Safety 
See Investigator’s Brochure (IB) 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. 


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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 
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 
 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 the 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 the 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 
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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 to the 340 
mg SC. The median IgG nadir concentration occurred prior to the last dose in the 680 mg 
cohort whereas for the 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional information is available in the current IB.  
 
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3.3. 
Benefit: Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with RVT-
1401 can be found in the 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 30 min post-dose.  
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 
immunodeficiency virus (HIV), hepatitis B 
virus (HBV), or Mycobacterium 
tuberculosis:   
- Participants must have negative 
test results for HBV surface antigen, 
HBV core antibody, HIV 1 and 2 
antibodies, and a negative 
QuantiFERON-TB Gold test at 
Screening.   
- Hepatitis C virus (HCV):  
- Participants must have a negative 
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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test result for HCV antibody  
or 
- Participants with a known history of 
HCV must have documented 
evidence of sustained virologic 
response that is consistent with cure 
of hepatitis C infection that is 
confirmed with a negative HCV RNA 
test at Screening. 
 
-Absolute neutrophil count <1500 
cells/mm3 
Sustained 
hypoalbuminemia 
Participants with baseline albumin levels 
<3.5 g/dL will be ineligible.  
 
Subjects with advanced liver disease 
including any diagnosis of cirrhosis of any 
stage will be ineligible. 
 
Non-alcoholic fatty liver disease (NAFLD) 
including non-alcoholic steatohepatitis 
(NASH) is allowable if there has been a 
recent (within 6 months) normal 
ultrasound, CT, or MRI.  If the ultrasound, 
CT, or MRI demonstrate fatty changes 
alone, the subject may be enrolled if s/he 
has a normal range fibroscan for liver 
fibrosis. 
 
AST or ALT ≥1.5x ULN at Screening. The 
subject may only be enrolled if s/he has a 
recent (within 6 months) normal 
ultrasound, CT, or MRI. If the ultrasound, 
CT, or MRI demonstrate fatty changes 
alone, the subject may be enrolled if s/he 
has a normal range fibroscan for liver 
fibrosis. 
Serum albumin levels will be monitored 
throughout the study (Section 8.1) by an 
unblinded Medical Monitor.  Treatment of 
any clinical signs/symptoms suspected to 
be associated with hypoalbuminemia will 
be left to the discretion of the investigator 
and decision on dosing will be discussed 
with the study medical monitor (Section 
6.8.4).  
 
 


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4. 
OBJECTIVE(S) AND ENDPOINT(S) 
Objectives 
Endpoints 
Primary 
To examine the effects of RVT-1401 versus 
placebo on proptosis responder rate at week 
13  
 
 
To assess the safety and tolerability of RVT-
1401 in patients with active, moderate to 
severe GO 
Proptosis responder rate (defined as 
percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in 
fellow eye).   
 
Assessment of safety and tolerability by 
analysis of adverse event (AE) data and 
changes from baseline in vital signs, ECGs, 
and clinical laboratory values 
Secondary 
 
To examine the effect of RVT-1401 versus 
placebo on proptosis responder rate at weeks   
2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 20 
 
 
To examine the effect of RVT-1401 versus 
placebo on proportion of patients with a CAS 
score of 0 or 1 
 
To examine the effect of RVT-1401 versus 
placebo on mean change from baseline in 
proptosis 
 
To examine the effect of RVT-1401 versus 
placebo on mean change from baseline in 
CAS  
 
To examine the effect of RVT-1401 versus 
placebo on overall ophthalmic improvement  
 
 
 
 
 
 
 
 
 
To examine the effect of RVT-1401 versus 
placebo on diplopia 
 
 
 
Proptosis responder rate (defined as 
percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in 
fellow eye).   
 
Proportion of patients with CAS of 0 or 1  
 
 
 
Change from baseline in proptosis  
 
 
 
Change from baseline in CAS  
 
 
 
Proportion of patients with overall ophthalmic 
improvement defined as when at least two of 
the following outcome measures improves in 
one eye, without worsening in any of these 
measures in either eye: 
• Reduction in proptosis by at least 2 mm; 
• Improvement of ≥ 8 degrees in motility in 
any duction or improvement in diplopia 
(disappearance or change in degree); 
• Improvement in CAS by at least 2 points 
 
Change from baseline in the Gorman Score 
for Diplopia  
 
 


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To examine the effect of RVT-1401 versus 
placebo on the Graves’ Ophthalmopathy 
Quality of Life (GO-QOL) score in the visual 
functioning and appearance subscales 
 
To assess the change in serum levels of anti-
TSHR antibodies and total IgG & IgG 
subclasses (1-4) 
 
 
 
 
To examine RVT-1401 PK following repeated 
doses in patients with active, moderate to 
severe GO 
 
To measure anti-RVT-1401 antibodies 
following repeated doses in patients with 
active moderate to severe GO 
Change from baseline in the GO-QOL visual 
functioning and appearance subscale scores 
 
 
 
Change from baseline in levels of anti-TSHR 
antibodies  
 
Change from baseline in levels of total IgG 
and IgG subclasses (1-4)  
 
 
Concentration of RVT-1401 pre-dose 
(Ctrough) 
 
 
Immunogenicity determined by number of 
participants with positive anti-RVT-1401 
antibodies 
Exploratory 
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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a Phase 2b, randomized, double-blind, placebo-controlled study to investigate the 
efficacy, safety and tolerability of RVT-1401 in GO patients.  The study design is 
illustrated in Section 5.2. 
Participants will screen to determine eligibility 3 to 6 weeks prior to first dose/baseline 
visit. Once eligibility is confirmed, on Day 1 participants will begin to receive RVT-1401 
as weekly SC injections for 12 weeks.  No dose adjustments of RVT-1401 are allowed 
during the study.  See Section 6.8 for additional information on stopping criteria.   
Following the initial dose at the Baseline Visit (Day 1), study visits will occur weekly 
throughout the treatment period.  Following the final dose at Week 12, visits will occur 
weekly through Week 14 and then at Week 16 and Week 20.  Refer to Section 8.1, Time 
and Events Table. 
Optional home visits will be offered to collect (at a minimum) blood samples, vital signs, 
and review adverse events and concomitant medications.  Alternatively, the participants 
will attend the clinic on the visits that could optionally be scheduled for home visits. 
Each participant will participate in the study for up to approximately 23-26 weeks i.e., 3-
6 week screening period (prior to baseline), a 12-week treatment period, and an 8-week 
follow up period. 
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5.2. 
Study Schematic 
 
Figure 2 Study Design 
 
 
Regimen A= RVT-1401 680 mg weekly for 12 weeks 
Regimen B= RVT-1401 340 mg weekly for 12 weeks  
Regimen C= RVT-1401 255 mg weekly for 12 weeks 
 
5.3. 
Treatment Arms and Duration 
Participants will be randomized 2:2:1:2 to RVT-1401 or placebo. Randomization will be 
stratified based on smoking status at the screening visit.  Refer to Figure 2 for dosing 
regimen details. 
 
6. 
PARTICIPANT POPULATION 
6.1. 
Type and Number of Participants 
A sufficient number of participants will be enrolled to achieve approximately 77 
evaluable participants.  Enrollment is competitive. 
In order to manage the total study enrollment, the Sponsor may suspend screening and/or 
enrollment 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 
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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. 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. 
3. 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. 
4. Clinical diagnosis of Graves' disease with hyperthyroidism associated with active, 
moderate to severe GO with a CAS ≥ 4 for the most severely affected eye at 
Screening and Baseline.  
5. Onset of active GO within 9 months of screening. 
6. Documented evidence at Screening of detectable anti-TSHR-Ab. 
7. Participant does not require immediate surgical intervention and is not planning 
corrective surgery/irradiation or medical therapy for GO during the course of the 
study. 
8. Moderate-to-severe active GO (not sight-threatening but has an appreciable impact 
on daily life), usually associated with one or more of the following: lid retraction ≥ 2 
mm, moderate or severe soft tissue involvement, proptosis ≥ 3 mm above normal for 
race and gender (see study specific manual), and/or inconstant or constant diplopia. 
9. Stable medical regimen; unlikely to require adjustment of thyroid medications during 
the 12-week treatment period. 
10. Participants must be euthyroid with the baseline disease under control or have mild 
hypo- or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine 
[FT3] levels < 50% above or below the normal limits) at Screening. Every effort 


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should be made to correct the mild hypo- or hyperthyroidism promptly and to 
maintain the euthyroid state for the entire duration of the clinical trial. 
11. Stable dose of allowed concomitant medications (e.g. antidepressants) for 3 months 
from Baseline. 
12. Participants who are rendered euthyroid by the block-and-replace regimen e.g., 
methimazole + adding levothyroxine) when FT4 and T3 have become normal are 
allowed. 
13. Participants who have received radioactive iodine treatment for Graves’ 
hyperthyroidism >6 months from Screening are allowed.  
14. 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 any steroid (IV, oral, steroid eye drops) for the treatment of GO or other 
conditions within 3 weeks prior to Screening.  Steroids cannot be initiated during the 
trial.  Exceptions include topical and inhaled steroids which are allowed.  
2. Use of rituximab, tocilizumab, or any monoclonal antibody/Fc-fusion biologic for 
immunomodulation within the past 9 months prior to Baseline. 
3. Use of selenium within 3 weeks prior to Baseline and use during the clinical trial 
(multivitamins that include selenium are allowed). 
4. Use of biotin within 48 hours prior to any laboratory collection (this includes 
multivitamins that include biotin). 
5. Participants with at least a 2-point decrease in CAS or 2 mm decrease in proptosis 
between screen & baseline assessments. 
6. Total IgG level < 6g/L at Screening.  
7. Absolute neutrophil count <1500 cells/mm3 at Screening. 
8. Albumin level <3.5 g/dL at Screening. 
9. Known advanced liver disease including any diagnosis of cirrhosis of any stage. 
Non- alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis 
(NASH) is allowable if there has been a recent (within 6 months) normal ultrasound, 
CT, or MRI. If the ultrasound, CT, or MRI demonstrate fatty changes alone, the 
participant may be enrolled if s/he has a normal range fibroscan for liver fibrosis. 
10. AST or ALT ≥1.5x ULN at Screening. The participant may only be enrolled if s/he 
has a recent (within 6 months) normal ultrasound, CT, or MRI. If the ultrasound, CT, 
or MRI demonstrate fatty changes alone, the participant may be enrolled if s/he has a 
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11. Participants with decreased best corrected visual acuity due to optic neuropathy as 
defined by a decrease in vision of 2 lines on the Snellen chart, new visual field 
defect, or color defect secondary to optic nerve involvement within the last 6 months 
at Screening.  
 
12. Previous orbital irradiation or surgery for GO.  
 
13. 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. 
14. Have known autoimmune disease other than GO, that would in the opinion of the 
Investigator and Medical Monitor, that would interfere with the course and conduct 
of the study. 
15. Medical history of primary immunodeficiency, T-cell or humoral, including common 
variable immunodeficiency. 
16. Have an active infection, a recent serious infection (i.e., requiring injectable 
antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening. 
17. History of or known infection with human immunodeficiency virus (HIV), hepatitis 
B virus (HBV), or Mycobacterium tuberculosis:   
-Participants must have negative test results for HBV surface antigen, HBV core 
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. 
18. Hepatitis C virus (HCV):  
-Participants must have a negative test result for HCV antibody 
or 
-Participants with a known history of HCV must have documented evidence of 
sustained virologic response that is consistent with cure of hepatitis C infection.  
This is defined as undetectable or unquantifiable HCV RNA at least 12 weeks after 
stopping HCV treatment (HCV Guidance: Recommendations for Testing, Managing, 
and Treating Hepatitis C; 2014-2018, AASLD and IDSA).   This should be 
confirmed with a negative HCV RNA test at Screening. 
19. Participant has any clinically significant history of allergic conditions (including 
drug allergies, anaphylactic reactions), that would in the opinion of the Investigator, 
contraindicates their participation. 
20. 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 
21. Body Mass Index (BMI) at Screening ≥ 40 kg/m2. 
22. Enrollment in a previous RVT-1401 clinical trial. 


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23. Use of investigational drug within 3 months or 5 half-lives of the drug (whichever is 
longer) before Screening.  
24. Currently participating or has participated in another GO clinical study within 28 
days prior to signing the informed consent form. 
25. 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.  
26. Participant has received a transfusion of any blood or blood products within 60 days 
or donated plasma within 7 days prior to baseline and during the treatment period. 
27. 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. 
28. Pregnant or lactating females as determined by positive serum or urine human 
chorionic gonadotropin test at screening or baseline. 
29. Participant has had their spleen removed. 
30. QTcF interval >450 milliseconds for males and >470 milliseconds for females at 
Screening (a single repeat is allowed for eligibility determination).  QTcF >480 msec 
in participants with Bundle Branch Block. 
 
6.4. 
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. 
 
6.5. 
Screening/Baseline Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently treated.  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). 
 
6.6. 
Lifestyle Restrictions 
6.6.1. 
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). 


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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. 
• 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 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.   
• 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 


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methods, they should not be entered into the study. 
 
6.7. 
Withdrawal Criteria 
6.7.1. 
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 
• 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 6.8 
If a participant meets a withdrawal criterion during treatment, an Early Termination 
visit will be required (Section 6.7.2). 
 
6.7.2. 
Participant Withdrawal Procedures 
If a participant is prematurely discontinued from investigational product(s), the Principal 
Investigator must make every effort to perform an Early Termination Visit per Section 
8.1, Time and Events Table 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”. 


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6.8. 
Stopping Criteria for Individual Participants 
6.8.1. 
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 an 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 or 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
Re-challenge 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 re-challenge. 
Re-challenge should not occur when the etiology of the liver test abnormalities is 
considered possibly drug induced. 
 
6.8.2. 
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; 


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x Alcoholic hepatitis; 
x Non-alcoholic steatohepatitis; or 
x 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. 
 
6.8.3. 
QTc Withdrawal Criteria 
x 
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 
 
6.8.4. 
Albumin Monitoring Criteria 
6.8.5. 
Other Individual Stopping Criteria 
x 
Subject has a serious infective episode requiring hospitalization or iv antibiotic 
therapy. 
x 
Participant has a severe systemic allergic reaction (i.e., anaphylaxis) to study 
therapy. 
x 
Participant requires rescue therapy for GO (e.g., corticosteroids). 
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6.9. 
Toxicity Management Criteria 
6.9.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and Injection 
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 
 


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Injection Site Reactions 
Injection site evaluations will be made by clinical staff following administration of study 
treatment as described below.  Additional details related to the specific injection site 
location will be included within a study specific manual or Study Reference Manual 
(SRM).  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. 
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 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: 
June 14, 2010). 
6.9.2. 
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.  
 
6.10. 
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. 


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7. 
STUDY TREATMENT 
7.1. 
Investigational Product 
The term study treatment is used throughout the protocol to describe RVT-1401.   
To maintain the study blind, all participants will receive two injections  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 or the 255 mg dose will receive 
one injection with RVT-1401 and one placebo injection.  Participants receiving placebo 
will receive two injections of placebo.   
Study Treatment Name: 
RVT-1401 
Placebo 
Manufacturer: 
 
 
 
Dosage formulation: 
Sterile solution for injection.  
Sterile solution for injection.  
Unit dose 
strength(s)/Dosage level(s): 
680 mg: 2 mL RVT-1401 in two 
syringes for a total of 4 mL  
 
340 mg: 2 mL RVT-1401 in one 
syringe and 2 mL placebo in the 
second syringe for a total of 4 mL 
 
255 mg: 1.5 mL RVT-1401 in one 
syringe and 1.5 mL placebo in the 
second syringe for a total of 3 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 30 
minutes post-dose before they leave the clinic. 
Dose Preparation 
The preparation procedure and expiry details will be included in 
the Pharmacy manual/product label. 
 
7.2. 
Treatment Assignment 
Randomization will occur centrally using an interactive web response system (IXRS) 
using central randomization.  Participants will be assigned in accordance with the 
randomization schedule, prepared prior to the start of the study. 
 
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), anti-TPO, anti-
PPD
PPD


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thyroglobulin, and anti-TSHR, and anti-IGF-1R antibody data post screening as this 
could potentially unblind them.  An unblinded Medical Monitor will review the lab data 
for IgG, albumin, total protein, and ALP on an ongoing basis for safety.  
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 IXRS 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..   
The Sponsor or their designee may unblind the treatment assignment for any participant 
with an 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.  The 
formulation consists of 170 mg/mL RVT-1401 in 100 mM L-Histidine/Histidine HCl, 
100 mM L-Arginine HCl and 0.02% Polysorbate 20, pH 6.0.  
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.  The placebo formulation consists of 100 mM L-
Histidine/Histidine HCl, 100 mM L-Arginine HCl and 0.02% Polysorbate 20, pH 6.0. 
Doses will be prepared by the unblinded pharmacist or designee with a label that includes 
at a minimum the study number, participant number, kit 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. 


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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.  
• 
While the Investigator is ultimately responsible, study treatment accountability, 
reconciliation, and record maintenance (i.e. receipt, reconciliation and final 
disposition records) can be designated to the Pharmacist or other designee.   
• 
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 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 
The individual dose for a participant is prepared by an Unblinded Pharmacist, licensed 
Pharmacy Technician, or designee.  The preparation of the dose will be reviewed and 
confirmed by a second unblinded member of the study site staff.  
The study treatment will be administered by an unblinded designee not involved in the 
assessment of the participant.  The date and time of each dose administered along with 
the location of each injection will be recorded in the source documents.  The location of 
each injection and study participant identification will be confirmed at the time of dosing 
by another member of the study site staff (this person can be blinded or unblinded 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, 


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• 
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. 
 
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 GO 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. 
 


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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 Table, 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 Table, Section 8.1.  
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 
 
Screening1 
Treatment Period 
Weekly Visit 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early Withdrawal 
Visit 
Study Timepoint 
W=Weeks 
D=Day 
Within 3-6 
weeks 
 
 
W1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
 
 
 
 
 
 
 
W7 
D43 
 
 
 
 
 
 
 
W8 
D50 
 
 
 
 
 
 
 
W9 
D57 
 
 
 
 
 
 
 
W10 
D64 
 
 
 
 
 
 
 
W11 
D71 
 
 
 
 
 
 
 
W12 
D78 
 
W13 
 
W14 
 
W16 
 
W20 
 
Time Window (days) 
 
 
 
 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic, 
medical/thyroid 
history, and smoking 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Ophthalmic 
examination9 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Dilated indirect 
ophthalmoscopy 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Color vision 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs2 
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 
 
 
 
X 
X 
Pregnancy test3 
(females) 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine Titers 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 


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Screening1 
Treatment Period 
Weekly Visit 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early Withdrawal 
Visit 
Study Timepoint 
W=Weeks 
D=Day 
Within 3-6 
weeks 
 
 
W1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
 
 
 
 
 
 
 
W7 
D43 
 
 
 
 
 
 
 
W8 
D50 
 
 
 
 
 
 
 
W9 
D57 
 
 
 
 
 
 
 
W10 
D64 
 
 
 
 
 
 
 
W11 
D71 
 
 
 
 
 
 
 
W12 
D78 
 
W13 
 
W14 
 
W16 
 
W20 
 
Time Window (days) 
 
 
 
 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
 days 
 
QuantiFERON® – 
TB GOLD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis2 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood chemistry and 
hematology2 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Hemoglobin A1c 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Fasting lipid panel 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Serum complement 
(CH50, C3)2 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Immunoglobulins 
(IgM, IgA)2 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Anti-TPO and anti-
thyroglobulin 
antibodies2 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
TSH, Free T3, Free 
T42 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Anti-TSHR2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Anti-TSHR (Cell 
based) 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Anti-IGF-1R2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Anti-IGF-1R (Cell 
based) 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
RVT-1401 PK 
sampling2 
 
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 
Immunoglobins  
(IgG subclasses)2 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 


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Screening1 
Treatment Period 
Weekly Visit 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early Withdrawal 
Visit 
Study Timepoint 
W=Weeks 
D=Day 
Within 3-6 
weeks 
 
 
W1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
 
 
 
 
 
 
 
W7 
D43 
 
 
 
 
 
 
 
W8 
D50 
 
 
 
 
 
 
 
W9 
D57 
 
 
 
 
 
 
 
W10 
D64 
 
 
 
 
 
 
 
W11 
D71 
 
 
 
 
 
 
 
W12 
D78 
 
W13 
 
W14 
 
W16 
 
W20 
 
Time Window (days) 
 
 
 
 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
 days 
 
Gene Expression 
Analysis2 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Pro-Inflammatory 
Biomarker Multiplex2 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
Anti- RVT-
1401antibody2, 4 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Nab Assessment2, 4 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Drug administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Injection site 
reactions5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Clinical Activity 
Score (CAS) 6 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Proptosis6 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
   X 
 
X 
X 
X 
X 
X 
X 
Motility6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Lid retraction 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Gorman Score for 
Diplopia6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
GO-QOL6 
 
X 
X 
 
X 
 
X 
 
X 
 
   X 
 
X 
X 
X 
X 
X 
X 
External 
Photographs7 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Orbital CT Scan8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Collect Methimazole 
(or other anti-thyroid 
medication) dose 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Satisfaction 
Questionnaire  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 


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Screening1 
Treatment Period 
Weekly Visit 
 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early Withdrawal 
Visit 
Study Timepoint 
W=Weeks 
D=Day 
Within 3-6 
weeks 
 
 
W1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
 
 
 
 
 
 
 
W7 
D43 
 
 
 
 
 
 
 
W8 
D50 
 
 
 
 
 
 
 
W9 
D57 
 
 
 
 
 
 
 
W10 
D64 
 
 
 
 
 
 
 
W11 
D71 
 
 
 
 
 
 
 
W12 
D78 
 
W13 
 
W14 
 
W16 
 
W20 
 
Time Window (days) 
 
 
 
 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
days 
 
+/-3 
 days 
 
Adverse events 
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 
1. 
Screening can take place over multiple days. 
2. 
Vitals, ECG, safety labs, PK, and PD assessments will be collected pre-dose on dosing days where specified. Microalbumin/creatinine ratio at baseline, week 12, and week 20 only (if urine protein abnormal).   
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 20, and early withdrawal. 
4. 
Participants with treatment emergent positive results (change from baseline) for anti- RVT-1401 antibody at Week 20 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 20 visit.  
5. 
Local injection site reactions will be assessed at approximately 10 minutes post dose and participants will be monitored for 30 minutes post dose. 
6. 
GO assessments will be assessed pre-dose when collected on dosing days. 
7. 
Photographs can be assessed pre or post each dose when performed (for participating sites). 
8. 
The baseline orbital scan should be scheduled once all entry criteria have been met. Scans can be performed within +/- 7 days of the scheduled visit (for participating sites). Note: Week 13 and Week 20 visit scans 
should only be completed for participants who are considered proptosis responders at Week 13. 
9. 
See Section 8.3.2 for details of Ophthalmic Examination.   
 
 


 
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8.2. 
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.  Smoking status will also be collected. 
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.  
 
8.3. 
Study Assessments and Procedures 
8.3.1. 
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). 
 
8.3.2. 
Ophthalmic Exams 
Ophthalmic exams will consist of: 
• best corrected visual acuity (Snellen chart) 
• automated perimetry to include a minimum of 24 degrees of visual field 
• pupil assessment to include swinging flashlight test for afferent pupillary defect 
• anterior segment slit lamp exam 
• intraocular pressure 
• posterior exam including dilated indirect ophthalmoscopy with optic disc and 
retinal/choroid assessment of posterior pole as well as periphery 
• color vision (Ishihara plates or equivalent).  
The exams will be conducted at the times indicated in the Time and Events Table 
(Section 8.1). Please note that the timing for 2 ophthalmic assessments: (1) dilated 
indirect ophthalmoscopy and (2) color vision, are listed separately in the T&E table as 
they have a different schedule than the other assessments that comprise the ophthalmic 


 
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exam. Results for all ophthalmic assessments will be recorded in the participant’s source 
document. 
If significant abnormalities are noted compared to previous visits, including a loss of 2 
lines or more of vision, development of pupil abnormalities, clinically significant  rise in 
intraocular pressure, or other abnormalities of concern to the ophthalmologist, further 
investigations of visual function will be conducted according to the ophthalmologist’s 
clinical judgment. 
8.3.3. 
Vital Signs 
Vital signs will be measured in supine position and will include temperature, systolic and 
diastolic blood pressure and pulse rate.  
 
8.3.4. 
Electrocardiogram (ECG) 
ECGs will be measured in 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. 
 
8.3.5. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments must be conducted in accordance with the 
SRM or Laboratory Manual, and Protocol Time and Event Table (Section 8.1).   
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 


 
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White Blood Cell (WBC) Count 
(absolute)  
Mean 
corpuscular 
hemoglobin 
(MCH) 
Lymphocytes 
Reticulocyte Count 
Mean 
corpuscular 
hemoglobin 
concentration 
(MCHC) 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
Hemoglobin A1c 
 
 
Clinical Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
AST (SGOT) 
Total and direct bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Total carbon 
dioxide (CO2 ) 
Gamma 
glutamyltransfera
se (GGT) 
Albumin 
Total Protein 
Sodium 
Calcium 
(corrected) 
Alkaline phosphatase 
(ALP) 
TSH, Free T3, Free T4 
Serum 
complement 
(CH50, C3) 
Immunoglobulin 
M (IgM) 
Immunoglobulin A 
(IgA) 
Immunoglobulin G 
(IgG) 
Fasted labs 
Glucose (fasted) 
Baseline and Week 12 only 
Lipid Panel 
(fasted)  
Baseline, weeks  
12, 20, and Early 
Withdrawal only 
Total cholesterol  
Triglycerides  
HDL cholesterol  
LDL cholesterol (calculated using Martin-Hopkins equation) 
Cholesterol/HDL ratio  
Non-HDL cholesterol (calculated) 
Since changes in IgG, ALP, total protein and albumin level can potentially unblind the 
investigator to which dose the participant has been randomized to, post-screening values 
for IgG, 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. 
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 


 
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Microscopic examination (if blood or urine protein is abnormal) 
Microalbumin/creatinine ratio at baseline, week 12, and week 20 only (if urine protein is abnormal) 
Other tests 
Viral Serology [HIV1/HIV2, Hepatitis B (HBsAg), Hepatitis B (Core antibody), Hepatitis C (Hep C 
antibody] 
Vaccine titers for: tetanus, diphtheria, Hepatitis A, Hepatitis B, Pneumococcal  
FSH (as needed for confirmation of postmenopausal status) 
Pregnancy Tests:  serum test at screening and Week 20, 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. 
 
8.3.6. 
Pharmacokinetics 
Blood samples for PK analysis of RVT-1401 will be collected at the time points indicated 
in Section 8.1, Time and Event Table.  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. 
 
8.3.7. 
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, Time and Event Table.  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-
RVT-1401 antibody titers are detected, they will be further characterized using a 
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8.3.8. 
Pharmacodynamics 
Blood samples for PD analysis will be collected at times indicated in the Time and Event 
Table (Section 8.1).   
Pharmacodynamic Markers 
Total IgG, and differentiation by class: 
IgG subclasses (IgG1, 2, 3, and 4)  
Anti-TSHR  
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. 
 
8.3.9. 
Exploratory Biomarkers 
 
8.4. 
Graves’ Ophthalmopathy Assessments 
8.4.1. 
Clinical Activity Score (CAS) 
The CAS measures the classical signs of acute inflammation (pain, redness, swelling, and 
impaired function) in GO [Mourits, 1989]. One point is given for the presence of each of 
the parameters assessed.  The sum of all points defines clinical activity: active GO if the 
score is .  At all visits the 7-item scale will be utilized.  Specific details on scoring the 
CAS can be found within the SRM or study specific manual. 
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8.4.2. 
Lid Retraction  
Lid retraction occurs when the eyelid is pulled away from the eyeball, either too far up in 
the case of the upper eyelid or too far down in lower eyelid.  The assessment of lid 
retraction will be collected at the times indicated in the Time and Events Table (Section 
8.1). 
8.4.3. 
Proptosis 
Proptosis will be assessed using the same instrument (provided by sponsor) and ideally 
with the same examiner for each participant.  The same intercanthal distance should be 
used on each occasion.  Proptosis will be assessed at the times indicated in the Time and 
Events Table (Section 8.1). 
8.4.4. 
Motility 
Motility will be assessed by the examiner by estimating the degrees of restriction in eye 
movements.  Ideally, the same examiner should be used for each participant.  Motility 
will be assessed at the times indicated in the Time and Events Table (Section 8.1).   
8.4.5. 
GO-Quality Of Life (GO-QOL) 
The GO-QOL is a patient-reported questionnaire designed to assess how their GO affects 
different aspects related to quality of life (visual functioning and psychosocial 
consequences) [Terwee, 1998].  There are 16 items that are graded on a 3-point Likert 
scale.  The points given to questions 1-8 and 9-16 are added to obtain 2 raw scores 
ranging from 8-24; one for visual functioning and one for appearance.  Specific details on 
scoring the GO-QOL can be found within the SRM or study specific manual. 
8.4.6. 
External Photographs (For participating sites only) 
External photographs of the participant’s eyes will be taken at the time points indicated in 
Section 8.1, Time and Event Table. Approximately 7 digital images will be taken at each 
visit according to a standardized protocol.  Images will be used to document changes in 
GO symptoms at the same time points when the CAS is assessed. Specific details on the 
photograph procedure can be found within the SRM or study specific manual. 
8.4.7. 
Orbital CT Scan (For participating sites only)  
CT-measured muscle volume, fat volume, total orbital volume, and proptosis will be 
assessed at the time points indicated in Section 8.1, Time and Event Table.  Note: post-
baseline orbital CT scans will only be conducted for proptosis responders (i.e., 
participants with a reduction of 2 or more mm of proptosis as assessed by 
exophthalmometer at Week 13).  
Dedicated orbital CT scans will be collected locally at each site and provided to a central 
reader for analysis.  Specific details can be found within the SRM or study specific 
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8.4.8. 
Gorman Score for Diplopia 
Diplopia will be assessed at the time points indicated in Section 8.1, Time and Event 
Table, based on three grades [Bahn, 1987]: 
Grade I - Intermittent diplopia:  This is present only when the patient is fatigued 
Grade II – Inconstant diplopia: This is present only on lateral or upward gaze 
Grade III – Constant diplopia: This is present on straight and level gaze  
Specific details can be found within the SRM or study specific manual. 
 
8.4.9. 
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 
For the primary endpoint, proptosis responder rate (defined as percentage with ≥2 mm 
reduction in study eye without deterioration (≥2 mm increase) in fellow eye. It will be 
assumed that the placebo arm will have a 5% response rate and the highest dosing arm 
(680 mg) will have a 50% response rate. Assuming a dropout rate of 15%, approximately 


 
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22 participants are to be randomized to the 680 mg, 340 mg, and placebo groups.  Eleven 
subjects are to be randomized to the 255 mg dose group. Using these assumptions, 19 
participants per arm will be sufficient to detect this treatment group difference with 
approximately 85% power using a two-sided Fisher’s Exact Test assuming an alpha of 
0.05.  
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. 
Safety Population 
All participants enrolled 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 
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.  
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 


 
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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). 
10.3.1. 
Primary Efficacy Endpoint  
The primary endpoint is defined as the Proptosis responder rate (defined as percentage 
with ≥2 mm reduction in study eye without deterioration (≥2 mm increase) in fellow eye 
at the end of treatment (Week 13).  The study eye is defined as the most severely affected 
eye at the baseline visit. In the event of both eyes being affected the same, then the right 
eye will be used as the study eye. The proportion of responders will be summarized for 
all participants in the ITT population by treatment group at each visit.  A fixed, sequential 
testing procedure will be used to test the three active treatment groups vs placebo. The 
highest dose will be tested vs placebo at a significance level of 0.05.  If that test is 
significant, then the middle dose will be tested against placebo at a significance level of 
0.05.  If this test is significant, the smallest dose level will be tested against placebo at a 
significance level of 0.05.  Testing will stop when a non-significant test occurs.   
10.3.2. 
Secondary Efficacy Endpoints 
All secondary endpoints will be evaluated with the end of the treatment period (Week 
13), unless otherwise specified. 
The following secondary endpoints will be evaluated: 
• Proportion of participants with ≥2-point reduction in CAS (using a 7-point scale) 
AND ≥2 mm reduction in proptosis at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 16, 
and 20  
• Proptosis responder rate (defined as percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in fellow eye) at Weeks 2, 3, 4, 5, 6, 
8, 10, 12, 14, 16, and 20 
• Proportion of participants with CAS of 0 or 1 at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 
14, 16, and 20 
• Change from baseline in proptosis at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 16, and 
20 
• Change from baseline in CAS at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 16, and 20 
• Proportion of participants with overall ophthalmic improvement at Weeks 2, 3, 4, 
5, 6, 8, 10, 12, 13, 14, 16, and 20 defined as when at least two of the following 
outcome measures improves in one eye, without worsening in any of these 
measures in either eye: 
o Reduction in proptosis by at least 2 mm; 


 
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o Improvement of ≥ 8 degrees in motility in any duction or improvement in 
diplopia (disappearance or change in degree); 
o Improvement in CAS by at least 2 points 
• Change from baseline in the Gorman Score for diplopia at Weeks 2, 3, 4, 5, 6, 8, 
10, 12, 13, 14, 16, and 20 
• Change from baseline in the GO-QOL visual and appearance subscale scores at 
Weeks 2, 4, 6, 8, 10, 12, 13, 14, 16, and 20  
 
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.  Treatment group differences will be evaluated using a 
mixed model for repeated measurements (MMRM) techniques with terms in the model 
for baseline treatment, visit, and treatment by visit interaction. Pairwise differences 
comparing both active arms to placebo will be performed assuming an alpha of 0.05. 
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.  Treatment group differences will be 
evaluated using a two-sided Fisher’s Exact test assuming an alpha of 0.05. 
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):  
Ctrough 
 


 
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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), anti-TSHR 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. 
10.3.6. 
Other Analyses 
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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 or Sponsor designee 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. 
 
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: 
x 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. 
x Exacerbation of a chronic or intermittent pre-existing condition including an 
increase in frequency and/or intensity of the condition. 
x Signs, symptoms, or the clinical sequelae of a suspected interaction (e.g. with 
medications or food). 
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x Signs, symptoms, or the clinical sequelae of an 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: 
x 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. 
x Abnormal or worsening laboratory, imaging, or other safety findings that are not 
clinically significant. 
x Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE. 
x 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 an 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.  
An SAE is any untoward medical occurrence that, at any dose: 
x 
Results in death 
x 
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. 
x 
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. 
x 
Results in disability/incapacity 
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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 participant 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, Time and Events Table. 
• 
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 
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?”  


 
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x 
“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:  
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 
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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. 
 
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 participants 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. 
 


 
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The Investigator who receives an Investigator safety report describing an 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 participant, or the partner of a participant, 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 participant will be asked to sign a partner 
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 


 
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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. 
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, where applicable. 
• Notifying the IRB/IEC of SAEs or other significant safety findings when 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. 
 


 
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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. 
 
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 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; 


 
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• 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 AE 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 
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. 
 


 
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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.  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.  Used investigational product and supplies may be 
returned or destroyed on an ongoing basis during the study, following review and 
verification from study monitor, as appropriate.  At the end of the study, following final 
drug inventory reconciliation by the monitor, the study site will return, all unused 
investigational medicinal product supplies.   
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. 
 


 
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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 within 21 days of enrollment of the first participant.  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 
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. 
Reasons for stopping the study may include but are not limited to:  
• 
New evidence that, in the opinion of the sponsor, makes continuation of the study 
unnecessary or unethical 
• 
The sponsor discontinues development of RVT-1401 
• 
Insufficient patient enrollment 


 
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14. 
REFERENCES 
Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010 Feb 25;362(8):726-38. 
Bahn RS, Dutton CM, Natt N, Joba W, Spitzweg C, Heufelder AE. Thyrotropin receptor 
expression in Graves' orbital adipose/connective tissues: potential autoantigen in Graves' 
ophthalmopathy. J Clin Endocrinol Metab. 1998 Mar;83(3):998-1002. 
Bahn RS, Gorman CA. Choice of therapy and criteria for assessing treatment outcome in 
thyroid-associated ophthalmopathy. Endocrinol Metab Clin North Am. 1987 
Jun;16(2):391-407. 
Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, Heckmann C, 
Esser J, Morgenthaler NG. Thyrotropin receptor autoantibodies are independent risk 
factors for Graves' ophthalmopathy and help to predict severity and outcome of the 
disease. J Clin Endocrinol Metab. 2006 Sep;91(9):3464-70. Epub 2006 Jul 11. 
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. 
HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C; 
2014-2018, AASLD and IDSA. www.hcvguidelines.org (last updated: May 24, 2018) 
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. 
Investigator’s Brochure RVT-1401. 
Krieger CC1, Neumann S, Place RF, Marcus-Samuels B, Gershengorn MC.  
Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan 
secretion by Graves' disease immunoglobins.  J Clin Endocrinol Metab. 2015 
Mar;100(3):1071-7. 
Lytton SD, Ponto KA, Kanitz M, Matheis N, Kohn LD, Kahaly GJ. A novel thyroid 
stimulating immunoglobulin bioassay is a functional indicator of activity and severity of 
Graves' orbitopathy. J Clin Endocrinol Metab. 2010 May;95(5):2123-31. doi: 
10.1210/jc.2009-2470. Epub 2010 Mar 17. 
Mourits, M.P., Koornneef, L, Wiersinga W.M., Prummel, M.F, Berghout, A and van der 
Gaag, R “Clinical criteria for the assessment of disease activity in Graves' 
ophthalmopathy: a novel approach,” British Journal of Ophthalmology, vol. 73, no. 8, pp. 
639–644, 1989. 


 
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Paunkovic N, Paunkovic J. The diagnostic criteria of Graves' disease and especially the 
thyrotropin receptor antibody; our own experience. Hell J Nucl Med. 2007 May-
Aug;10(2):89-94. 
Ponto KA, Kanitz M, Olivo PD, Pitz S, Pfeiffer N, Kahaly GJ. Clinical relevance of 
thyroid-stimulating immunoglobulins in graves' ophthalmopathy. Ophthalmology. 2011 
Nov;118(11):2279-85. doi: 10.1016/j.ophtha.2011.03.030. 
Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ. Immunoglobulin activation of T 
cell chemoattractant expression in fibroblasts from patients with Graves' disease is 
mediated through the insulin-like growth factor I receptor pathway. J Immunol. 2003 Jun 
15;170(12):6348-54. 
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev 
Immunol. 2007 Sep;7(9):715-25. 
Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli 
A1, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink 
EM, Woodward RM, Gabriel K, Magni G, Douglas RS. Teprotumumab for Thyroid-
Associated Ophthalmopathy. N Engl J Med. 2017 May 4;376(18):1748-1761. 
Starkey KJ, Janezic A, Jones G, Jordan N, Baker G, Ludgate M. Adipose thyrotrophin 
receptor expression is elevated in Graves' and thyroid eye diseases ex vivo and indicates 
adipogenesis in progress in vivo. J Mol Endocrinol. 2003 Jun;30(3):369-80. 
Terwee, C.B., Gerding, M.N., Dekker, F.W., Prummel, M.F., Wiersinga, W.M. 
Development of a disease-specific quality of life questionnaire for patients with Graves' 
ophthalmopathy (The GO-QOL) . Br J Ophthalmol. 1998;82:773–779. 
Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, 
Douglas RS, Smith TJ. Evidence for an association between thyroid-stimulating hormone 
and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves' 
disease. J Immunol. 2008 Sep 15;181(6):4397-405. 
Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH-R 
expression and cytokine profile in orbital tissue of active vs. inactive Graves' 
ophthalmopathy patients. Clin Endocrinol (Oxf). 2003 Mar;58(3):280-7. 
  
 


 
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15. 
APPENDICES 
15.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
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 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CAS 
Clinical activity score 
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 
GO 
Graves’ ophthalmopathy  
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 
IGF-1R 
Insulin-like growth factor receptor  
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational new drug 
INR 
International normalized ratio 
IP 
Investigational product 


 
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IRB 
Institutional review board 
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 
MAb 
Monoclonal antibody 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MSDS 
Material safety data sheet 
NAb 
Neutralizing Antibody 
NSAID 
Non-steroidal anti-inflammatory agents 
PD 
Pharmacodynamic 
PE 
Plasma exchange 
pIgG 
Pathogenic IgG  
PIS 
Post-Intervention Status  
PK 
Pharmacokinetic 
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 
TPO 
Thyroperoxidase  
TSH 
Thyroid stimulating hormone 
TSHR 
Thyroid stimulating hormone receptor 
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 an 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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15.3. 
Appendix 3: Protocol Amendment Summary of Changes 
Amendment 02 Changes 
Rationale for the amendment: Dosing was extended from 6 to 12 weeks in order to 
maximize the potential benefit of RVT-1401 treatment.  The follow up period was 
shortened from 12 weeks to 8 weeks to decrease the overall visit schedule for participants 
while still allowing sufficient time for PD effects to return back to normal range and near 
baseline values. Associated changes related to the updated study design have also been 
made to the objectives and endpoints, entry criteria, and the timing of assessments in the 
Time and Events Table.  Additional laboratory tests were also included in order to 
characterize the impact of possible changes in albumin on other parameters, HbA1c and 
the 
.  Repeat CT scans will only be completed 
for week 13 proptosis responders instead of for all participants. Other administrative 
changes have also been made throughout.  The detailed changes are listed below:    
Change #1:  Title Page 
Added ASCEND GO2 to study title 
Change #2: Title Page 
Added all regulatory #s to the title page, including moving the EUDRA CTA # from page 
4 to the title page:  
IND: 141988 
CTA: 226455 
EUDRA CTA: 2018-004676-35 
Change #3: Title Page, Sponsor Signature Page 
Updated 
 title: 
 
Change #4: Medical Monitor/Sponsor Information Page 
Updated the Medical Monitor contact from 
 to 
 
Change #5: Section 2 Protocol Summary, Section 4 Objectives and Endpoints, 
Section 10.3.1 Primary Efficacy Endpoint, Section 10.3.2 Secondary Efficacy 
Endpoint 
Updated the primary endpoint from Week 7 to Week 13 
Updated the secondary endpoints based on 12 weeks of dosing where appropriate 
PPD
PPD
PPD
PPD
PPD


 
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Change #6: Section 2 Protocol Summary and Section 6.1 Type and Number of 
Participants  
Updated the number of participants from 70 to approximately 77 
Change #7: Section 2 Protocol Summary, Section 3.2.2 Dose Rationale, Section 5.2 
Study Schematic 
Updated the duration of treatment from 6 weeks to 12 weeks 
Change #8: Section 2 Protocol Summary and Section 8.1 Time and Events Table 
(footnote 4) 
Clarified the anti-RVT-1401 antibodies as “treatment emergent”  
Change #9: Section 3.2.2 Dose Rationale, 6th paragraph 
Previous text: 
The proposed weekly doses are expected to provide an average total IgG reduction of 
approximately 75-80%, 65-70%, and 45-55% for 680 mg, 340 mg, and 255 mg 
respectively, by the fourth or fifth dose. It is predicted that the nadir IgG reduction will be 
achieved by the 5th dose and maintained following the sixth dose before rising back to 
baseline over the next 6 to 8 weeks. 
Current text: 
The proposed weekly doses are expected to provide an average total IgG reduction of 
approximately 75-80%, 65-70%, and 45-55% for 680 mg, 340 mg, and 255 mg 
respectively, by the fourth or fifth dose. It is predicted that the nadir IgG reduction will be 
achieved by the 3rd-5th dose (depending on dose studied) and maintained following the 
remaining doses before rising back to baseline over the next 6 to 8 weeks after stopping 
treatment. 
Change #10: Section 3.3.1 Risk Assessment, Sustained hypogammaglobulinemia and 
Sustained hypoalbuminemia 
Previous text: 
Potential Risk of 
Clinical Significance 
 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and Stopping Criteria OR 
Management Criteria 
Sustained 
hypogammaglobulinemia 
The following participants will be 
ineligible: 
-Participants with a total IgG level of 
<6g/L at screening  
-Participant has had their spleen 
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 


 
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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 
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 
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-
2001. 
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 (Section 6.8.4). 
 
Current text: 
Potential Risk of 
Clinical Significance 
 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and Stopping Criteria OR 
Management Criteria 
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.  
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 


 
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- History of or known infection with 
human immunodeficiency virus (HIV), 
hepatitis B virus (HBV), or 
Mycobacterium tuberculosis:   
- Participants must have negative 
test results for HBV surface 
antigen, HBV core antibody, HIV 1 
and 2 antibodies, and a negative 
QuantiFERON-TB Gold test at 
Screening.   
- Hepatitis C virus (HCV):  
- Participants must have a 
negative test result for HCV 
antibody  
or 
- Participants with a known 
history of HCV must have 
documented evidence of 
sustained virologic response that 
is consistent with cure of hepatitis 
C infection that is confirmed with 
a negative HCV RNA test at 
Screening. 
 
-Absolute neutrophil count <1500 
cells/mm3 
in short-term trials similar to RVT-1401-
2001. 
Sustained 
hypoalbuminemia 
Participants with baseline albumin 
levels <3.5 g/dL will be ineligible.  
 
Subjects with advanced liver disease 
including any diagnosis of cirrhosis of 
any stage will be ineligible. 
 
Non-alcoholic fatty liver disease 
(NAFLD) including non-alcoholic 
steatohepatitis (NASH) is allowable if 
there has been a recent (within 6 
months) normal ultrasound, CT, or 
MRI.  If the ultrasound, CT, or MRI 
demonstrate fatty changes alone, the 
subject may be enrolled if s/he has a 
normal range fibroscan for liver 
fibrosis. 
 
AST or ALT ≥1.5x ULN at Screening. 
Serum albumin levels will be monitored 
throughout the study (Section 8.1) by an 
unblinded Medical Monitor.  Treatment of 
any clinical signs/symptoms 
suspected to be associated with 
hypoalbuminemia will be left to the 
discretion of the investigator and decision 
on dosing will be discussed with the 
study medical monitor (Section 6.8.4).  


 
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The subject may only be enrolled if 
s/he has a recent (within 6 months) 
normal ultrasound, CT, or MRI. If the 
ultrasound, CT, or MRI demonstrate 
fatty changes alone, the subject may 
be enrolled if s/he has a normal range 
fibroscan for liver fibrosis. 
Change #11: Section 4 Objective and Endpoints and Section 10.3.6 Other Analyses 
Change #12: Section 5.1 Overall Design 
Previous text: 
This is a Phase 2b, randomized, double-blind, placebo-controlled study to investigate the 
efficacy, safety and tolerability of RVT-1401 in GO patients.  The study design is 
illustrated in Section 5.2. 
Participants will screen to determine eligibility 3 to 6 weeks prior to first dose/baseline 
visit. Once eligibility is confirmed, on Day 1 participants will begin to receive RVT-1401 
as weekly SC injections for 6 weeks.  No dose adjustments of RVT-1401 are allowed 
during the study.  See Section 6.8 for additional information on stopping criteria.   
Following the initial dose at the Baseline Visit (Day 1), study visits will occur weekly 
throughout the treatment period.  Following the final dose at Week 6, visits will occur 
weekly through Week 10 and then every 2 weeks until Week 18.  Refer to Section 8.1, 
Time and Events Table. 
Optional home visits will be offered to collect (at a minimum) blood samples, vital signs, 
and review adverse events and concomitant medications.  Alternatively, the participants 
will attend the clinic on the visits that could optionally be scheduled for home visits. 
Each participant will participate in the study for up to approximately 21-24 weeks i.e.,  
3-6 week screening period (prior to baseline), a 6-week treatment period, and a 12-week 
follow up period. 
Current text: 
This is a Phase 2b, randomized, double-blind, placebo-controlled study to investigate the 
efficacy, safety and tolerability of RVT-1401 in GO patients.  The study design is 
illustrated in Section 5.2. 
Participants will screen to determine eligibility 3 to 6 weeks prior to first dose/baseline 
visit. Once eligibility is confirmed, on Day 1 participants will begin to receive RVT-1401 
as weekly SC injections for 12 weeks.  No dose adjustments of RVT-1401 are allowed 
during the study.  See Section 6.8 for additional information on stopping criteria.   
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Following the initial dose at the Baseline Visit (Day 1), study visits will occur weekly 
throughout the treatment period.  Following the final dose at Week 12, visits will occur 
weekly through Week 14 and then at Week 16 and Week 20.  Refer to Section 8.1, 
Time and Events Table. 
Optional home visits will be offered to collect (at a minimum) blood samples, vital signs, 
and review adverse events and concomitant medications.  Alternatively, the participants 
will attend the clinic on the visits that could optionally be scheduled for home visits. 
Each participant will participate in the study for up to approximately 23-26 weeks i.e., 3-
6 week screening period (prior to baseline), a 12-week treatment period, and a 8-week 
follow up period. 
Change #13: Section 5.2 Study Schematic. Figure 2 
Updated the schematic (Figure 2) from 6 weeks to 12 weeks of dosing 
Figure 3 Study Design 
 
Regimen A= RVT-1401 680 mg weekly for 12 weeks 
Regimen B= RVT-1401 340 mg weekly for 12 weeks  
Regimen C= RVT-1401 255 mg weekly for 12 weeks 
Change #14 Section 6.2 Inclusion Criteria 
Updated criteria # 9 to include the 12-week dosing period 
Added new criteria # 13 for radioactive iodine treatment: 
13. Participants who have received radioactive iodine treatment for Graves’ 
hyperthyroidism >6 months from Screening. 
Change #15: Section 6.3 Exclusion Criteria 
Combined criteria #1 through criteria #3 
Previous text: 


 
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1. Use of oral and/or IV corticosteroid use for conditions other than GO within 3 weeks 
prior to Screening (topical steroids for dermatological conditions are allowed).  
These cannot be initiated during the trial. 
2. Use of any steroid (IV or oral) with a cumulative dose equivalent to  
≥ 1 g of methylprednisolone for the treatment of GO within 3 weeks prior to 
Screening.   
3. Previous steroid use (IV or oral) with a cumulative dose of <1 g methylprednisolone 
or equivalent for the treatment of GO and previous use of steroid eye drops is 
allowed if the corticosteroid was discontinued at least 3 weeks prior to Screening. 
Current text: 
1. Use of any steroid (IV, oral, steroid eye drops) for the treatment of GO or other 
conditions within 3 weeks prior to Screening.  Steroids cannot be initiated during 
the trial.  Exceptions include topical and inhaled steroids which are allowed.  
 
Clarified the CAS criteria: 
Previous text: 
Participants with ≥ 2 pts (CAS) or 2 mm (proptosis) decrease between screen & baseline. 
Current text: 
Participants with at least a 2-point decrease in CAS or 2 mm decrease in proptosis 
between screen & baseline assessments. 
Added criteria for albumin, liver disease, AST and ALT  
Albumin level <3.5 g/dL at Screening. 
 
Known advanced liver disease including any diagnosis of cirrhosis of any stage. 
Non- alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis 
(NASH) is allowable if there has been a recent (within 6 months) normal ultrasound, 
CT, or MRI. If the ultrasound, CT, or MRI demonstrate fatty changes alone, the 
participant may be enrolled if s/he has a normal range fibroscan for liver fibrosis. 
AST or ALT ≥1.5x ULN at Screening. The participant may only be enrolled if s/he has a 
recent (within 6 months) normal ultrasound, CT, or MRI. If the ultrasound, CT, or MRI 
demonstrate fatty changes alone, the participant may be enrolled if s/he has a normal 
range fibroscan for liver fibrosis. 
Updated criteria for HIV, HBV, and HCV 
Previous text: 
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 
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will be allowed one retest; if not negative on retesting, the participant will be 
excluded. 
Current text: 
History of or known infection with human immunodeficiency virus (HIV), hepatitis B 
virus (HBV), or Mycobacterium tuberculosis:   
-Participants must have negative test results for HBV surface antigen, HBV core 
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. 
Hepatitis C virus (HCV):  
-Participants must have a negative test result for HCV antibody 
or 
-Participants with a known history of HCV must have documented evidence of 
sustained virologic response that is consistent with cure of hepatitis C infection.  
This is defined as undetectable or unquantifiable HCV RNA at least 12 weeks after 
stopping HCV treatment (HCV Guidance: Recommendations for Testing, Managing, 
and Treating Hepatitis C; 2014-2018, AASLD and IDSA).   This should be 
confirmed with a negative HCV RNA test at Screening. 
Updated criteria for allergic reactions: 
Previous text: 
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. 
Current text: 
Participant has any clinically significant history of allergic conditions (including drug 
allergies, anaphylactic reactions), that would in the opinion of the Investigator, 
contraindicates their participation. 
Updated BMI criteria: 
Previous text: 
Body Mass Index (BMI) at Screening ≥ 35 kg/m2. 
Current text: 
Body Mass Index (BMI) at Screening ≥ 40 kg/m2. 
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Enrollment in a previous RVT-1401 clinical trial. 
Updated criteria for blood transfusion or blood product donation 
Previous criteria: 
Participant has received a transfusion of any blood or blood products within 60 days or 
donated plasma within 7 days prior to baseline. 
Current criteria: 
Participant has received a transfusion of any blood or blood products within 60 days or 
donated plasma within 7 days prior to baseline and during the treatment period. 
Change # 16:  Section 6.6.1 Contraception: Contraceptive Methods with a Failure 
Rate of <1%, 5th bullet 
Previous text: 
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. 
Current text: 
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 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.   
Change #17: Section 6.8.4 Albumin Monitoring Criteria 
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Change #18 Section 6.8.5 Other Individual Stopping Criteria 
Added text: 
x 
Subject has a serious infective episode requiring hospitalization or iv antibiotic 
therapy. 
x 
Participant has a severe systemic allergic reaction (i.e., anaphylaxis) to study 
therapy. 
x 
Participant requires rescue therapy for GO (e.g., corticosteroids). 
Change #19: Section 6.9.1. Toxicity Management Criteria (AEs, Cardiovascular, 
and Injection Site Reactions), Table 2 
Removed Grade 4 and Grade 5 events 
Change #20: Section 7.1 Investigational Product 
Updated the dosing instructions so that participants are closely monitored for reactions 
for up to 30 minutes post dose instead of 1 hour 
Change #21: Section 7.3 Blinding  
Previous text: 
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), anti-TPO, anti-
thyroglobulin, and anti-TSHR and anti-IGF-1R 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, with the exception of the anti-TPO and anti-thyroglobulin data 
which are exploratory endpoints.  
The following will apply throughout the study: 
x 
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 IXRS or via the unblinded 
pharmacist.  
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• 
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.   
Current text: 
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), anti-TPO, anti-
thyroglobulin, and anti-TSHR, and anti-IGF-1R antibody data post screening as this 
could potentially unblind them.  An unblinded Medical Monitor will review the lab data 
for IgG, albumin, total protein, and ALP on an ongoing basis for safety. 
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 IXRS 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. 
Change #22:  Section 7.5 Preparation/Handling/Storage/Accountability, bullet 2 
Previous text: 
• 
The Pharmacist or designee is responsible for study treatment accountability, 
reconciliation, and record maintenance (i.e. receipt, reconciliation and final 
disposition records).   
Current text: 


 
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x 
While the Investigator is ultimately responsible, study treatment 
accountability, reconciliation, and record maintenance (i.e. receipt, 
reconciliation and final disposition records) can be designated to the 
Pharmacist or other designee.   
Change #23: Section 7.6 Compliance with Study Treatment Administration 
Previous text: 
The individual dose for a participant is prepared by a Pharmacist, licensed Pharmacy 
Technician, or designee.  The preparation of the dose will be reviewed and confirmed by 
a second member of the study site staff.  
The IP will be administered by an unblinded designee.  The date and time of each dose 
administered along with the location of each injection will be recorded in the source 
documents.  The location of each injection 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. 
Current text: 
The individual dose for a participant is prepared by an Unblinded Pharmacist, licensed 
Pharmacy Technician, or designee.  The preparation of the dose will be reviewed and 
confirmed by a second unblinded member of the study site staff.  
The study treatment will be administered by an unblinded designee not involved in the 
assessment of the participant.  The date and time of each dose administered along with 
the location of each injection will be recorded in the source documents.  The location of 
each injection and study participant identification will be confirmed at the time of dosing 
by another member of the study site staff (this person can be blinded or unblinded to 
study treatment) other than the person administering the study drug. 
 
Change #24: Section 8.1 Time and Events Table 
Updated visit schedule and assessments to reflect 12 weeks of dosing and an 8 week follow up 
period 
Added the following assessments:  dilated indirect ophthalmoscopy assessment, color vision 
assessment, vaccine titers, lipid panel, and, and microalbumin/creatinine ratio if urine protein 
abnormal. 
Added Hemoglobin A1c sampling at baseline, Week 12 and early withdrawal 
 
Changed the observation post dose period from 1 hour to 30 minutes 
Removed IGF1-R sampling from screening visit 
 
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Change #25: Section 8.3.2 Ophthalmic Exams 
Previous text: 
Ophthalmic exams will consist of cornea, lens, intraocular pressure, and optic neuropathy 
assessments (disc, choroidal folds). The exams will be conducted at the times indicated in 
the Time and Events Table (Section 8.1). If significant abnormalities are noted compared 
to previous visits, including a loss of 2 lines or more of vision, development of pupil 
abnormalities, rise in intraocular pressure, or other abnormalities of concern to the 
ophthalmologist, further investigations of visual function will be conducted according to 
the ophthalmologist decision. 
Current text: 
Ophthalmic exams will consist of: 
• best corrected visual acuity (Snellen chart) 
• automated perimetry to include a minimum of 24 degrees of visual field 
• pupil assessment to include swinging flashlight test for afferent pupillary defect 
• anterior segment slit lamp exam 
• intraocular pressure 
• posterior exam including dilated indirect ophthalmoscopy with optic disc and 
retinal/choroid assessment of posterior pole as well as periphery 
• color vision (Ishihara plates or equivalent).  
The exams will be conducted at the times indicated in the Time and Events Table 
(Section 8.1). Please note that the timing for 2 ophthalmic assessments: (1) dilated 
indirect ophthalmoscopy and (2) color vision, are listed separately in the T&E table as 
they have a different schedule than the other assessments that comprise the ophthalmic 
exam. Results for all ophthalmic assessments will be recorded in the participant’s source 
document. 
If significant abnormalities are noted compared to previous visits, including a loss of 2 
lines or more of vision, development of pupil abnormalities, clinically significant  rise in 
intraocular pressure, or other abnormalities of concern to the ophthalmologist, further 
investigations of visual function will be conducted according to the ophthalmologist’s 
clinical judgment. 
Change #26: Section 8.3.3 Vital Signs and Section 8.3.4 Electrocardiogram 
Changed the position for these assessments from semi-supine to supine. 
Change #27: Section 8.3.5 Clinical Safety Laboratory Assessments 


 
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Added Hemoglobin A1c to the hematology panel 
Added a fasted lipid panel, clarified the timepoints for fasted glucose, updated the 
urinalysis with microalbumin/creatinine ratio, and added vaccine titers. 
Clinical Chemistry 
Fasted labs 
Glucose (fasted) 
Baseline and Week 12 only 
Lipid Panel (fasted)  
Baseline, weeks  
12, 20, and Early 
Withdrawal only 
Total cholesterol  
Triglycerides  
HDL cholesterol  
LDL cholesterol (calculated using Martin-Hopkins equation) 
Cholesterol/HDL ratio  
Non-HDL cholesterol (calculated) 
Routine Urinalysis 
Specific gravity, pH 
glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or urine protein is abnormal) 
Microalbumin/creatinine ratio at baseline, week 12, and week 20 only (if urine protein is 
abnormal) 
Other tests 
Viral Serology [HIV1/HIV2, Hepatitis B (HBsAg), Hepatitis B (Core antibody), Hepatitis C (Hep 
C antibody] 
Vaccine titers for: tetanus, diphtheria, Hepatitis A, Hepatitis B, Pneumococcal  
FSH (as needed for confirmation of postmenopausal status) 
Pregnancy Tests:  serum test at screening and Week 20, and early withdrawal and urine 
dipstick pre-dose at other timepoints. Positive urine tests should be confirmed with a serum 
test. 
 
Change #28: Section 8.3.5 Clinical Safety Laboratory Assessments, 4th paragraph 
Added IgG to the blinded lab parameters 
Previous text: 
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. 
Current text: 


 
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Since changes in IgG, ALP, total protein and albumin level can potentially unblind the 
investigator to which dose the participant has been randomized to, post-screening values 
for IgG, 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. 
Change #29: Section 8.3.9 Exploratory Biomarkers 
Change #30: Section 8.4.3 Proptosis  
Removed Hertel from the type of instrument used to measure proptosis 
Change #31: Section 8.4.7 Orbital CT Scan (For participating sites only) 
Previous text: 
CT-measured muscle volume, fat volume, total orbital volume, and proptosis will be 
assessed at the time points indicated in Section 8.1, Time and Event Table. 
Dedicated orbital CT scans will be collected locally at each site and provided to a central 
reader for analysis.  Specific details can be found within the SRM or study specific 
manual. 
Current text: 
CT-measured muscle volume, fat volume, total orbital volume, and proptosis will be 
assessed at the time points indicated in Section 8.1, Time and Event Table.  Note: post-
baseline orbital CT scans will only be conducted for proptosis responders (i.e., 
participants with a reduction of 2 or more mm of proptosis as assessed by 
exophthalmometer at Week 13). 
Dedicated orbital CT scans will be collected locally at each site and provided to a central 
reader for analysis.  Specific details can be found within the SRM or study specific 
manual. 
Change #32: Section 8.4.8 Gorman Score for Diplopia 
Updated the grading scale to 3 grades and removed prisms 
Previous text: 
Diplopia will be assessed at the time points indicated in Section 8.1, Time and Event 
Table, based on four grades [Bahn, 1987]: 
Grade I - Intermittent diplopia:  This is present only when the patient is fatigued 
Grade II – Inconstant diplopia: This is present only on lateral or upward gaze 
Grade III – Constant diplopia: This is present on straight and level gaze and is correctable 
with prisms. 
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Grade IV – Constant diplopia: This is present on straight and level gaze but is not 
correctable with prisms.   
Current text: 
Diplopia will be assessed at the time points indicated in Section 8.1, Time and Event 
Table, based on three grades [Bahn, 1987]: 
Grade I - Intermittent diplopia:  This is present only when the patient is fatigued 
Grade II – Inconstant diplopia: This is present only on lateral or upward gaze 
Grade III – Constant diplopia: This is present on straight and level gaze  
Change #33: Section 10.1 Sample Size Considerations 
Previous text: 
For the primary endpoint, proptosis responder rate (defined as percentage with ≥2 mm 
reduction in study eye without deterioration (≥2 mm increase) in fellow eye. It will be 
assumed that the placebo arm will have a 5% response rate and the highest dosing arm 
(680 mg) will have a 50% response rate. Using these assumptions, 19 participants per 
arm will be sufficient to detect this treatment group difference with at least 80% power 
using a two-sided Fisher’s Exact Test assuming an alpha of 0.05.  
Current text: 
For the primary endpoint, proptosis responder rate (defined as percentage with ≥2 mm 
reduction in study eye without deterioration (≥2 mm increase) in fellow eye. It will be 
assumed that the placebo arm will have a 5% response rate and the highest dosing arm 
(680 mg) will have a 50% response rate. Assuming a dropout rate of 15%, 
approximately 22 participants are to be randomized to the 680 mg, 340 mg, and 
placebo groups.  Eleven subjects are to be randomized to the 255 mg dose group. 
Using these assumptions, 19 participants per arm will be sufficient to detect this 
treatment group difference with approximately 85% power using a two-sided Fisher’s 
Exact Test assuming an alpha of 0.05. 
Change #34: Section 10.2.2 Interim Analysis 
The interim analysis was removed from the statistical plan 
Change #35: Section 10.3.1 Primary efficacy Endpoint 
Previous text: 
The primary endpoint is defined as the Proptosis responder rate (defined as percentage 
with ≥2 mm reduction in study eye without deterioration (≥2 mm increase) in fellow eye 
at the end of treatment (Week 7).  The proportion of responders will be summarized for 
all participants in the ITT population by treatment group at each visit.  A closed, 
sequential testing procedure will be used to test the three active treatment groups vs 


 
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placebo. The highest dose will be tested vs placebo at a significance level of 0.05.  If that 
test is significant, then the middle dose will be tested against placebo at a significance 
Current text: 
The primary endpoint is defined as the Proptosis responder rate (defined as percentage 
with ≥2 mm reduction in study eye without deterioration (≥2 mm increase) in fellow eye 
at the end of treatment (Week 13).  The study eye is defined as the most severely 
affected eye at the baseline visit. In the event of both eyes being affected the same, 
then the right eye will be used as the study eye. The proportion of responders will be 
summarized for all participants in the ITT population by treatment group at each visit.  A 
fixed, sequential testing procedure will be used to test the three active treatment groups 
vs placebo. The highest dose will be tested vs placebo at a significance level of 0.05.  If 
that test is significant, then the middle dose will be tested against placebo at a 
significance level of 0.05.  If this test is significant, the smallest dose level will be tested 
against placebo at a significance level of 0.05.  Testing will stop when a non-significant 
test occurs.   
Change #36: Section 10.3.2 Secondary Efficacy Endpoints  
Previous text: 
All secondary endpoints will be evaluated with the end of the treatment period (Week 7), 
unless otherwise specified. 
The following secondary endpoints will be evaluated: 
• Proportion of participants with ≥2-point reduction in CAS (using a 7-point scale) 
AND ≥2 mm reduction in proptosis   
• Proptosis responder rate (defined as percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in fellow eye).   
o (Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, and 18) [Not Week 7] 
• Proportion of participants with CAS of 0 or 1 
• Change from baseline in proptosis 
• Change from baseline in CAS  
• Proportion of participants with overall ophthalmic improvement defined as when 
at least two of the following outcome measures improves in one eye, without 
worsening in any of these measures in either eye: 
o Reduction in proptosis by at least 2 mm; 
o Improvement of ≥ 8 degrees in motility in any duction or improvement in 
diplopia (disappearance or change in degree); 
o Improvement in CAS by at least 2 points 
• Change from baseline in the Gorman Score for diplopia  
• Change from baseline in the GO-QOL visual and appearance subscale scores. 
 
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 


 
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visit and treatment group using the n, mean, SD, median, first and third quartiles, 
minimum, and maximum values.  Treatment group differences will be evaluated using 
ANCOVA techniques with terms in the model for baseline and treatment. Pairwise 
differences comparing both active arms to placebo will be performed assuming an alpha 
of 0.05. 
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.  Treatment group differences will be 
evaluated using a two-sided Fisher’s Exact test assuming an alpha of 0.05. 
Current text: 
All secondary endpoints will be evaluated with the end of the treatment period (Week 
13), unless otherwise specified. 
The following secondary endpoints will be evaluated: 
• Proportion of participants with ≥2-point reduction in CAS (using a 7-point scale) 
AND ≥2 mm reduction in proptosis at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 16, 
and 20 
• Proptosis responder rate (defined as percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in fellow eye) at Weeks 2, 3, 4, 5, 6, 
8, 10, 12, 14, 16, and 20 
 
• Proportion of participants with CAS of 0 or 1 at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 
14, 16, and 20 
• Change from baseline in proptosis at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 16, 
and 20 
• Change from baseline in CAS at Weeks 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 16, and 20 
• Proportion of participants with overall ophthalmic improvement at Weeks 2, 3, 4, 
5, 6, 8, 10, 12, 13, 14, 16, and 20 defined as when at least two of the following 
outcome measures improves in one eye, without worsening in any of these 
measures in either eye: 
• Reduction in proptosis by at least 2 mm; 
• Improvement of ≥ 8 degrees in motility in any duction or improvement in diplopia 
(disappearance or change in degree); 
• Improvement in CAS by at least 2 points 
• Change from baseline in the Gorman Score for diplopia at Weeks 2, 3, 4, 5, 6, 8, 
10, 12, 13, 14, 16, and 20 
• Change from baseline in the GO-QOL visual and appearance subscale scores at 
Weeks 2, 4, 6, 8, 10, 12, 13, 14, 16, and 20  
 
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.  Treatment group differences will be evaluated using a 
mixed model for repeated measurements (MMRM) techniques with terms in the 


 
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model for baseline treatment, visit, and treatment by visit interaction. Pairwise 
differences comparing both active arms to placebo will be performed assuming an alpha 
of 0.05. 
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.  Treatment group differences will be 
evaluated using a two-sided Fisher’s Exact test assuming an alpha of 0.05. 
Change #37: Section 10.3.6 Other Analyses 
Previous text: 
Current text: 
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Change # 38: Section 13.1.7 Drug Accountability 
Previous text: 
The Principal Investigator or designee (i.e., pharmacist) is responsible for ensuring 
adequate accountability of all used and unused investigational product.  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 
destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and 
verified by the study monitor over the course of the study. 
Current text: 
The Principal Investigator or designee (i.e., pharmacist) is responsible for ensuring 
adequate accountability of all used and unused investigational product.  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. 
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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.  Used investigational product and supplies may be 
returned or destroyed on an ongoing basis during the study, following review and 
verification from study monitor, as appropriate.  At the end of the study, following 
final drug inventory reconciliation by the monitor, the study site will return, all unused 
investigational medicinal product supplies.   
All drug supplies and associated documentation will be periodically reviewed and 
verified by the study monitor over the course of the study. 
Change # 39: Section 13.2.3 Posting of Information on Publicly Available Clinical 
Trial Registers 
Previous text: 
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. 
Current text: 
Study information from this protocol will be posted on publicly available clinical trial 
registers within 21 days of enrollment of the first participant.  Results will be posted as 
required. 
Change #40 Section 13.3.3 Study Discontinuation 
Previous text: 
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. 
Current text: 
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. 
Reasons for stopping the study may include but are not limited to:  
• 
New evidence that, in the opinion of the sponsor, makes continuation of the 
study unnecessary or unethical 
• 
The sponsor discontinues development of RVT-1401 
• 
Insufficient patient enrollment 
 


 
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Change # 41: Section 14 References 
Added the following reference: 
HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C; 
2014-2018, AASLD and IDSA. www.hcvguidelines.org (last updated: May 24, 2018) 
 
 
 
 


 
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Amendment 01 Changes 
Rationale for the amendment: 
The following items were updated based on FDA feedback:  
x Definition for proptosis responder was updated to remove subjects with < 3 mm 
proptosis at baseline 
x Additional details on method for primary analysis was added  
x Additional information to note that the first interim analysis will be blinded was 
added 
To simplify the CAS administration, this was changed from the 10-item to the 7-item 
CAS which is more commonly used by physicians.  As a result, proptosis and motility 
assessments have been added. 
The clinical experience including safety, PK, and PD sections were updated to reflect 
current data and an update to the IB. 
Other administrative changes were also made. 
Change #1: Section 2 Protocol Summary for RVT-1401-2001: Criteria for 
Evaluation: Primary, Section 4 Objectives and Endpoints  
Removed the following text: 
Proptosis responder rate (defined as percentage ZLWK mm reduction in study eye 
without deteriorDWLRQPPLQFUHDVHLQIHOORZH\H).   
Change #2: Section 3.2.2 Dose Rationale Figure 1 
Original text: 
Figure 1: 
Serum IgG (Mean +/-SD) Reduction Following Multiple Doses of RVT-
1401 (Study RVT-1401-1001) 
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Revised text: 
Figure 1: 
Serum IgG (Mean +/-SD) Reduction Following Multiple Doses of RVT-
1401 (Study RVT-1401-1001) 
 
 


 
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Change #3:  Section 3.2.2 Clinical Experience, Section 3.2.3.1 Safety, Section 3.2.3.2 
Pharmacokinetics, Section 3.2.3.3 Pharmacodynamics 
Original text: 
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 (IV 
and SC) and multiple (SC) doses in healthy participants.  As of November 22, 2018 
RVT-1401 has been administered to 65 healthy participants at the following doses: 0.1 
mg/kg as a 1-hour 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. 
3.2.3.1 Safety 
RVT-1401 has been well tolerated.  There were no Grade 3 or 4 adverse events (AEs), 
and no withdrawals due to AEs.  Note: an SAE (Malpighian carcinoma in left side of the 
neck) considered unrelated to study drug was received by the sponsor following the data 
cut-off of Nov 22, 2018 (see Investigator’s Brochure for description). 
All AEs in subjects receiving RVT-1401 have been reported as mild, except for moderate 
AEs summarized in Table 1.  One subject who received placebo experienced severe 
(Grade 3) muscular pain that caused the subject to vomit. 
 
Table 1: 
Moderate AEs Following Administration of RVT-1401 or Placebo  
Number of Subjects with Moderate Adverse Events 
Adverse Event 
RVT-1401 (N=65) 
Placebo (N=18) 
Gastroenteritis 
1 
0 
Headache 
5 
2 
Chest pain 
1 
0 
Upper respiratory infection 
1 
0 
Dizziness due to catheter insertion 
1 
0 
Muscular pain 
0 
3 
 
Mild AEs that were reported in more than 10% of subjects in either RVT-1401 or placebo 
are presented in Table 2.  Table 2 illustrates that the most common mild AEs occurred at 
similar rates in the placebo and RVT-1401 groups with the only exception being the 
number of RVT-1401 subjects experiencing a mild headache.    
Table 2: 
Mild AEs Following Administration of RVT-1401 or Placebo   
Mild AEs Occurring in >10% of subjects (either RVT-1401 or Placebo) 
Adverse Event 
RVT-1401 (N=65) 
Placebo (N=18) 
Injection site reactions (erythema and/or swelling) 
32 
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Headache 
7 
0 
8SSHUUHVSiratory tract related issues 
8 
4 
Nausea 
3 
2 
Dizziness 
2 
3 
Generalized pain 
7 
3 
Rash 
4 
2 
 
The most frequent mild 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.   
An independent safety monitoring committee reviewed safety, PK, and PD data for each 
cohort prior to every dose escalation and no concerns have been identified with RVT-
1401. 
3.2.3.2 Pharmacokinetics 
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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 reductions occurred following the 765 mg SC 
dose (average ~14.5%) but were not considered to be clinically significant 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 
Day 35 data that were included in preliminary PD analysis for 680 mg cohort and 7 
subjects with Day 49 data that were included in analysis for the 340 mg cohort.  Data 
from the one subject that only received 2 doses of 340 mg prior to early study withdrawal 
due to personal reasons was not included.  There were 4 placebo subjects with Day 35 
data pooled across the two cohorts that were included in the PD analysis.  
Figure 1 presents the mean IgG concentration-time profiles for both weekly SC 
administration of 340 mg and 680 mg doses.  A summary of the major PD parameters for 
IgG are found in Table 4 for placebo, 340, and 680 mg dose groups.  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 to 340 mg SC. The median IgG nadir concentration occurred prior to the last 
dose in the 680 mg cohort whereas in 340 mg it occurred approximately 3 days after the 
last dose.  
Table 4 summarizes the changes in IgG across cohorts.  The data demonstrate that in 
addition to greater percent reduction from baseline in serum IgG, there was also less 
variability around the maximum percent reduction from baseline in IgG for weekly 680 
mg doses than for weekly 340 mg doses, even though the baseline IgG levels were higher 
for the 680 mg cohort.  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 would be 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%.  Although there is only preliminary data out to 
day 35 after the first dose for the 680 mg cohort, this data shows an initial rate of return 
to baseline for serum IgG that appears to be like the 340 mg cohort.  The return towards 
baseline would suggest the effect is reversible, similar to what has been observed 
following single dose administration. 
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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 (Table 5).  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 or 35 g/L) for serum albumin and recovered back to 90% of baseline in less 
than 3 weeks after the last dose.  Following weekly administration of 680 mg of RVT-
1401, serum albumin levels dropped below normal limits (>3.5 g/dL) but remained above 
3.0 g/dL for the duration of dosing except in one individual.  Most individuals had nadir 
albumin concentration prior to the last dose, indicating no further reduction occurred after 
the last dose.  The one subject who had albumin concentrations below 3.0 g/dL had a 
similar percent reduction from baseline, however their baseline albumin level of 4.1 g/dL 
was lower than rest of the group, which may explain the lower absolute albumin 
concentration level that was observed.  There were no other clinical signs or symptoms 
reported with transient albumin reduction.  In most individuals, albumin levels began to 
rise within 7 days following the last dose of either 340 mg or 680 mg indicating the 
reversibility of this effect.  Weekly albumin levels will be reviewed throughout the 
current trial; specific stopping criteria are described in Section 6.8.4. 
 


 
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Additional information is available in the current Investigator’s Brochure (IB). 
 
Revised text: 
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 (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 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. 
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.   
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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 
 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 day 35, that were included in preliminary PD analysis for 680 mg cohort and 7 
subjects with data out to day 49 were included in analysis for 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 1presents 
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 last dose in the 680 mg cohort whereas in 340 mg it 


 
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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 
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).  
Change #4: Section 5.2 Study Schematic 
Original text: 


 
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Regimen A= RVT-1401 680 mg weekly for 6 weeks 
Regimen B= RVT-1401 340 mg weekly for 6 weeks  
Regimen C= RVT-1401 255 mg weekly for 6 weeks 
 
 
 
Revised text: 
 
Change #5: Treatment Arms and Duration-added smoking stratification  
Original text: 
Participants will receive RVT-1401 or placebo as two SC injections for 6 weeks.  Refer 
to Figure 3 for dosing regimen details. 
Revised text: 


 
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Participants will be randomized 2:2:1:2 to RVT-1401 or placebo. Randomization will be 
stratified based on smoking status at the screening visit.  Refer to Figure 2 for dosing 
regimen details. 
Change #6: Section 6.2 Inclusion Criteria, Criteria # 4 
Original text: 
Clinical diagnosis of Graves' disease with hyperthyroidism associated with active, 
moderate to severe GO with a CAS ≥ 4 for the most severely affected eye at Screening. 
(on the 7-item scale) and Baseline (on the 10-item scale). 
Revised text: 
Clinical diagnosis of Graves' disease with hyperthyroidism associated with active, 
moderate to severe GO with a CAS ≥ 4 for the most severely affected eye at Screening. 
Change #7: Section 6.2 Inclusion Criteria, Criteria #6  
Original text: 
Documented evidence at Screening of detectable autoantibodies (anti-TSHR-Ab, anti-
IGF-1R-Ab, or both). 
Revised text: 
Documented evidence at Screening of detectable anti-TSHR-Ab. 
Change #8 Section Exclusion Criteria, Criteria #4 
Original text: 
Use of rituximab, tocilizumab, or any monoclonal antibody for immunomodulation 
within the past 9 months prior to Baseline. 
Revised text: 
Use of rituximab, tocilizumab, or any monoclonal antibody/Fc-fusion biologic for 
immunomodulation within the past 9 months prior to Baseline. 
Change #9: Section 6.3 Exclusion Criteria, Criteria # 5 
Original text: 
Use of selenium 3 months prior to Baseline and use during the clinical trial 
(multivitamins that include selenium are allowed). 
Revised text: 


 
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Use of selenium within 3 weeks prior to Baseline and use during the clinical trial (this 
includes multivitamins that include selenium). 
Change #10: Section 7.3 Blinding, Section 8.3.4 Clinical Safety Laboratory 
Assessments 
Added alkaline phosphatase (ALP) to a blinded safety laboratory assessment 
Change #11: Section 8.1 Time and Events Table,  
Added/updated text:  
Added collection of thyroid history to medical history at baseline 
Added Ophthalmic exam at Screening 
Added Proptosis and Motility assessments 
Updated timepoints for the Anti IGF-1R and Anti-TSHR samples 
Added a footnote to clarify the ophthalmic exam 
Change #12: Section 8.1 Time and Events Table, Section 8.3.4 Clinical Safety 
Laboratory Assessments 
Clarified that serum pregnancy tests are required at screening, Week 18, and Early 
Withdrawal. At other timepoints urine dipstick tests are acceptable. 
Change #13: Section 8.3.2 Ophthalmic Exams 
Added text: 
If significant abnormalities are noted compared to previous visits, including a loss of 2 
lines or more of vision, development of pupil abnormalities, rise in intraocular pressure, 
or other abnormalities of concern to the ophthalmologist, further investigations of visual 
function will be conducted according to the ophthalmologist decision. 
Change #14: Section 8.3.4 Clinical Safety Laboratory Assessments 
Changed glucose fasting lab test to Day 1 (baseline) and Week 7 only.  Added 
Immunoglobulin G (IgG) to the chemistry lab panel to be analysed at the central lab. 
Change #15: Section 8.3.8 Pharmacodynamics 
Updated table to remove total and activating as follows: 


 
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Pharmacodynamic Markers 
Total IgG, and differentiation by class: 
IgG subclasses (IgG1, 2, 3, and 4)  
Anti-TSHR (Total & Activating) 
Anti-IGF-1R (Total & Activating) 
 
Change #16: Section 8.3.9 Exploratory Biomarkers 
Change #17: Section 8.4 Graves Ophthalmopathy Assessments 
In Section 8.4.1 Clinical Activity Score (CAS), removed the 10-point scale and changed 
the scoring to a 7-point scale at all visits. 
Added Section 8.4.3 Proptosis and Section 8.4.4 Motility to the assessments 
Proptosis will be assessed using the same Hertel instrument (provided by sponsor) and 
ideally with the same examiner for each participant.  The same intercanthal distance 
should be used on each occasion.  Proptosis will be assessed at the times indicated in the 
Time and Events Table (Section 8.1). 
Motility will be assessed by the examiner by estimating the degrees of restriction in eye 
movements.  Ideally, the same examiner should be used for each participant.  Motility 
will be assessed at the times indicated in the Time and Events Table (Section 8.1).   
Change #18: Section 10.1 Sample Size Considerations 
Original text: 
For the primar\HQGSRLQWSURSWRVLVUHVSRQGHUUDWHGHILQHGDVSHUFHQWDJHZLWKPP
reduction in sWXG\H\HZLWKRXWGHWHULRUDWLRQPm increase) in fellow eye. For 
participants with proptosis that is < 3 mm at baseline, response will be defined as 
returning to normal limits for race and gender. It will be assumed that the placebo arm 
will have a 5% response rate and the highest dosing arm (680 mg) will have a 50% 
response rate. Using these assumptions, 19 participants per arm will be sufficient to 
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detect this treatment group difference with at least 80% power using a two-sided Fisher’s 
Exact Test assuming an alpha of 0.05. 
Revised text: 
For the primary endpoint, proptosis responder rate (defined as percentage with ≥2 mm 
reduction in study eye without deterioration (≥2 mm increase) in fellow eye. It will be 
assumed that the placebo arm will have a 5% response rate and the highest dosing arm 
(680 mg) will have a 50% response rate. Using these assumptions, 19 participants per 
arm will be sufficient to detect this treatment group difference with at least 80% power 
using a two-sided Fisher’s Exact Test assuming an alpha of 0.05. 
Change #19: Section 10.2.2 Interim Analysis 
Original text: 
Two interim analyses will be performed: 
The first interim analysis will be a performed when 50% of the participants complete the 
Week 7 visit.  This interim will be performed on the primary endpoint only, for the 
purpose of increasing the sample size as needed.  Since there is no plan to stop the study 
early based on these results, alpha spending should not be necessary.   
The second interim analysis will occur after the last participant completes the Week 7 
visit of the study.  All endpoints will be evaluated for this analysis.    Since this analysis 
is occurring at the end of the treatment phase, no adjustments of the alpha level are 
necessary.  This analysis will serve as the primary analysis and an additional analysis will 
occur, summarizing the endpoints after the treatment-free phase. 
Revised text: 
Two interim analyses will be performed: 
The first interim analysis will be a blinded review performed when 50% of the 
participants complete the Week 7 visit.  This interim will be performed on the primary 
endpoint only, for the purpose of increasing the sample size as needed.  Since there is no 
plan to stop the study early based on these results, alpha spending should not be 
necessary.   
The second interim analysis will occur after the last participant completes the Week 7 
visit of the study.  All endpoints will be evaluated for this analysis.    Since this analysis 
is occurring at the end of the treatment phase, no adjustments of the alpha level are 
necessary.  This analysis will serve as the primary analysis and an additional analysis will 
occur, summarizing the endpoints after the treatment-free phase. 
Change #20: Section 10.3.1 Primary Efficacy Endpoint 
Original text: 


 
Immunovant Sciences GmbH RVT-1401-2001, Amendment 02: Version 3.0 
 
 
 
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109 
The primary endpoint is defined as the Proptosis responder rate (defined as percentage 
with ≥2 mm reduction in study eye without deterioration (≥2 mm increase) in fellow eye 
For participants with proptosis that is < 3 mm at baseline, response will be defined as 
returning to normal limits for race and gender.) at the end of treatment (Week 7).  The 
proportion of responders will be summarized for all participants in the ITT population by 
treatment group at each visit.   
Revised text: 
The primary endpoint is defined as the Proptosis responder rate (defined as percentage 
with ≥2 mm reduction in study eye without deterioration (≥2 mm increase) in fellow eye 
at the end of treatment (Week 7).  The proportion of responders will be summarized for 
all participants in the ITT population by treatment group at each visit.  A closed, 
sequential testing procedure will be used to test the three active treatment groups vs 
placebo. The highest dose will be tested vs placebo at a significance level =0.05.  If that 
test is significant, then the middle dose will be tested against placebo at a significance 
level of 0.05.  If this test is significant, the smallest dose level will be tested against 
placebo at a significance level =0.05.  Testing will stop when a non-significant test 
occurs. 
Change #21: Section 10.3.2 Secondary Efficacy Endpoints 
Original text: 
All secondary endpoints will be evaluated with the end of the treatment period (Week 7), 
unless otherwise specified. 
The following secondary endpoints will be evaluated: 
• Proportion of participants with ≥2-point reduction in CAS (using a 7-point scale) 
AND ≥2 mm reduction in proptosis (or return to normal limits for race and gender 
if proptosis baseline <3 mm) 
• Proptosis responder rate (defined as percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in fellow eye).  For participants with 
proptosis but < 3 mm at baseline, response will be defined as returning to normal 
limits for race and gender. 
• Proportion of participants with CAS of 0 or 1 
• Change from baseline in proptosis 
• Change from baseline in CAS  
• Proportion of participants with overall ophthalmic improvement defined as when 
at least two of the following outcome measures improves in one eye, without 
worsening in any of these measures in either eye: 
o Reduction in proptosis by at least 2 mm; 
o Improvement of ≥ 8 degrees in motility in any duction or improvement in 
diplopia (disappearance or change in degree); 
o Improvement in CAS by at least 2 points 
• Change from baseline in the Gorman Score for diplopia  
• Change from baseline in the GO-QOL visual and appearance subscale scores  


 
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110 
 
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.  Treatment group differences will be evaluated using 
ANCOVA techniques with terms in the model for baseline and treatment. Pairwise 
differences comparing both active arms to placebo will be performed assuming an alpha 
of 0.05. 
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.  Treatment group differences will be 
evaluated using a two-sided Fisher’s Exact test assuming an alpha of 0.05. 
Revised text: 
All secondary endpoints will be evaluated with the end of the treatment period (Week 7), 
unless otherwise specified. 
The following secondary endpoints will be evaluated: 
Proportion of participants with ≥2-point reduction in CAS (using a 7-point scale) AND 
≥2 mm reduction in proptosis (Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, and 18) [Not Week 7] 
• Proptosis responder rate (defined as percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in fellow eye).   
o (Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, and 18) [Not Week 7] 
• Proportion of participants with CAS of 0 or 1 
• Change from baseline in proptosis 
• Change from baseline in CAS  
• Proportion of participants with overall ophthalmic improvement defined as when 
at least two of the following outcome measures improves in one eye, without 
worsening in any of these measures in either eye: 
o Reduction in proptosis by at least 2 mm; 
o Improvement of ≥ 8 degrees in motility in any duction or improvement in 
diplopia (disappearance or change in degree); 
o Improvement in CAS by at least 2 points 
• Change from baseline in the Gorman Score for diplopia  
• Change from baseline in the GO-QOL visual and appearance subscale scores  
 
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.  Treatment group differences will be evaluated using 
ANCOVA techniques with terms in the model for baseline and treatment. Pairwise 


 
Immunovant Sciences GmbH RVT-1401-2001, Amendment 02: Version 3.0 
 
 
 
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111 
differences comparing both active arms to placebo will be performed assuming an alpha 
of 0.05. 
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.  Treatment group differences will be 
evaluated using a two-sided Fisher’s Exact test assuming an alpha of 0.05. 

SAP_001.pdf: 
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RVT-1401-2001 (Amendment 1, Version 2.0) 
Statistical Analysis Plan 
 
 
Study Title 
ASCEND GO2: A Phase 2b, Multicenter, Randomized, 
Double-blind, Placebo-controlled, Study of RVT-1401 
for the Treatment of Patients with Active, Moderate to 
Severe Graves’ 
 
 
Study Protocol Number 
RVT-1401-2001 
 
 
Study Protocol Version / 
Date of Study Protocol 
Amendment 2, Version 3.0 / 09-AUG-2019 
 
 
Sponsor: 
Immunovant Sciences GmbH 
 
 
Document Version / Date 
Amendment 1, Version 2.0 / 09-MAY-2022 
 
 
 
 


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RVT-1401-2001 (Amendment 1, Version 2.0) 
Version History 
Date 
Version Description of 
Change  
Section Affected 
Author 
12-Mar-2021 
1.0 
Original version 
 
09-May-2022 
2.0 
Moved secondary 
efficacy objectives and 
endpoints to exploratory 
and to analyze as 
exploratory analyses 
Introduction 
1.1.2 Secondary 
Objectives 
1.1.3 Exploratory 
Objectives 
5.2.2. Secondary Efficacy 
Endpoints (Included in 
Safety Analysis) 
5.2.3 Exploratory 
Endpoints 
5.2.4. Exploratory 
Efficacy Endpoints 
(Included in Safety 
Analysis) 
9.3. Exploratory Efficacy 
Analyses 
 
 
 
Analyze clinical 
laboratory evaluations in 
safety population in 
addition to modified 
safety population 
10.2 Clinical Laboratory 
Evaluations (Safety and 
Modified Safety 
Population) 
 
 
 
Added Section 11: 
Change from protocol 
11. Change from protocol 
 
 
 
Added version history 
Version history 
 
 
 
 
 




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RVT-1401-2001 (Amendment 1, Version 2.0)
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1.
INTRODUCTION ........................................................................................................8 
1.1. 
Study objectives ............................................................................................................8 
1.1.1. 
Primary Objective .........................................................................................................8 
1.1.2. 
Secondary Objectives ...................................................................................................8 
1.1.3. 
Exploratory Objectives .................................................................................................9 
2.
STUDY DESIGN AND CONDUCT ..........................................................................10 
2.1. 
Treatment groups and duration ...................................................................................10 
2.2. 
Schedule of assessments .............................................................................................10 
3.
ANALYSIS POPULATIONS.....................................................................................16 
3.1. 
Intention to Treat (ITT) ...............................................................................................16 
3.2. 
Modified Intention to Treat (mITT) ............................................................................16 
3.3. 
Safety Population ........................................................................................................16 
3.4. 
Modified Safety Population ........................................................................................16 
3.5. 
Curtailed Safety Population ........................................................................................16 
4.
SAMPLE SIZE AND POWER CALCULATION .....................................................16 
5.
OUTCOME VARIABLE DEFINITIONS .................................................................17 
5.1. 
Efficacy Assessments..................................................................................................17 
5.1.1. 
Clinical Activity Score (CAS) ....................................................................................17 
5.1.2. 
Gorman Score for Diplopia .........................................................................................17 
5.1.3. 
Graves’ Ophthalmopathy Quality of Life ...................................................................17 
5.2. 
Efficacy Endpoints ......................................................................................................17 
5.2.1. 
Primary Efficacy Endpoint .........................................................................................17 
5.2.2. 
Secondary Efficacy Endpoints (Included in Safety Analysis) ....................................17 
5.2.3. 
Exploratory Efficacy Endpoints ..................................................................................18 
5.2.4. 
Exploratory Efficacy Endpoints (Included in Safety Analysis) ..................................19 
6.
VIOLATIONS AND DEVIATIONS .........................................................................19 
7.
STATISTICAL ANALYSIS: GENERAL CONVENTIONS ...................................19 


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7.1. 
Baseline .......................................................................................................................19 
7.2. 
Baseline Age ...............................................................................................................20 
7.3. 
Study Day ...................................................................................................................20 
7.4. 
Change From Baseline ................................................................................................20 
7.5. 
Visit Windows ............................................................................................................20 
7.6. 
Definition of Time ......................................................................................................21 
7.7. 
Missing and Partial Data .............................................................................................21 
8. 
PARTICIPANT CHARACTERISTICS, DISPOSITION, AND EXPOSURE 
TO STUDY DRUG ....................................................................................................23 
8.1. 
Demographic and Baseline Characteristics (Itt, Mitt, Safety, and Modified 
Safety Populations) .....................................................................................................23 
8.2. 
Participant Disposition (Itt, Mitt, Safety, Modified Safety, and Curtailed Safety 
Populations) ................................................................................................................23 
8.3. 
Treatment Exposure (Safety and Modified Safety Populations) .................................24 
8.4. 
Concomitant Medications and Therapies (Safety and Modified Safety 
Populations) ................................................................................................................25 
9. 
EFFICACY ANALYSES ...........................................................................................25 
9.1. 
Handling of Missing Data in Efficacy Analyses .........................................................25 
9.2. 
Primary Efficacy Analysis ..........................................................................................25 
9.2.1. 
Sensitivity Analyses of the Primary Efficacy Analysis ..............................................27 
9.3. 
Exploratory Efficacy Analyses ...................................................................................27 
10. 
SAFETY ANALYSES ...............................................................................................29 
10.1. 
Adverse Events (Safety and Modified Safety Populations) ........................................29 
10.2. 
Clinical Laboratory Evaluations (Safety and Modified Safety Population) ................30 
10.2.1. 
Hematology .................................................................................................................30 
10.2.2. 
Clinical Chemistry ......................................................................................................31 
10.2.3. 
Lipid Panel ..................................................................................................................31 
10.2.4. 
Additional Analyses of Laboratory Parameters ..........................................................31 
10.2.5. 
Thyroid Function Tests ...............................................................................................34 
10.2.6. 
Additional Analyses of Thyroid Function Tests .........................................................34 
10.2.7. 
Urinalysis ....................................................................................................................34 
10.3. 
Physical Examination (Safety Population) .................................................................34 
10.4. 
12-Lead Electrocardiogram (Safety Population) ........................................................34 
10.5. 
Ophthalmic Examination (Safety Population) ............................................................34 
10.6. 
Vital Signs (Safety Population) ..................................................................................36 


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RVT-1401-2001 (Amendment 1, Version 2.0) 
10.7. 
Injection Site Reactions (Safety and Modified Safety Population) ............................36 
11. 
CHANGE FROM PROTOCOL .................................................................................36 
12. 
APPENDIX.................................................................................................................37 
12.1. 
Stratified Mantel-Haenszel test ...................................................................................37 
12.2. 
MMRM Analysis ........................................................................................................39 
12.2.1. 
MMRM code for proptosis and CAS ..........................................................................39 
12.2.2. 
MMRM Code for Other Endpoints .............................................................................40 
12.3. 
ANCOVA Analysis ....................................................................................................41 
 
LIST OF TABLES 
Table 1. 
Schedule of Time and Events .....................................................................................11 
Table 2. 
Classification of Visits ................................................................................................20 
Table 3. 
ATP Classification of Lipid Parameters .....................................................................33 
Table 4. 
CTCAE Classification of Total Cholesterol and Triglyceride ...................................33 
LIST OF FIGURES 
Figure 1. 
Study Design ...............................................................................................................10 


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RVT-1401-2001 (Amendment 1, Version 2.0) 
LIST OF ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
adverse event 
anti-TPO 
antithyroperoxidase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-t 
area under the concentration-time curve from zero to last time 
BLQ 
below limit of quantitation 
CAS 
clinical activity score 
CI 
confidence interval 
Cmax 
maximum serum concentration 
Ctrough 
concentration at end of dosing interval 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
GO 
Graves’ ophthalmopathy 
GO-QOL 
Graves’ Ophthalmopathy Quality of Life 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IGF-1R 
insulin-like growth factor receptor 
IgG 
Total immunoglobulin G 
ITT 
intent to treat 
LOCF 
Last observation carried forward 
LS 
least-squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
Preferred term 
QC 
quality control 
QTcF 
corrected QT interval according to Fridericia’s formula 
SAP 
Statistical analysis plan 
SD 
standard deviation 
SI 
International System of Units 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, listings, and figures 
tmax 
time to maximum serum concentration 
TPO 
Thyroperoxidase 
TSH 
thyroid-stimulating hormone 
TSHR 
Anti-thyroid stimulating receptors 


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RVT-1401-2001 (Amendment 1, Version 2.0) 
1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented for the interim analysis of data 
collected within the scope of Immunovant protocol RVT-1401-2001 Amendment 02: Version 3.0 
[ASCEND GO2: A Phase 2b, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Study of RVT-1401 for the Treatment of Patients with Active, Moderate to 
Severe Graves’ Ophthalmopathy]. Based upon a composite review and data suggesting a 
drug-related effect of RVT-1401 on lipids, the study was paused, and an interim analysis is being 
conducted. 
At the time of the pause, 65 subjects were enrolled, with 47 subjects completing 12 weeks on 
treatment or withdrawing early (1 pregnancy and 1 early termination at Week 5) and an additional 
18 subjects were under treatment at the time of the pause. 
 has prepared this SAP. On 
 received 
unblinded data from Immunovant that included subject IDs, treatment assignments, visit, albumin, 
creatinine, glucose, IgG, TSH, cholesterol/HDL cholesterol ratio, microalbumin/creatinine ratio, 
granular casts, hyaline casts, non-HDL cholesterol, HDL cholesterol, RBC casts, triglycerides, 
WBC casts, sex, age, race, ethnicity, and dose start date
provided Immunovant 
with listings and descriptive statistics by treatment group and visit, for total cholesterol, HDL 
cholesterol, LDL cholesterol, and triglycerides. A memorandum describing the unblinding that 
occurred when the safety signal was identified is filed in the RVT-1401-2001 Trial Master File. 
The analyses outlined in this SAP will generally follow the conventions described in the protocol. 
In instances where the analyses outlined in the SAP differ from those in the protocol, a 
justification for the difference will be given. This SAP is an expansion of the Safety SAP dated 
and includes all safety and efficacy endpoints and analyses from the Safety 
SAP. Due to the early termination of this study, efficacy information obtained from this study was 
limited, thus the SAP has been updated, keeping the primary outcomes related to efficacy and 
safety, and secondary outcomes related to safety, but analyzing other secondary endpoints as 
exploratory. 
1.1. 
Study objectives 
1.1.1. Primary Objective 
x To examine the effects of RVT-1401 versus placebo on proptosis responder rate at 
Week 13 
x To assess the safety and tolerability of RVT-1401 in subjects with active, moderate to 
severe Graves’ ophthalmopathy (GO) 
1.1.2. Secondary Objectives 
x To assess the change in serum levels of anti-thyroid-stimulating hormone receptors 
(TSHR) antibodies and total immunoglobulin G (IgG) and IgG subclasses (1-4) 


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RVT-1401-2001 (Amendment 1, Version 2.0) 
1.1.3. Exploratory Objectives 


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RVT-1401-2001 (Amendment 1, Version 2.0)
2.
STUDY DESIGN AND CONDUCT
This trial is a Phase 2b, randomized, double-blind, placebo-controlled study to investigate the efficacy, 
safety, and tolerability of RVT-1401 in GO subjects.
2.1.
Treatment groups and duration
Patients were randomized 2:2:1:2 to RVT-1401 (680 mg/week, 340 mg/week, and 255 mg/week) or 
placebo. Randomization was stratified based on smoking status at the screening visit. Refer to Figure 1
for dosing regimen details. Patients were screened to determine eligibility 3 to 6 weeks prior to first
dose/baseline visit.
Once eligibility was confirmed, on Day 1 subjects received RVT-1401 or placebo as weekly 
subcutaneous injections for 12 weeks. No dose adjustments of RVT-1401 were allowed during the 
study. See protocol Section 6.8 for additional information on stopping criteria. Each subject was to
participate in the study for up to approximately 23 to 26 weeks (i.e., 3–6-week screening period prior to
baseline, a 12-week treatment period, and an 8-week follow up period). (See Figure 1.)
To maintain the study blind, all patients received 2 injections by an unblinded designee; subjects 
receiving the 680 mg dose were to receive 2 injections of RVT-1401, while subjects receiving the 
340 mg or the 255 mg dose were to receive 1 injection with RVT-1401 and 1 placebo injection. 
Patients receiving placebo were to receive 2 injections of placebo.
Figure 1.
Study Design
2.2.
Schedule of assessments
Following the initial dose at the Baseline Visit (Day 1), study visits occurred weekly throughout the
treatment period. Following the final dose at Week 12, visits occurred weekly through Week 14 and
then at Week 16 and Week 20. Refer to Table 1 for time and events.
Optional home visits were offered to collect (at a minimum) blood samples, vital signs, and review
adverse events (AEs) and concomitant medications. Alternatively, the subjects could attend the clinic 
on the visits that could optionally be scheduled for home visits.


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RVT-1401-2001 (Amendment 1, Version 2.0) 
Table 1. 
Schedule of Time and Events 
 
Screenin
g1 
Treatment Period 
Weekly Visit 
Follow-up Period Weekly 
Visit (Weeks) 
Early 
Withdrawa
Study Timepoint 
W=Weeks D=Day 
Within 3-
6 weeks 
W
1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
W7 
D43 
W8 
D50 
W
9 
D5
7 
W1
0 
D64 
W1
1 
D71 
W1
2 
D78 
W13 
W1
4 
W1
6 
W20 
 
Time Window 
(days) 
 
 
+/-
1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-
1 
da
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic, 
medical/thyroid history, 
and smoking status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Ophthalmic examination
9 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Dilated indirect 
ophthalmoscopy 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Color vision 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs
2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead 
Electrocardiogram
2 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 


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RVT-1401-2001 (Amendment 1, Version 2.0) 
 
Screenin
g1 
Treatment Period 
Weekly Visit 
Follow-up Period Weekly 
Visit (Weeks) 
Early 
Withdrawa
Study Timepoint 
W=Weeks D=Day 
Within 3-
6 weeks 
W
1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
W7 
D43 
W8 
D50 
W
9 
D5
7 
W1
0 
D64 
W1
1 
D71 
W1
2 
D78 
W13 
W1
4 
W1
6 
W20 
 
Time Window 
(days) 
 
 
+/-
1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-
1 
da
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
 
Pregnancy test
3 
(females) 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine Titers 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
QuantiFERON® – TB 
GOLD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis
2 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood chemistry and 
hematology
2 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Hemoglobin A1c 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Fasting lipid panel 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Serum complement 
(CH50, C3)
2 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Immunoglobulins 
(IgM, IgA)
2 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Anti-TPO and anti- 
thyroglobulin 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
TSH, Free T3, Free T4
2 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Anti-TSHR
2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 


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RVT-1401-2001 (Amendment 1, Version 2.0) 
 
Screenin
g1 
Treatment Period 
Weekly Visit 
Follow-up Period Weekly 
Visit (Weeks) 
Early 
Withdrawa
Study Timepoint 
W=Weeks D=Day 
Within 3-
6 weeks 
W
1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
W7 
D43 
W8 
D50 
W
9 
D5
7 
W1
0 
D64 
W1
1 
D71 
W1
2 
D78 
W13 
W1
4 
W1
6 
W20 
 
Time Window 
(days) 
 
 
+/-
1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-
1 
da
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
 
Anti-TSHR (Cell based)
2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Anti-IGF-1R
2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Anti-IGF-1R (Cell based)
2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
RVT-1401 PK sampling
2 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
Total IgG
2 
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 
X 
Gene Expression Analysis
2 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
Pro-Inflammatory 
Biomarker Multiplex
2 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
Anti- RVT-1401 
antibody
2,4 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Nab Assessment
2,4 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Drug administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Screenin
g1 
Treatment Period 
Weekly Visit 
Follow-up Period Weekly 
Visit (Weeks) 
Early 
Withdrawa
Study Timepoint 
W=Weeks D=Day 
Within 3-
6 weeks 
W
1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
W7 
D43 
W8 
D50 
W
9 
D5
7 
W1
0 
D64 
W1
1 
D71 
W1
2 
D78 
W13 
W1
4 
W1
6 
W20 
 
Time Window 
(days) 
 
 
+/-
1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-
1 
da
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
 
Injection site reactions
5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Clinical Activity Score 
(CAS)
6 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Proptosis
6 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Motility
6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Lid retraction 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Gorman Score for 
Diplopia
6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
GO-QOL
6 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
External Photographs
7 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Orbital CT Scan
8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Collect Methimazole (or 
other anti-thyroid 
medication) dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Satisfaction Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 


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Screenin
g1 
Treatment Period 
Weekly Visit 
Follow-up Period Weekly 
Visit (Weeks) 
Early 
Withdrawa
Study Timepoint 
W=Weeks D=Day 
Within 3-
6 weeks 
W
1 
D1 
BL 
W2 
D8 
W3 
D15 
W4 
D22 
W5 
D29 
W6 
D36 
W7 
D43 
W8 
D50 
W
9 
D5
7 
W1
0 
D64 
W1
1 
D71 
W1
2 
D78 
W13 
W1
4 
W1
6 
W20 
 
Time Window 
(days) 
 
 
+/-
1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-
1 
da
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
 
Adverse events 
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 
1. Screening can take place over multiple days. 
2. Vitals, ECG, safety labs, PK, and PD assessments will be collected pre-dose on dosing days where specified. Microalbumin/creatinine ratio at baseline, Week 12, and 
Week 20 only (if urine protein abnormal). 
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 20, and early 
withdrawal. 
4. Subjects with treatment emergent positive results (change from baseline) for anti- RVT-1401 antibody at Week 20 will be requested to return at approximately 6, 9, and 
12 months postdose 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 20 visit. 
5. Local injection site reactions will be assessed at approximately 10 minutes postdose and subjects will be monitored for 30 minutes postdose. 
6. GO assessments will be assessed pre-dose when collected on dosing days. 
7. Photographs can be assessed pre or after each dose when performed (for participating sites). 
8. The baseline orbital scan should be scheduled once all entry criteria have been met. Scans can be performed within +/- 7 days of the scheduled visit (for participating sites). 
Note: Week 13 and Week 20 visit scans should only be completed for subjects who are considered proptosis responders at Week 13. 
9. See protocol Section 8.3.2 for details of Ophthalmic Examination.


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3. 
ANALYSIS POPULATIONS 
3.1. 
Intention to Treat (ITT) 
This population includes all randomized subjects who receive at least one dose of RVT-1401 or 
placebo and had 1 post-baseline visit. 
3.2. 
Modified Intention to Treat (mITT) 
This population includes all randomized subjects who had the opportunity to complete Week 13 
(not impacted by the pause before Week 13) and / or early terminated prior to the pause date and 
received at least 1 dose of RVT-1401 or placebo and had 1 post-baseline visit. 
3.3. 
Safety Population 
The safety population includes all randomized subjects who have received at least one dose of 
either RVT-1401 or placebo. Subjects will be summarized by actual treatment group. 
3.4. 
Modified Safety Population 
The modified safety population includes all randomized subjects who had the opportunity to 
complete the Week 13 visit (not impacted by the pause before Week 13) and/or early terminated 
prior to the pause date and received at least 1 dose of either RVT-1401 or placebo. This population 
does not include any participant that was impacted by the pause prior to Week 13. 
3.5. 
Curtailed Safety Population 
This population includes all randomized and curtailed (paused) subjects who received at least 1 
dose or RVT-1401 or placebo. 
4. 
SAMPLE SIZE AND POWER CALCULATION 
The sample size determination as outlined in the protocol is as follows: “For the primary endpoint, 
proptosis responder rate is defined as percentage with ≥2 mm reduction in study eye without 
deterioration (≥2 mm increase) in fellow eye. It will be assumed that the placebo arm will have a 
5% response rate and the highest dosing arm (680 mg) will have a 50% response rate. Assuming a 
dropout rate of 15%, approximately 22 subjects are to be randomized to the 680 mg, 340 mg, and 
placebo groups. Eleven subjects are to be randomized to the 255 mg dose group. Using these 
assumptions, 19 subjects per arm will be sufficient to detect this treatment group difference with at 
least approximately 85% power using a 2-sided Fisher’s exact test assuming an alpha of 0.05.” 


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5. 
OUTCOME VARIABLE DEFINITIONS 
For all efficacy assessments, the study eye is defined as the most severely affected eye in terms of 
proptosis at the baseline visit. In the event of both eyes being affected to the same extent, then the 
right eye will be used as the study eye. 
5.1. 
 
Efficacy Assessments 
5.1.1. 
Clinical Activity Score (CAS) 
The CAS measures the classical signs of acute inflammation (pain, redness, swelling, and impaired 
function) in GO. One point is given for the presence of each of the parameters assessed. At visits 
where CAS is reported, the 7-item scale will be utilized, and the total score will be collected in the 
eCRF. The sum of all points defines clinical activity: active GO if the score is ≥ 4. 
5.1.2. 
Gorman Score for Diplopia 
Diplopia will be assessed based on 3 grades: 
x Grade I - Intermittent diplopia:  This is present only when the subject is fatigued, 
x Grade II – Inconstant diplopia: This is present only on lateral or upward gaze, 
x Grade III – Constant diplopia: This is present on straight and level gaze and is 
correctable. 
5.1.3. 
Graves’ Ophthalmopathy Quality of Life 
The GO-QOL questions 1 through 8 make up the visual functioning subscale and questions 9 
through 16 make up the appearance subscale. The raw score is the sum of the responses in each 
subscale. In each subscale the score will be calculated in the following manner: 
x Score = 100 × (raw score – 8)/16, if no missing responses 
x Score = 100 × (raw score – Number of Completed Items)/(2 × Number of Completed 
Items), if there are ≤ 4 missing responses, and 
x Score will be missing if there are greater than 4 missing responses. 
5.2. 
Efficacy Endpoints 
This section presents efficacy and safety endpoints separately. 
5.2.1. 
Primary Efficacy Endpoint 
The primary efficacy variable is proptosis responder rate defined as percentage of subjects with at 
least 2 mm reduction in study eye without deterioration (at least 2 mm increase) in fellow eye at 
the end of treatment (Week 13). 
5.2.2. 
Secondary Efficacy Endpoints (Included in Safety Analysis) 
The secondary efficacy endpoints to be included in safety analysis are as follows: 
x Percent change from baseline in levels of TSHR antibodies at Week 13 
x Percent change from baseline in total immunoglobulin G (IgG) at Week 13 


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x Percent change from baseline in IgG subclass (1 -4) at Week 13 
5.2.3. 
Exploratory Efficacy Endpoints 


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5.2.4. 
Exploratory Efficacy Endpoints (Included in Safety Analysis) 
6. 
VIOLATIONS AND DEVIATIONS 
Important protocol deviations will be summarized by randomized treatment group. Sensitivity 
analyses for the primary and secondary efficacy outcomes will be performed if the deviations have 
the potential to have a non-trivial impact on the analysis. 
7. 
STATISTICAL ANALYSIS: GENERAL CONVENTIONS 
Descriptive statistics will be used to summarize results of protocol RVT-1401-2001. Standard 
descriptive statistics, such as mean, SD, quartiles, and other relevant percentiles, minimum, and 
maximum, will be calculated for continuous variables. For discrete variables, descriptive analyses 
will be based on numbers of participants and related percentages. 
All data listings, summaries, and statistical analyses will be generated using SAS® Version 9.4 or 
higher or other validated software. 
The following sections describe the conventions and analyses to be used for the study. 
7.1. 
Baseline 
Baseline is the last available assessment prior to time of the first dose unless it is specified 
otherwise and is identified as Day 1.


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7.2. 
Baseline Age 
Subject’s age in years is defined as the age at the date of consent. 
x Age (year) = Floor ([date of consent – date of birth]/365.25). 
7.3. 
Study Day 
Study day is the day relative to the date of randomization. Day 1 is defined as the date of 
randomization, unless otherwise specified for the calculation of baseline. Assessments that occur 
after randomization but before the first dose of study drug are considered to occur on study 
Day 1. 
For visits (or events) after randomization, day is calculated as: 
Study day = visit (or event) date - date of randomization + 1 
For visits (or events) before randomization, day is calculated as:  
Study day = visit (or event) date - date of randomization 
For listings (such as for adverse events) the quantity days since first (or last dose) is defined as: 
days since first (or last dose) = event date – date of first (or last dose) + 1 
7.4. 
Change From Baseline 
Change from baseline is calculated using the baseline value (Section 7.1) and the value closest to 
the target study day, using the rules defined in Section 7.5. 
7.5. 
Visit Windows 
Because clinical visits may occur outside protocol-specified windows, instead of relying solely 
on visit labels in the clinical database, analysis visits and their windows are defined using derived 
study day. Study day is calculated for each scheduled and unscheduled assessment and compared 
to the target study day for each analysis visit. Data analysis and summaries are based on the 
collection date that is closest to the protocol scheduled target study day. Visit windows will be 
applied for any early withdrawal visit and for any unscheduled visits. All unscheduled and early 
withdrawal data will be presented in data listings. If two visits are equidistant from the target day, 
the earlier visit will be used. The early withdrawal and all other visits will be assigned according 
to Table 2. All presentations will use the analysis visits as defined in Table 2. 
Table 2. 
Classification of Visits 
Analysis Visit 
Study Day Analysis Window 
Week 1 Day 1 
Day 1 (Randomization) 
Week 2 Day 8 (+/- 1 day) 
Day 5 to 11 
Week 3 Day 15 (+/- 1 day) 
Day 12 to 18 
Week 4 Day 22 (+/- 1 day) 
Day 19 to Day 25 
Week 5 Day 29 (+/- 1 day) 
Day 26 to Day 32 
Week 6 Day 36 (+/- 1 day) 
Day 33 to Day 39 
Week 7 Day 43 (+/- 1 day) 
Day 40 to Day 46 


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Analysis Visit 
Study Day Analysis Window 
Week 8 Day 50 (+/- 1 day) 
Day 47 to Day 53 
Week 9 Day 57 (+/- 1 day) 
Day 54 to Day 60 
Week 10 Day 64 (+/- 1 day) 
Day 61 to Day 67 
Week 11 Day 71 (+/- 1 day) 
Day 68 to Day 74 
Week 12 Day 78 (+/- 1 day) 
Day 75 to Day 81 
Week 13 Day 85 (+/- 3 days) 
Day 82 to Day 88 
Week 14 Day 92 (+/- 3 days) 
Day 89 to Day 98 
Week 16 Day 106 (+/- 3 days) 
Day 99 to Day 119 
Week 20 Day 134 (+/- 3 days) 
Day 120 to Day 148 
2 Weeks Post-Dose (Curtailed) 
Post-Dose Day 11-20 
4 Weeks Post-Dose (Curtailed) 
Post-Dose Day 21-41 
8 Weeks Post-Dose (Curtailed) 
Post-Dose Day 42-70 
7.6. 
Definition of Time 
For visits (or events) that occur on or after randomization, time is calculated in days as: 
time = visit (or event) date – date of randomization + 1 
For visits (or events) that occur prior to randomization, time is calculated in days as: 
time = visit (or event) date – date of randomization 
For listings (e.g., for adverse events), the number of days since first (or last) dose is defined as: 
days since first (or last) dose = event date – date of first (or last) dose + 1 
For summaries that present distribution of time expressed in weeks and months, weeks will be 
defined as days divided by seven and months as days divided by 30.4. 
7.7. 
Missing and Partial Data 
For the analysis of safety variables, only partial dates may be imputed; otherwise, missing data 
will be treated simply as missing. The algorithms for imputation of partial dates depend upon the 
parameter. 
Adverse event onset 
x If onset date is completely missing, date is set to date of first dose. 
x If year is present and month and day are missing or year and day are present and 
month is missing: 
• 
If year = year of first dose, then set month and day to month and day of 
first dose. 
• 
If year < year of first dose, then set month and day to 31 December. 
• 
If year > year of first dose, then set month and day to 01 January. 
x If month and year are present and day is missing: 


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• 
If year = year of first dose and 
• 
month = month of first dose, then set day to day of first dose date. 
• 
month < month of first dose, then set day to last day of month. 
• 
For all other cases, set date to date of first dose. Adverse event end date 
x If year is present and month and day are missing or year and day are present and 
month is missing, set end month and day to 31 December. 
x If month and year are present and day is missing, set the day to last day of the month. 
x If fatal event, date is set to minimum of imputed end date and death date. 
x For all other cases, set date to missing. 
Concomitant medication 
x If start date is completely missing, start date will not be imputed. 
x If start year is present and month and day are missing or year and day are present and 
month is missing, set start month and day to 01 January. 
x If start year and month are present and day is missing, set start day to 1st day of 
month. 
x If end date is completely missing, end date will not be imputed. 
x If end year is present and month and day are missing or year and day are present and 
month is missing, set end month and day to 31 December. 
x If end year and month are present and day is missing, set end day to last day of the 
month. 
x The imputed dates must be logical, ensuring that no end date is after database lock or 
death or before the start date. 
If site queries fail to resolve partial dates for laboratory values and vital signs, including for 
efficacy, the date is missing and will not be imputed. 
Further details regarding the handling of missing values are provided in the sections describing 
the primary and secondary analyses which will be provided in the final SAP.


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8. 
PARTICIPANT CHARACTERISTICS, DISPOSITION, AND 
EXPOSURE TO STUDY DRUG 
8.1. 
Demographic and Baseline Characteristics (Itt, Mitt, Safety, and 
Modified Safety Populations) 
Descriptive statistics will be used to describe demographic and baseline characteristics of the 
participants. Sample size, mean, SD, quartiles, minimum, and maximum will be used to 
summarize continuous variables, while number and percentages of participants will be used for 
categorical variables. The following demographic and baseline characteristics, as available, will be 
summarized: age, gender, ethnicity, race, smoking status, medical/thyroid history, height, body 
weight, physical examination, ophthalmic examination, dilated indirect ophthalmoscopy, color 
vision, vital signs, 12-lead electrocardiogram, pregnancy test, viral serology, QuantiFERON® – 
TB GOLD test result, vaccine titers, urinalysis, blood chemistry and hematology, TSH, Free T3, 
Free T4, Anti-TSHR, Anti-TSHR (Cell based), Anti-IGF-1R, 
Anti-IGF-1R (Cell based), RVT-1401 PK sampling, Total IgG, Immunoglobins (IgG subclasses), 
gene expression analysis, pro-inflammatory biomarker multiplex, Anti-RVT-1401 antibody, Nab 
assessment, clinical activity score (CAS), proptosis, motility, lid retraction, Gorman Score for 
Diplopia, GO-QOL, external photographs, orbital CT scan, Methimazole (or other anti- thyroid 
medication) dose, adverse events, injection site reactions, and concomitant medication. 
Age in years will be calculated as the integer portion of the following: ([date of randomization - 
date of birth] + 1) / 365.25. 
Unless otherwise stated, percentages will be calculated relative to the number of participants in the 
safety population. All demographic data will be listed. 
Summary tables will describe baseline ocular characteristics for each treatment group. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) 
and summarized, for each treatment group, by system organ class (SOC) and preferred term (PT). 
Medical history may also be listed for all participants in the safety and modified safety 
populations. Medical history may be sorted by treatment group and descending overall frequency, 
by SOC and PT, in the summary tables. Medical history data may be sorted by treatment group, 
participant number, start date, SOC, and PT. 
8.2. 
Participant Disposition (Itt, Mitt, Safety, Modified Safety, and 
Curtailed Safety Populations) 
The study has a single timepoint of evaluation for the primary outcome: Week 13. The disposition 
of all participants will be listed and summarized by treatment group. Tables will present the 
number and percentage of participants who were screened, randomized, received treatment, or 
withdrew from the study early by treatment group and overall. For participants who were 
randomized but withdrew from the study early, the number and percentage withdrawing by reason 
will be presented by treatment group and overall. 
Participants may discontinue treatment before completion of the study for any number of reasons. 
Discontinuation will be summarized based on the reasons listed in the CRF. In addition, any 
participant may be discontinued for any sound medical reason at the discretion of the Investigator. 


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8.3. 
Treatment Exposure (Safety and Modified Safety Populations) 
Administration of RVT-1401 will be summarized descriptively by randomized treatment group for 
each protocol-specified injection. 
The presentations will also show how many participants have discontinued study treatment and the 
reason based on the following stopping criteria outlined in the protocol: liver chemistry, liver test 
abnormalities, QTc criteria, albumin monitoring criteria, and other individual stopping criteria. 
For each week during the treatment period (Week 1 through Week 12), the distribution of number 
of injections will be summarized by treatment group.


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8.4. 
Concomitant Medications and Therapies (Safety and Modified Safety 
Populations) 
Information on concomitant medication may be summarized by generic name as reported on the 
concomitant medication CRF. Prior and concomitant medications will be coded by the 
Anatomical Therapeutic Chemical (ATC) classification system according to the World Health 
Organization Drug Dictionary (WHO-DD). 
The number and percentage of participants who took at least one drug within each generic type 
will be presented. Participants will only be counted once if they are taking the same generic 
medication more than once. 
9. 
EFFICACY ANALYSES 
All significance levels will be reported as nominal. For all efficacy analyses, the stratification 
factor of smoking status is incorporated into the analysis. This approach differs from that outlined 
in the protocol which did not include smoking status in the models described for efficacy 
analyses. 
9.1. 
Handling of Missing Data in Efficacy Analyses 
For sensitivity analyses of the primary efficacy endpoint of proptosis responder rate, the following 
approaches for missing data will be used: 
x Last observation carried forward (LOCF), the most recent measure of proptosis will be 
used to determine if the subject is a responder. 
x Any missing outcome value will be assumed to be a non-responder. 
All other analyses will use the observed data and missing values will not be imputed. 
9.2. 
Primary Efficacy Analysis 
For the primary analysis each of the three dose groups will be compared to placebo with the 
hypotheses stated as described below.


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680 mg dose group 
The null and alternative hypotheses for this group are as follows: 
x H01: the proportion of proptosis responders in the 680 mg group is equal to that of the 
placebo group 
x Ha1: The proportion of proptosis responders in the 680 mg group is not equal to that of 
the placebo group 
340 mg dose group 
The null and alternative hypotheses for this group are as follows: 
x H02: the proportion of proptosis responders in the 340 mg group is equal to that of the 
placebo group 
x Ha2: The proportion of proptosis responders in the 340 mg group is not equal to that of 
the placebo group 
255 mg dose group 
The null and alternative hypotheses for this group are as follows: 
x H03: the proportion of proptosis responders in the 255 mg group is equal to that of the 
placebo group 
x Ha3: The proportion of proptosis responders in the 255 mg group is not equal to that of 
the placebo group 
Each dose group will be compared to placebo using a stratified Mantel-Haenszel test with smoking 
status as the stratification factor. The details of this analysis and pseudo SAS code are provided in 
Section 12.1. For the primary analysis, the data will be analyzed as observed and missing values 
will not be imputed.


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9.2.1. 
Sensitivity Analyses of the Primary Efficacy Analysis 
The following analyses will be conducted as sensitivity analyses supporting the primary analysis: 
x The primary analysis will be repeated using LOCF to replace missing values. 
x The primary analysis will be repeated treating all missing values as nonresponders. All 
primary analyses will be presented using a forest plot. 
9.3. 
Exploratory Efficacy Analyses  


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10. 
SAFETY ANALYSES 
Listings will be provided for all subjects in the curtailed safety population. 
10.1. 
Adverse Events (Safety and Modified Safety Populations) 
All AE summaries will be restricted to treatment-emergent AEs (TEAEs), which are defined as 
those AEs satisfying the following: 
x the AE started on or after the date and time of the first dose of study drug or 
x the AE started on or before 30 days after the last dose of study drug or 
x the AE had no recorded start date and the stop date is not before the first dose of study 
drug. 
x If it cannot be determined whether the AE is treatment-emergent due to a partial onset 
date, the date will be imputed following the rules described in Section 7.7. Verbatim 
terms in the eCRFs will be coded to the lowest level term; reporting will include the 
preferred terms and system organ classes using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.1. 
A treatment-emergent adverse event (TEAE) is one that was not present at or before the first dose 
of study medication in each period or represents the exacerbation of a pre-existing condition. 
The safety outputs will include descriptions of the following: 
x Patients with TEAEs by Preferred Term (PT) 
x Patients with TEAEs by system organ class (SOC) and PT within SOC 
x Patients with any severe TEAE 
x Patients with any serious TEAE 
x Patients with any related TEAE 
x Patients with TEAEs that result in termination from the study 
Adverse events will be summarized by treatment group. When summarizing TEAEs, each subject 
will be counted only once within a system organ class or preferred term. Summaries that are 
displayed by system organ class and preferred terms will include all treatment arms and be ordered 
by descending order of incidence of system organ class and preferred term within each system 
organ class under treatment group RVT-1401 680 mg/week. 
The following summaries will be presented for both the safety and modified safety populations: 
x Overall summary of TEAEs that contain an overview of each item below. 
x Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system 
organ class and preferred term. 
x Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
highest severity. At each level of subject summarization, a subject is classified 
according to the highest severity if the subject reported 1 or more events. Adverse 
events with missing severity will be categorized as “missing” for tabular summaries. 


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x Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
closest relationship to study drug (Related/Not Related). Related AEs are those reported 
as “Probably Related” or “Possibly Related” and unrelated AEs are those reported as 
“Not Related.” At each level of subject summarization, a subject is classified according 
to the closest relationship if the subject reported 1 or more events. Adverse events with 
a missing relationship will be considered related for this summary. 
x Subject incidence of severity Grade 3 or higher, treatment-related TEAEs by MedDRA 
system organ class, preferred term. 
x Subject incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA system organ class and preferred term. 
x Subject incidence of TEAEs leading to study discontinuation. 
All summarized AEs and serious AEs will be listed by subject for the safety population with a 
column indicating membership in the modified safety population. TEAEs considered an injection 
site reaction or a liver event will be identified in the AE and serious AE data listings.A listing of 
subjects who died will be presented for the safety population. Subject deaths will be determined 
from end of study data (where reason for discontinuation is death) and AE data (where Severity is 
“Grade 5 / Death” and outcome is “Fatal”). 
An AE leading to discontinuation is defined as any AE with an action code of “Drug Withdrawn” 
or collected as a primary reason for study completion discontinuation. A by-subject listing of AEs 
leading to discontinuation will be provided. 
A listing of all TEAEs and AEs in the curtailed safety population will also be presented. 
10.2. 
Clinical Laboratory Evaluations (Safety and Modified Safety 
Population) 
For each of the evaluations described below descriptive statistics will be provided. The descriptive 
analyses will include a summary of the raw values and the change from baseline (mean, median, 
standard deviation, min, max, IQ range). Boxplots of the raw values and the change from baseline 
over time will also be presented. 
A set of laboratory listings will be created for the safety population with a column indicating the 
subjects that also belong to the curtailed safety population. 
Only central laboratory values will be used for these analyses. 
10.2.1. 
Hematology 
The hematology parameters, measured at baseline, Week 2, Week 3, Week 4, Week 5, Week 6, 
Week 8, Week 10, Week 12, Week 14, and Week 20. The parameters that will be included are as 
follows: 
x Platelet count 
x Red blood cell indices: red blood cell count, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte 
count, hemoglobin, hematocrit 


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x Automated white blood cell differential: white blood cell count (absolute), neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, Hemoglobin A1c (only on Day 1, 
Week 12 and Week 20) 
10.2.2. 
Clinical Chemistry 
The clinical chemistry parameters, measured at baseline, Week 2, Week 3, Week 4, Week 5, 
Week 6, Week 8, Week 10, Week 12, Week 14, and Week 20. The parameters that will be included 
are as follows: 
x Liver function: aspartate aminotransferase, total and direct bilirubin, Alanine 
aminotransferase, γ-Glutamyltransferase, alkaline phosphatase 
x Kidney function: creatinine, blood urea nitrogen, uric acid, total protein, total carbon 
dioxide 
x Other: Serum complement (CH50, C3), total IgG, Immunoglobulin M, Immunoglobulin 
A, fasting glucose at baseline and Week 12, albumin, albumin grade 
x Electrolytes: potassium, chloride, sodium, calcium (total and corrected) 
10.2.3. 
Lipid Panel 
The lipid panel is measured at baseline, Week 12, and Week 20. The values to be presented include 
the following: 
x Total cholesterol, HDL cholesterol, LDL cholesterol (calculated using Martin- Hopkins 
equation), non-HDL cholesterol (calculated) 
x Triglycerides 
x Total cholesterol/HDL cholesterol ratio 
x LDL / HDL cholesterol ratio 
10.2.4. 
Additional Analyses of Laboratory Parameters 
Additional analyses in the modified safety population will include the following:


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Lipid Parameters 
x Tables of percentage increases in all lipid values by treatment group. For each of the 
lipid measures tables will be constructed presenting the number and percentage of 
subjects with increases ≥ 10%, ≥ 20%, ≥ 40%, ≥ 50%, ≥ 60%, ≥ 80%, ≥100%. 
x Lipid parameters will be classified based on the Adult Treatment Panel Guidelines 
(ATP) as provided in Table 3. Frequency distributions and shift tables of these 
classifications will be presented by treatment group. 
x Total cholesterol and triglycerides will be classified based on the CTCAE Version 5 as 
outlined in Table 4. Frequency distributions and shift tables of these classifications will 
be presented by treatment group. 
x Boxplots and tables of the percent change from baseline in lipid parameters will be 
presented by treatment group over time. 
x Spaghetti plots of all lipid values will be presented by treatment group. 
Albumin 
x Boxplots and tables of the percent change from baseline in albumin will be presented 
by treatment group over time. 
x Plots of mean values and standard deviation of albumin over time will be presented by 
treatment group. 
x Frequency distributions of values meeting the following thresholds will be presented 
by time and treatment group:  ≤ 2.5, ≤ 2.7, <3.0, ≤ 3.2, and ≤ 3.5. 
x Spaghetti plots of albumin will be presented by treatment group. 
x Scatter plots of albumin versus LDL and total cholesterol will be presented by 
treatment group. 
IgG 
x Boxplots and tables of the percent change from baseline in total IgG will be presented 
by treatment group over time. 
x Plots of mean values and standard deviation of total IgG over time will be presented by 
treatment group.  
x Scatter plots of total IgG versus LDL cholesterol and total IgG versus albumin will be 
presented by treatment group. 
x Evaluation of drug-induced serious hepatotoxicity (eDISH) plots will be presented by 
treatment group. 
Anti-TSHR antibodies 
x Plots of mean values and standard deviation of anti-TSHR antibodies over time will be 
presented by treatment group. 
x Plots of change from baseline values and standard deviation of anti-TSHR antibodies 
over time will be presented by treatment group. 


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x Plots of percent change from baseline and standard deviation of anti-TSHR antibodies 
over time will be presented by treatment group. 
Additional analyses 
Additional analyses in the curtailed safety population will include the following: 
x Spaghetti plots of all lipid values will be presented by treatment group. 
x Spaghetti plots of albumin values will be presented by treatment group.  
IgG and anti-TSHR antibodies will also be analyzed using an ANCOVA model with the percent 
change from baseline as the outcome and treatment group and smoking stratum as covariates in 
ITT population. The details of this analysis are presented in Section 12.3. 
Table 3. 
ATP Classification of Lipid Parameters 
Lipid parameter 
Value 
Classification 
Total 
< 200 
200 – 239 
≥ 240 
Desirable 
Borderline high 
High 
LDL cholesterol 
< 100 
100-129 
130-159 
160-189 
≥ 190 
Optimal 
Near optimal/above optimal 
Borderline high 
High 
Very high 
HDL 
< 40 
≥ 60 
Low 
High 
Triglycerides 
< 150 
150 – 199 
200 – 499 
≥ 500 
Normal 
Borderline high 
High 
Very high 
Table 4. 
CTCAE Classification of Total Cholesterol and Triglyceride 
Parameter 
Value 
Grade 
Cholesterol high 
>300 mg/dL 
1 
 
>300 - 400 mg/dL 
2 
 
>400 - 500 mg/dL 
3 
 
> 500 mg/dL 
4 
Hypertriglyceridemia 
150 mg/dL – 300 mg/dL 
1 
 
>300 mg/dL - 500 mg/dL 
2 
 
>500 mg/dL - 1000 mg/dL 
3 
 
>1000 mg/dL 
4 


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10.2.5. 
Thyroid Function Tests 
The following thyroid function tests, measured at baseline, Week 2, Week 3, Week 4, Week 5, 
Week 6, Week 8, Week 10, Week 13, Week 16, and Week 20 will be presented descriptively: 
x TSH, Free T3, Free T4. 
10.2.6. 
Additional Analyses of Thyroid Function Tests 
Additional analyses of thyroid function in the modified safety population include the following: 
x Plots of mean values of TSH, Free T3, and Free T4 over time by treatment group. 
x Scatter plots of the Week 10 values of thyroid function (TSH, Free T3, Free T4) versus 
the Week 12 values of LDL cholesterol by treatment group. 
10.2.7. 
Urinalysis 
The following urinalysis measures collected at baseline, Week 2, Week 3, Week 4, Week 5, 
Week 6, Week 8, Week 10, Week 12, Week 14, and Week 20 will be presented descriptively: 
x Specific gravity, pH 
x Glucose, protein, blood, and ketones by dipstick 
x Microscopic examination (if blood or urine protein is abnormal) 
x Microalbumin/creatinine ratio at baseline, Week 12, and Week 20 only if urine protein 
is abnormal 
10.3. 
Physical Examination (Safety Population) 
Abnormalities identified on the physical examination will be presented as listings for the safety 
population. 
10.4. 
12-Lead Electrocardiogram (Safety Population) 
Electrocardiogram (ECG) results (heart rate, PR, QRS, QT, and corrected QT interval by 
Fridericia (QTcF) will be summarized descriptively. 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 postbaseline 
(normal, abnormal and clinically significant, or abnormal but not clinically significant) at each 
scheduled postbaseline visit will be provided by treatment group. 
Summaries of ECG data will be provided for the safety population. ECG data will also be listed. 
10.5. 
Ophthalmic Examination (Safety Population) 
The ophthalmic exams, occurring at baseline, Week 2, Week 4, Week 6, Week 8, Week 10, 
Week 12, Week 14, Week 16, and Week 20 consisted of the following assessments: 
x Best corrected visual acuity (Snellen chart) 
x Automated perimetry to include a minimum of 24 degrees of visual field 
x Pupil assessment to include swinging flashlight test for afferent pupillary defect 
x Anterior segment slit lamp exam 


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x Intraocular pressure 
x Posterior exam including dilated indirect ophthalmoscopy with optic disc and 
retinal/choroid assessment of posterior pole as well as periphery 
x Color vision (Ishihara plates or equivalent)


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Descriptive statistics of baseline, post-baseline, and change from baseline values, as available, for 
intraocular pressure will be provided by eye and treatment group for all scheduled time points. An 
additional summary of the results by eye and treatment group for the cornea (No Abnormalities, 
Keratopathy, Ulcer, Other), lens (Clear, Cataract), disc (Normal, Atrophic, Swollen), choroidal 
folds (Yes, No), and evidence of optic neuropathy assessments (Yes, No, Equivocal) will be 
presented. 
10.6. 
Vital Signs (Safety Population) 
Vital signs (temperature [°C], systolic blood pressure [mmHg], diastolic blood pressure [mm Hg], 
pulse rate [bpm]) will be summarized descriptively. Descriptive statistics of baseline, postbaseline, 
and change from baseline values for each parameter will be presented by treatment group for all 
scheduled time points. Vital sign values will also be listed. 
10.7. 
Injection Site Reactions (Safety and Modified Safety Population) 
The injection sites were monitored for pain, tenderness, erythema and swelling. Each injection site 
reaction was categorized as mild, moderate, or severe or medically significant using the grading 
scheme provided in the protocol. 
11. 
CHANGE FROM PROTOCOL 
Due to the early termination of this study, efficacy information obtained from this study was 
limited, thus the SAP has been updated, keeping the primary outcomes related to efficacy and 
safety, and secondary outcomes related to safety, but analyzing other secondary endpoints as 
exploratory.  


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12. 
APPENDIX 
This appendix contains details for programming the stratified Mantel-Haenszel test and the 
MMRM. This code is pseudo code and may be modified at the time of analysis. 
12.1. 
Stratified Mantel-Haenszel test 
The stratified Mantel-Haenszel test will be applied to obtain a 95% confidence interval and an 
estimate of the risk difference between each of the dose groups and placebo. 
Table 5 contains pseudo SAS code with the variables defined as follows: 
x DOSE – treatment group assignment with dose of 680 mg, 340 mg, 255 mg, or placebo 
x VISITNUM – denotes time of measurement (Week 2, Week 3, Week 4, Week 5, 
Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 13) 
x SMOKE_STRAT – smoking stratum


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12.2. 
MMRM Analysis 
The MMRM models that are described for each of the efficacy endpoints will be very similar and differ 
only with respect to the number of timepoints included in an analysis. The within-participant correlations 
in the outcome over time will be modeled using an unstructured covariance structure applying the 
Kenward-Roger approximation for computing the denominator degrees of freedom for the tests of fixed 
effects. Because an unstructured covariance structure will be used with a REPEATED statement, all 
effects will be assigned the between-participant degrees of freedom to provide better approximations to the 
relevant sampling distributions. 
In the unlikely situation that this model does not converge, the following strategy will be adopted: 
1. First, a Toeplitz structure will be used. This method assumes that measurements from observations 
taken closer together in time are more highly correlated than measurements taken farther apart in 
time. 
2. If the model using a Toeplitz structure does not converge, the model will use an autoregressive 
model of order 1 (AR[1]) structure, which makes the same assumption as the Toeplitz structure but 
is mathematically more restrictive. 
3. Finally, if the model using the AR(1) structure does not converge, the model will use a compound 
symmetry structure, which assumes equal correlation for a participant’s measurements regardless 
of how far apart in time they were taken. 
The difference in the change from baseline is computed for each of the models through the use of an 
estimate or lsmeans statement. 
12.2.1. 
MMRM code for proptosis and CAS 
Table 6 contains pseudo SAS code with the variables defined as follows: 
x DOSE – treatment group assignment with dose of 680 mg, 340 mg, 255 mg, and placebo with 
dose being equal to 1 for 680 mg, 2 for 340 mg, 3 for 255 mg, and 4 for placebo 
x VISITNUM – denotes time of measurement (Week 2, Week 3, Week 4, Week 5, Week 6, 
Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 13, Week 14, Week 16, 
Week 20) 
x SMOKE_STRAT – smoking stratum• 
BASE_VAR – denotes the baseline value of the variable 
that is being modeled 
x 
CHG – change from baseline in variable being modeled 
x 
VISITNUM*DOSE – interaction of visit and dose group 
The LSMEANS statement will be provide information on all possible differences for DOSE*VISITNUM. 
The ESTIMATE statements provide information for the specific comparison and should be checked 
against the LSMEANS output to ensure that the correct values were extracted. 


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The code in Table 6 will be used for the MMRM analyses proposed in this SAP for proptosis and CAS 
with appropriate modifications made for the variable names and number of repeated measures. Additional 
example code will be provided for other endpoints. Note that the estimate statements provide the mean 
differences and associated significance levels for Week 13. All values can be found in the lsmeans output. 
The Week 13 values should be checked against those in the lsmeans output as well. 
12.2.2. 
MMRM Code for Other Endpoints 
The remaining endpoints have differing numbers of repeated measures. To obtain the mean values and 
associated test statistics at the timepoints of interest, the following code can be used. Note that all values 
can be obtained from the output of the lsmeans statement. Table 7 contains the generic code for a MMRM 
model with CHG denoting the change from baseline in the outcome of interest. All other variables are 
described in Section 12.2.1. 


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12.3. 
ANCOVA Analysis 
For endpoints using ANCOVA the model will include the change from baseline as the outcome, the 
baseline value of the outcome, smoking stratum, and dose group as covariates. All variables are defined as 
for the MMRM analyses. 




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