Clinical trial NCT03922321
Conditions: Graves' Ophthalmopathy
Keywords: IMVT-1401 Graves' Orbitopathy Thyroid Eye Disease
Sponsor: Immunovant Sciences GmbH
Start date: 2019-04-22; Completion date: 2020-05-21
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate safety, tolerability, and pharmacodynamic parameters of RVT-1401 in graves' ophthalmopathy (GO) patients.

Detailed description:

Arms: arm 1: RVT-1401 680 milligrams (mg) weekly for two weeks followed by 340 mg weekly for four weeks, administered subcutaneously
Interventions: intervention 1: RVT-1401
Intervention descriptions: intervention 1: RVT-1401 is a fully human anti-neonatal Fc receptor (FcRn) monoclonal antibody.

Protocol documents:
Prot_000.pdf: 
Immunovant Sciences GmbH Protocol RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
1 
CLINICAL STUDY PROTOCOL 
Title: 
A Phase 2a, Multicenter, Open-Label Study of RVT-1401 for the 
Treatment of Patients with Moderate to Severe Active 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-1401-1002 
Indication 
Graves’ Ophthalmopathy 
Development Phase 
2a 
Version/ 
Effective Date: 
Amendment 03: Version 4.0 
07-FEB-2019
Amendment 02: Version 3.0
10-JAN-2019
Amendment 01: Version 2.0
17-DEC-2018
Original: Version 1.0
7-DEC-2018
Immunovant, Inc. 
Study Director 
, 
Telephone: 
Email: 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under control of Sponsor, 
and is provided to you in confidence as an investigator, potential investigator or consultant, for review by you, your 
staff, and an applicable Institutional Review Board or Independent Ethics Committee. The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described in the protocol. You 
will not disclose any of the information to others without written authorization from Sponsor, except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 


lmmunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
SPONSOR SIGNATURE PAGE: 
Study title: A Phase 2a, Multicenter, Open-Label Study of RVT-140 I for the Treatment 
of Patients with Moderate to Severe Active Graves' Ophthalmopathy 
Protocol Number: 
RVT-1401-1002 
This protocol has been approved by Sponsor's representative. The following signatures 
document this approval. 
Date 
Immunownt, Inc. 
Confidential 
2 


lmmunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Medical Monitor/SAE Contact Information: 
Role 
Primary 
Medical 
Monitor 
SAE 
contact 
information 
Contact 
Study Sponsor: 
Immunovant Sciences GmbH Registered Address: 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Immunovant, Inc. Address: 
320 W. 37th St. 
New York, NY 10018 
USA 
Confidential 
3 
Day Time Phone Number and 
After-hours 
email address 
Phone/Cell/ 
Pager 
Number 
Cell: 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
4 
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 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
5 
1.
TABLE OF CONTENTS
PAGE 
1.
TABLE OF CONTENTS ........................................................................................... 5 
2.
PROTOCOL SUMMARY FOR STUDY RVT-1401-1002 ........................................... 8 
3.
INTRODUCTION ...................................................................................................... 9 
3.1. 
Background .................................................................................................. 9 
3.1.1. 
Graves’ Ophthalmopathy ............................................................... 9 
3.2. 
Rationale .................................................................................................... 10 
3.2.1. 
Study Rationale ........................................................................... 10 
3.2.2. 
Dose rationale ............................................................................. 11 
3.2.3. 
Clinical Experience ...................................................................... 12 
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 ......................................................................................... 22 
5.3. 
Treatment Arms and Duration ..................................................................... 23 
6.
PARTICIPANT POPULATION ................................................................................ 23 
6.1. 
Type and Number of Participants ................................................................ 23 
6.2. 
Inclusion Criteria ......................................................................................... 23 
6.3. 
Exclusion Criteria ........................................................................................ 24 
6.4. 
Other Eligibility Criteria Considerations ....................................................... 26 
6.5. 
Screening/Baseline Failures ....................................................................... 26 
6.6. 
Lifestyle Restrictions ................................................................................... 26 
6.6.1. 
Contraception .............................................................................. 26 
6.7. 
Withdrawal Criteria ..................................................................................... 28 
6.7.1. 
Reasons for Withdrawal ............................................................... 28 
6.7.2. 
Participant Withdrawal Procedures .............................................. 28 
6.8. 
Stopping Criteria for Individual Participants ................................................. 29 
6.8.1. 
Liver Chemistry Stopping Criteria ................................................ 29 
6.8.2. 
Criteria for Permanent Discontinuation of Study Treatment 
in Association with Liver Test Abnormalities ................................ 29 
6.8.3. 
QTc Withdrawal Criteria ............................................................... 30 
6.8.4. 
Albumin Monitoring Criteria .......................................................... 30 
6.9. 
Toxicity Management Criteria ..................................................................... 31 
6.9.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and 
Site Reactions) ............................................................................ 31 
6.9.2. 
Other Management Criteria ......................................................... 32 
6.10. 
Participant and Study Completion ............................................................... 32 
7.
STUDY TREATMENT ............................................................................................ 33 
7.1. 
Investigational Product ................................................................................ 33 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
6 
7.2. 
Treatment Assignment ................................................................................ 33 
7.3. 
Blinding ....................................................................................................... 33 
7.4. 
Packaging and Labeling .............................................................................. 33 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 34 
7.6. 
Compliance with Study Treatment Administration ....................................... 34 
7.7. 
Treatment of Study Treatment Overdose .................................................... 34 
7.8. 
Treatment After the End of the Study .......................................................... 35 
7.9. 
Concomitant Medications and Non-Drug Therapies .................................... 35 
7.9.1. 
Permitted Medications and Non-Drug Therapies .......................... 35 
7.9.2. 
Prohibited Medications and Non-Drug Therapies ......................... 35 
8.
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 35 
8.1. 
Time and Events Table ............................................................................... 36 
8.2. 
Screening and Critical Baseline Assessments ............................................ 40 
8.3. 
Study Assessments and Procedures .......................................................... 40 
8.3.1. 
Physical Exams ........................................................................... 40 
8.3.2. 
Ophthalmic Exams ....................................................................... 40 
8.3.3. 
Vital Signs .................................................................................... 40 
8.3.4. 
Electrocardiogram (ECG) ............................................................. 40 
8.3.5. 
Clinical Safety Laboratory Assessments ...................................... 41 
8.3.6. 
Pharmacokinetics ........................................................................ 42 
8.3.7. 
Anti-Drug Antibody (ADA) and Neutralizing Antibody 
(NAb) ........................................................................................... 42 
8.3.8. 
Pharmacodynamics ..................................................................... 43 
8.3.9. 
Exploratory Biomarkers ................................................................ 43 
8.4. 
Graves’ Ophthalmopathy Assessments ...................................................... 44 
8.4.1. 
Clinical Activity Score (CAS) ........................................................ 44 
8.4.2. 
Proptosis...................................................................................... 44 
8.4.3. 
Motility ......................................................................................... 44 
8.4.4. 
Lid Retraction .............................................................................. 44 
8.4.5. 
GO-Quality Of Life (GO-QOL) ...................................................... 44 
8.4.6. 
External Photographs .................................................................. 44 
8.4.7. 
Orbital CT Scan ........................................................................... 45 
8.4.8. 
Gorman Score for Diplopia .......................................................... 45 
8.4.9. 
Satisfaction Questionnaire ........................................................... 45 
9.
DATA MANAGEMENT ........................................................................................... 45 
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ................................. 46 
10.1. 
Sample Size Considerations ....................................................................... 46 
10.2. 
Data Analysis Considerations ..................................................................... 46 
10.2.1. 
Analysis Populations .................................................................... 46 
10.2.2. 
Interim Analysis ........................................................................... 46 
10.3. 
Final Analysis ............................................................................................. 47 
10.3.1. 
Primary Endpoint ......................................................................... 47 
10.3.2. 
Secondary Endpoints ................................................................... 47 
10.3.3. 
Exploratory Endpoints .................................................................. 48 
10.3.4. 
Safety Analyses ........................................................................... 48 
10.3.5. 
Pharmacokinetic Analyses ........................................................... 48 
10.3.6. 
Pharmacodynamic Analyses ........................................................ 49 
10.3.7. 
Other Analyses ............................................................................ 49 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
7 
11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAES) ................ 49 
11.1. 
Definition of Adverse Events ....................................................................... 50 
11.2. 
Definition and Reporting of Serious Adverse Events ................................... 50 
11.3. 
Time Period and Frequency for Collecting AE and SAE Information ........... 51 
11.4. 
Method of Detecting and Reporting AEs and SAEs .................................... 52 
11.5. 
Assessing Severity of AEs and SAEs ......................................................... 52 
11.6. 
Assessing Causality of AEs and SAEs ........................................................ 53 
11.7. 
Follow-up of AEs and SAEs ........................................................................ 53 
11.8. 
Regulatory Reporting Requirements for SAEs ............................................ 54 
11.9. 
Overdose .................................................................................................... 54 
12. PREGNANCY REPORTING .................................................................................. 54 
13. RESPONSIBILITIES .............................................................................................. 55 
13.1. 
Principal Investigator Responsibilities ......................................................... 55 
13.1.1. 
Good Clinical Practice (GCP) ....................................................... 55 
13.1.2. 
Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) Approval ........................................................... 55 
13.1.3. 
Informed Consent ........................................................................ 56 
13.1.4. 
Confidentiality .............................................................................. 56 
13.1.5. 
Study Files and Retention of Records .......................................... 56 
13.1.6. 
Electronic Case Report Forms (eCRF) ........................................ 58 
13.1.7. 
Drug Accountability ...................................................................... 58 
13.1.8. 
Inspections .................................................................................. 58 
13.1.9. 
Protocol Compliance .................................................................... 58 
13.2. 
Sponsor Responsibilities ............................................................................. 59 
13.2.1. 
Protocol Modifications .................................................................. 59 
13.2.2. 
Study Report and Publications ..................................................... 59 
13.2.3. 
Posting of Information on Publicly Available Clinical Trial 
Registers ..................................................................................... 59 
13.3. 
Joint Investigator/Sponsor Responsibilities ................................................. 59 
13.3.1. 
Access to Information for Monitoring ............................................ 59 
13.3.2. 
Access to Information for Auditing or Inspections ......................... 59 
13.3.3. 
Study Discontinuation .................................................................. 59 
14. REFERENCES ....................................................................................................... 61 
15. APPENDICES ........................................................................................................ 63 
15.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 63 
15.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments .............................................................................................. 66 
15.3. 
Appendix 3: Protocol Amendment Summary of Changes ............................ 68 
 
 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
8 
2.
PROTOCOL SUMMARY FOR STUDY RVT-1401-1002
Study Title 
A Phase 2a, Multicenter, Open-Label Study of RVT-
1401 for the Treatment of Patients with Moderate to 
Severe Active Graves’ Ophthalmopathy 
Objectives 
Primary 
To assess the safety and tolerability of RVT-1401 in 
patients with moderate to severe active GO over a 6-
week treatment period 
To assess the change in serum levels of anti-TSHR 
antibodies and total IgG & IgG subclasses (1-4) 
Secondary 
To examine the effect of RVT-1401 on mean change 
in proptosis 
To examine the effect of RVT-1401 on proptosis 
responder rate  
To examine RVT-1401 PK following repeat doses in 
patients with moderate to severe active GO 
To measure anti-RVT-1401 antibodies following repeat 
doses in patients with moderate to severe active GO 
Study Phase 
Phase 2a 
Target Population 
Graves’ Ophthalmopathy 
Number of 
Participants Planned 
Approximately 8 participants 
Number of Study 
Centers Planned 
Approximately 4 
Study Design 
Phase 2a, Multicenter, Open-Label Study to 
investigate the safety, tolerability, PK, PD, and efficacy 
of RVT-1401 
Duration of Treatment 
6 weeks 
Criteria for Evaluation 
(Endpoints) 
Primary 
Assessment of safety and tolerability by analysis of AE 
data and changes from baseline in vital signs, clinical 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
9 
laboratory values, and electrocardiograms 
Change from baseline in levels of anti-TSHR 
antibodies 
Change from baseline in levels of total IgG and IgG 
subclasses (1-4) 
Secondary 
Change from baseline in proptosis 
Proptosis responder rate (defined as percentage with 
≥2 mm reduction in study eye without deterioration (≥2 
mm increase) in fellow eye).    
PK Parameters of AUC (0-168 h) and Cmax after first 
and last dose  
Concentration of RVT-1401 pre-dose (Ctrough) 
Immunogenicity determined by number of participants 
with positive anti-RVT-1401 antibodies and 
characterization of any anti-RVT-1401 to confirm 
neutralization potential 
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 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
10 
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.   
RVT-1401 will reduce levels of all pathogenic IgG (pIgG), 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 
patient-friendly subcutaneous (SC) mode of administration. 
 
3.2. 
Rationale 
3.2.1. 
Study Rationale 
The purpose of the current study is to confirm safety/tolerability and key 
pharmacodynamic (PD) effects that are considered to drive clinical benefit (reduction of 
total IgG, anti-TSHR-IgG and anti-IGF-1R-IgG) in GO patients. Results from this trial 
will be used to support progression into a larger and longer study designed to confirm 
clinical efficacy.      


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
11 
3.2.2. 
Dose rationale 
Autoimmunity 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 
virtually all 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 has been evaluated in healthy participants using single and repeat SC doses  
(Section 3.2.3).  Changes in serum IgG concentrations were used as a biomarker to assess 
the effects of repeat administration of RVT-1401 (340 mg and 680 mg).  Following 
weekly administration of 340 mg and 680 mg SC for 4 weeks, serum IgG was reduced 
from baseline an average of 62.7% and 78.4% respectively, compared to 9.05% for 
placebo. Serum IgG levels began to return to baseline approximately 7 days after the last 
dose in both 340 and 680 mg cohorts. In the 340 mg cohort, IgG values returned to within 
70% of their baseline value by 4 weeks post last dose and preliminary data also shows 
that rate of return to baseline for 680 mg cohort follows a similar trajectory, thus 
indicating the effect is reversible for both doses (consistent with other anti-FcRN’s that 
are currently in development for other indications).  
RVT-1401 will be administered as a weekly 680 mg SC injection for two weeks followed 
by weekly 340 mg SC injection for four weeks. These doses represent the upper limit of 
RVT-1401 which can be administered as two SC injections (680 mg) and one SC 
injection (340 mg) per week.  In the proposed study, the first two weekly SC 
administrations of 680 mg is predicted to quickly reduce IgG to ~64% below baseline and 
the following four weekly doses of 340 mg would maintain this level of IgG reduction 
before recovering back to baseline over the next 6 to 8 weeks.  This regimen would also 
be expected to maintain serum albumin levels within normal limits for most participants.  
This dosing regimen of RVT-1401 produces a significant reduction in total serum IgG 
within two weeks, which in GO patients would also include anti-TSHR IgG. Thus, 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 reduce serum IgG quickly with induction dosing 
and then maintain that reduction over the next 5 weeks.  The doses used in this regimen 
have been well-tolerated while producing robust reductions in total IgG in healthy 
participants.      


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
12 
Figure 1: Mean(+/-SD) Serum IgG Reduction Following Multiple SC Doses of RVT-
1401  
Note: On Day 42 in 680 mg Cohort, only 1 subject had Serum IgG data at the time of data cut off therefore 
no error bars are presented. 
 
3.2.3. 
Clinical Experience 
RVT-1401 has been studied in two Phase 1 clinical studies (HL161BKN-001 and RVT-
1401-1001) designed to assess the safety, tolerability, PK, and PD following single 
(intravenous [IV] and SC) and multiple (SC) doses in healthy participants.  As of 
November 22, 2018 RVT-1401 has been administered to 65 healthy participants at the 
following doses: 0.1 mg/kg as a 1-hour intravenous (IV) infusion (n=4), 100 mg as a 1-
hour IV infusion (n=6), 340 mg as a 1-hour IV infusion (n=6), 0.5 mg/kg SC injection 
(n=3), 1.5 mg/kg SC injection (n=6), 5 mg/kg SC (n=6), 340 mg SC injection (n=6), 500 
mg SC injection (n=6), 765 mg SC injection (n=6). Eight participants have received 
repeated 340 mg SC injections weekly for 4 weeks and 8 participants have received 
repeated 680 mg SC injections weekly for 4 weeks. 
3.2.3.1. 
Safety 
RVT-1401 has been well tolerated.  There have been no Grade 3 or 4 adverse events 
(AEs) and no withdrawals due to AEs. An SAE (Malpighian carcinoma 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. 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
13 
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 
11 
Headache 
7 
0 
Upper respiratory 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. 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
14 
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 reductions occurred following the 765 mg SC dose 
 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 


lmmunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
personal reasons was not included. There were 4 placebo subjects with Day 35 data 
pooled across the two coho1ts 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 Sllilllllaty of the major PD parameters for 
IgG ai·e found in Table 4 for placebo, 340, and 680 mg dose groups. Figure 1 shows a 
reduction in sernm IgG as a percent of pre-dose across both 340 mg and 680 mg coho1ts. 
In contrast, the placebo group demonstrated minimal changes in sernm IgG as a percent 
of pre-dose. The reduction in sennn IgG was more rapid following the 680 mg SC 
compai·ed to 340 mg SC. The median IgG nadir concentration occmTed prior to the last 
dose in the 680 mg coho1t whereas in 340 mg it occmTed approximately 3 days after the 
last dose. 
Table 4 sUilllllai·izes the changes in IgG across coho1ts. The data demonstrate that in 
addition to greater percent reduction from baseline in sernm IgG, there was also less 
vai-iability 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 coho1t. The finding that the 680 mg coho1t achieved nadir concentration 
following the 3rd dose and maintained sernm 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 
sernm IgG from baseline of~ 75-80%. Although there is only preliminai·y data out to 
day 3 5 after the first dose for the 680 mg coho1t, this data shows an initial rate of retmn 
to baseline for sernm IgG that appeai·s to be like the 340 mg cohort. The retmn towards 
baseline would suggest the effect is reversible, similai· to what has been observed 
following single dose administration. 
cmTent trial; specific stopping criteria are described in Section 6.8.4. 
Confidential 
15 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
16 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
17 
Table 4: 
Summary of Total IgG PD Parameters [Mean (SD)] following multiple 
dose administration of RVT-1401 
Dose 
(mg) 
N 
Weight2 
(kg) 
Baseline 
(g/L) 
Nadir IgG 
Concentration 
(g/L) 
Maximum IgG 
Reduction from 
Baseline (%) 
Time to Nadir IgG 
Concentration2,3 
(Days) 
340 
71 
80.6 
(66.8, 84.4) 
11.4 
(2.68) 
4.43 
(2.19) 
62.7 
(10.7) 
24 
(21, 28) 
680 
8 
70.9 
(59.2, 90.3) 
12.5 
(2.91) 
2.75 
(0.872) 
78.4 
(2.39) 
21 
(21, 24) 
Placebo4 
4 
76.1 
(75.4, 106) 
10.5 (2.29) 
9.57 
(2.13) 
9.05 
(3.11) 
24 
(21, 28) 
1.
N=7 for PD as 1 subject dropped out prior to 4th and final dose 
2.
Median (Min, Max) 
3.
Time to nadir is relative to administration of first dose 
4.
Placebo Group is pooled from subjects receiving placebo from both treatment groups
Additional information is available in the current Investigator’s Brochure (IB). 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
18 
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 1 hr post-dose before 
they leave the clinic.  
If during the course of study drug 
administration, the participant 
experiences a drug related AE of Grade 3 
(severe) or greater severity, study drug 
administration will be stopped. 
Changes in circulating 
complement 
None 
Serum complement will be monitored 
throughout the study (Section 8.1).  
Abnormal values will be discussed with 
the study medical monitor. 
Sustained 
hypogammaglobulinemia 
The following participants will be 
ineligible: 
-Participants with a total IgG level of 
<6g/L at screening  
-Participant has had their spleen 
removed. 
-Participant has a past medical history of 
primary immunodeficiency, T-cell or 
humoral, including common variable 
immunodeficiency. 
-History of or known infection with human 
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 
Total IgG levels will be monitored 
throughout the study (Section 8.1).   
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-
1002. 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
19 
will be excluded. 
-Absolute neutrophil count <1500 
cells/mm3 
Sustained 
hypoalbuminemia 
Investigator discretion  
Serum albumin levels will be monitored 
throughout the study (Section 8.1).  
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). 
 
 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
20 
4.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of RVT-
1401 in patients with moderate to severe 
active GO over a 6-week treatment period 
To assess the change in serum levels of anti-
TSHR antibodies and total IgG & IgG 
subclasses (1-4) 
Assessment of safety and tolerability by 
analysis of AE data and changes from 
baseline in vital signs, clinical laboratory 
values, and electrocardiograms 
Change from baseline in levels of anti-TSHR 
antibodies 
Change from baseline in levels of total IgG 
and IgG subclasses (1-4) 
Secondary 
To examine the effect of RVT-1401 on mean 
change in proptosis 
To examine the effect of RVT-1401 on 
proptosis responder rate  
To examine RVT-1401 PK following repeat 
doses in patients with moderate to severe 
active GO 
To measure anti-RVT-1401 antibodies 
following repeat doses in patients with 
moderate to severe active GO 
Change from baseline in proptosis 
Proptosis responder rate (defined as 
percentage with ≥2 mm reduction in study 
eye without deterioration (≥2 mm increase) in 
fellow eye).    
PK Parameters of AUC (0-168 h) and Cmax 
after first and last dose  
Concentration of RVT-1401 pre-dose 
(Ctrough) 
Immunogenicity determined by number of 
participants positive for anti-RVT-1401 
antibodies and characterization of any anti-
RVT-1401 to confirm neutralization potential 
Exploratory 
To assess the change in serum levels of anti-
IGF-1R antibodies 
To examine the effect of RVT-1401 on the 
pro-inflammatory and FcRn gene expression 
in peripheral blood mononuclear cells.   
To examine the effect of RVT-1401 on the 
level of circulating pro-inflammatory 
cytokines/chemokines 
Change from baseline in levels of anti-IGF-1R 
antibodies 
Change from baseline in the level of gene 
expression  
Change from baseline in the circulating level 
of pro-inflammatory cytokines/chemokines  


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
21 
To assess FcRn receptor occupancy following 
RVT-1401 administration in whole blood 
To assess the change in the ratio of 
stimulatory to total serum levels of anti-TSHR 
and anti-IGF-1R antibodies 
To examine the effect of RVT-1401 on levels 
of anti-thyroperoxidase (anti-TPO) and anti-
thyroglobulin antibodies  
To assess the change in levels of TSH, free 
T3, and free T4 
To examine the effect of RVT-1401 on overall 
responder rate 
To examine the effect of RVT-1401 on mean 
change in Clinical Activity Score (CAS) 
To examine the effect of RVT-1401 on CAS 
responder rate  
To examine the effect of RVT-1401 on overall 
ophthalmic improvement 
To examine the effect of RVT-1401 on 
subjective diplopia 
To examine the effect of RVT-1401 on the 
Graves’ Ophthalmopathy Quality of Life (GO-
QOL) score in the visual functioning and 
appearance subscales 
To examine the effect of RVT-1401 on 
methimazole (or other anti-thyroid treatment) 
FcRn receptor occupancy following RVT-1401 
administration  
Change from baseline in ratios of stimulatory 
to total anti-TSHR and anti-IGF-1R antibodies 
Change from baseline in the levels of anti-
TPO and anti-thyroglobulin antibodies  
Change from baseline in levels of TSH, free 
T3, and free T4 
Proportion of subjects with ≥2-point reduction 
in CAS (using a 7-point scale) AND ≥2 mm 
reduction in proptosis  
Change from baseline in CAS 
Proportion of subjects with CAS of 0 or 1 
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  
Change from baseline in the GO-QOL visual 
functioning and appearance subscale scores 
Change from baseline in methimazole (or 
other anti-thyroid treatment) dose 


lmmunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
dosage requirements to achieve/maintain 
euthyroid state 
To examine the effect of RVT-1401 on 
Computed Tomography (CT) measured 
muscle volume, fat volume, total orbital 
volume, and proptosis 
5.
STUDY DESIGN
5.1. 
Overall Design
Change from baseline in CT-measured 
muscle volume, fat volume, total orbital 
volume, and proptosis 
This is a Phase 2a, open label study to investigate the safety, tolerability, PK, PD, and 
efficacy ofRVT-1401 in GO patients. The study design is illustrated in Section 5.2. 
Paiiicipants will screen to detennine eligibility 3 to 6 weeks prior to first dose/baseline 
visit. Once eligibility is confinned, on Day 1 paiticipants will begin to receive RVT-1401 
as weekly SC injections for 6 weeks. No dose adjustments ofRVT-1401 are allowed 
during the study. See Section 6.8 for additional info1mation on stopping criteria. 
Following the initial dose at the Baseline Visit (Day 1), study visits will occur at Days 3 
and 5 and then weekly throughout the treatment period. Following the final dose at Week 
6, two study visits will occur at Days 38 and 40, and then weekly through Week 10 and 
then every 2 weeks until Week 18. Safety, PK, PD, and clinical assessments will be 
collected throughout the study. Refer to Section 8.1, Time and Events Table. 
Optional home visits will be offered to collect (at a minimum) blood sainples, 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 pa1iicipant will paiiicipate 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.
5.2. 
Study Schematic 
Figure 3 Study Design 
-
onfidential 
RVT-1401 
680 mg x 2 weeks+ 340 mgx 4 
weeks 
N=8 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
23 
5.3. 
Treatment Arms and Duration 
Participants will receive RVT-1401 for 6 weeks (680 mg/weekly for 2 weeks followed by 
340 mg/weekly for 4 weeks). 
 
6. 
PARTICIPANT POPULATION 
6.1. 
Type and Number of Participants 
A sufficient number of participants will be enrolled to achieve approximately 8 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 
essential. 
To determine participant eligibility at screening, a single repeat of certain tests such as 
laboratory values, vital signs, or ECGs is allowed at the discretion of the Principal 
Investigator. 
6.2. 
Inclusion Criteria 
A participant will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Male or female ≥ 18 years of age. 
2. 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. 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
24 
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 (on the 7-item scale) and Baseline (on the 10-item scale).  
5. Onset of active GO within 9 months of screening. 
6. Documented evidence at Screening of detectable autoantibodies (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 SRM), and/or inconstant or constant diplopia. 
9. Stable medical regimen; unlikely to require adjustment of thyroid medications during 
the 6-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 
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 
(methimazole + adding levothyroxine) when FT4 and T3 have become normal are 
allowed.  
13. 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 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 (intravenous [IV] or oral) with a cumulative dose equivalent to  
≥ 1 g of methylprednisolone for the treatment of TED within 3 weeks prior to 
Screening.    


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
25 
3.
Previous steroid use (IV or oral) with a cumulative dose of <1 g methylprednisolone
or equivalent for the treatment of TED and previous use of steroid eye drops is
allowed if the corticosteroid was discontinued at least 3 weeks prior to Screening.
4.
Use of rituximab, tocilizumab, or any monoclonal antibody for immunomodulation
within the past 9 months prior to Baseline.
5.
Use of selenium 3 weeks prior to Baseline and use during the clinical trial
(multivitamins that include selenium are allowed).
6.
Use of biotin within 48 hours prior to any laboratory collection (this includes
multivitamins that include biotin).
7.
Participants with ≥ 2 pts (CAS) or 2 mm (proptosis) decrease between screen &
baseline.
8.
Total IgG level < 6g/L at Screening.
9.
Absolute neutrophil count <1500 cells/mm3 at Screening.
10. 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.
11. Previous orbital irradiation or surgery for GO.
12. 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.
13. Have known autoimmune disease other than GO that would interfere with the course
and conduct of the study.
14. Medical history of primary immunodeficiency, T-cell or humoral, including common
variable immunodeficiency.
15. Have an active infection, a recent serious infection (i.e., requiring injectable
antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening.
16. History of or known infection with human immunodeficiency virus (HIV), hepatitis
B virus (HBV), hepatitis C virus (HCV), or Mycobacterium tuberculosis.
Participants must have negative test results for HBV surface antigen, HBV core
antibody, HCV antibody, HIV 1 and 2 antibodies, and a negative QuantiFERON®-
TB Gold test at Screening. Participants with an indeterminate QuantiFERON®-TB
Gold test result will be allowed one retest; if not negative on retesting, the participant
will be excluded.
17. 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.
18. 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


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
26 
19. Body Mass Index (BMI) at Screening ≥ 35 kg/m2.
20. Use of investigational drug within 3 months or 5 half-lives of the drug (whichever is
longer) before Screening.
21. Currently participating or has participated in another GO clinical study within 28
days prior to signing the informed consent form.
22. 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.
23. Participant has received a transfusion of any blood or blood products within 60 days
or donated plasma within 7 days prior to baseline.
24. 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.
25. Pregnant or lactating females as determined by positive serum or urine human
chorionic gonadotropin test at screening or baseline.
26. Participant has had their spleen removed.
27. 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 Clinical 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). 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
27 
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 at least 4 weeks before Screening.
•
Sterilized male participants who have had vasectomy with documented
azoospermia post procedure can be included.
•
Non-sterilized male participants who are sexually active with a female partner of
childbearing potential must use effective method of double barrier contraception.
Male participants practicing true sexual abstinence (when this is in line with the
preferred and usual lifestyle of the participant) can be included. In addition, male
participants must be advised not to donate sperm during this period from signing
of Informed Consent Form (ICF), throughout the duration of the study, and for 90
days after the last administration of study drug.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring participants understand how to properly use these methods of contraception. 
Participants must be completely informed of the unknown risks of pregnancy and agree 
not to become pregnant during the time they are participating in this study. If there is any 
question that a participant will not be reliable in the use of appropriate contraceptive 
methods, they should not be entered into the study. 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
28 
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”. 
 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
29 
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 a SAE: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)> 8 x 
upper limit of normal (ULN); or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international 
normalized ratio (INR) > 1.5 
• 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; 
• Alcoholic hepatitis; 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
30 
•
Non-alcoholic steatohepatitis; or
•
Autoimmune hepatitis.
If an alternative cause for hepatotoxicity is identified, then it should be determined (based 
on the severity of the hepatotoxicity or event) whether Study Treatment should be 
withheld or permanently discontinued as appropriate for the safety of the participant. 
6.8.3. 
QTc Withdrawal Criteria 
•
QTc prolongation defined as QTcF >500 ms, or an increase of QTcF >60 ms above
baseline on the 12-lead ECG, confirmed (persistent for >5 minutes) on repeated 12-
lead ECGs
6.8.4. 
Albumin Monitoring Criteria 
In addition to lowering IgG, treatment with RVT-1401 is also expected to reduce 
albumin levels (Section 3.2.3.3).  The site will utilize the following criteria to inform 
study drug discontinuation: 
•
Grade 3-4 (albumin levels are <2 g/dL): discontinue study drug
•
Grade 2 (albumin levels <3-2 g/dL): study drug should be interrupted or
discontinued if there are accompanying clinical signs and/or symptoms (edema,
hypotension, etc) attributable to decreased albumin.


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
31 
6.9. 
Toxicity Management Criteria 
6.9.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and Site 
Reactions) 
The severity of each AE will be graded and managed according to the criteria in Table 6. 
Table 6 
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 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
32 
Injection Site Reactions 
Injection site evaluations will be made by clinical staff following administration of RVT-
1401 as described below.  Additional details related to the specific injection site location 
will be included within the 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 7. 
Table 7: 
Criteria for Determining the Grade/Severity of Injection Site 
Reactions 
Grade 
Criteria 
1/Mild 
Tenderness with or without associated symptoms (e.g., warmth, 
erythema, itching) 
2/Moderate 
Pain; lipodystrophy; edema; phlebitis 
3/Severe or medically significant 
Ulceration or necrosis; severe tissue damage; operative
intervention indicated 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: 
June 14, 2010). 
6.9.2. 
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. 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
33 
7.
STUDY TREATMENT
7.1. 
Investigational Product
The term study treatment is used throughout the protocol to describe RVT-1401.
Study Treatment Name: 
RVT-1401 
Supplier: 
Dosage formulation: 
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: 1 mL RVT-1401 in one syringe for a total of 2 mL 
Route of Administration 
SC injection 
Dosing instructions: 
The detailed methods are indicated in the Pharmacy Manual. 
Participants will be closely monitored for reactions for up to 1 hr 
post-dose before they leave the clinic. 
Dose Preparation 
The preparation procedure and expiry details will be included in 
the Pharmacy manual/product label. 
7.2. 
Treatment Assignment 
All participants will receive open label RVT-1401 for 6 weeks (680 mg/weekly for 2 
weeks followed by 340 mg/weekly for 4 weeks). 
. 
7.3. 
Blinding 
This will be an open-label study.  
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.  
Doses will be prepared by the 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 clinic staff.  
See Pharmacy Manual for exact instructions on dose preparation. 
All labels will meet all local applicable requirements and Annex 13 of Good 
Manufacturing Practices: Manufacture of investigational medicinal products (July 2010) 
and/or other local regulations as applicable. 


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
34 
7.5. 
Preparation/Handling/Storage/Accountability 
A description of the methods and materials required for preparation will be detailed in the 
SRM. 
•
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.
•
The Pharmacist or designee is responsible for study treatment accountability,
reconciliation, and record maintenance (i.e. receipt, reconciliation and final
disposition records).
•
Under normal conditions of handling and administration, study treatment is not
expected to pose significant safety risks to site staff.  In the case of unintentional
occupational exposure notify the 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 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 delivered to the Principal Investigator or designee to administer the dose, 
under medical supervision. The date and time of each dose administered along with the 
location of each injection will be recorded in the source documents.  The location and 
study participant identification will be confirmed at the time of dosing by a member of 
the study site staff other than the person administering the study treatment.  
7.7. 
Treatment of Study Treatment Overdose 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose the Investigator or treating physician should: 
•
contact the Medical Monitor immediately,
•
closely monitor the participant for AEs/SAEs and laboratory abnormalities.
•
obtain a plasma sample for PK analysis within 2 days from the date of the last dose
of study treatment if requested by the Medical Monitor (determined on a case-by-
case basis)


Immunovant Sciences GmbH RVT-1401-1002, Amendment 03, Version 4.0 
 
 
Confidential 
35 
• 
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. 
 
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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
36 
8.1. 
Time and Events Table 
Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 3-6 
weeks 
Day 1 
(Baseline) 
Day 
3 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
Time Window 
(days) 
+1
day
+1
day
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1
day
+1
day
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 
days 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X 
X 
Demographics, 
medical history, 
and smoking 
status 
X 
Height 
X 
Body weight 
X 
X 
Complete physical 
examination 
X 
X 
Brief physical 
examination 
X 
X 
Ophthalmic 
examination 
X 
X 
X 
X 
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 
X 
X 
12-lead
Electrocardiogram2
X 
X 
X 
X 
X 
X 
X 
Pregnancy test3 
(females) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral Serology 
X 
QuantiFERON® – 
TB GOLD 
X 
Urinalysis2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry 
and hematology2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
37 
Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 3-6 
weeks 
Day 1 
(Baseline) 
Day 
3 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
Time Window 
(days) 
+1
day
+1
day
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1
day
+1
day
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 
days 
Serum 
complement 
(CH50, C3)2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulins 
(IgM, IgA)2
X 
X 
X 
X 
X 
X 
X 
X 
Anti-TPO and anti-
thyroglobulin 
antibodies2 
X 
X 
X 
X 
X 
TSH, Free T3, 
Free T42 
X 
X 
X 
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 
X 
X 
X 
X 
Anti-TSHR (Cell 
based) 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-IGF-1R2 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RVT-1401 PK 
sampling2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total IgG2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobins 
(IgG subclasses)2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gene Expression 
Analysis2 
X 
X 
X 
X 
X 
X 
Pro-Inflammatory 
Biomarker 
Multiplex2 
X 
X 
X 
X 
X 
X 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
38 
Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 3-6 
weeks 
Day 1 
(Baseline) 
Day 
3 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
Time Window 
(days) 
+1
day
+1
day
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1
day
+1
day
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 
days 
Receptor 
Occupancy2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti- RVT-
1401antibody2,4 
X 
X 
X 
X 
X 
X 
Nab Assessment2 
X 
X 
X 
X 
X 
X 
Drug 
administration 
X 
X 
X 
X 
X 
X 
Injection site 
reactions5 
X 
X 
X 
X 
X 
X 
Clinical Activity 
Score (CAS) 6 
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 
Motility6 
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 
GO-QOL6 
X 
X 
X 
X 
X 
X 
X 
X 
External 
Photographs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Orbital CT Scan8 
X 
X 
X 
X 
Lid retraction 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
Satisfaction 
Questionnaire 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
39 
Screening1 
Treatment Period 
Week 1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
Withdrawal 
Visit 
Study Timepoint 
(Weeks) 
Within 3-6 
weeks 
Day 1 
(Baseline) 
Day 
3 
Day 
5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
Time Window 
(days) 
+1
day
+1
day
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1
day
+1
day
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 
days 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1.
Screening can take place over multiple days.
2.
Vitals, ECG and blood draws for safety, PK, and PD assessment will be collected pre-dose on dosing days where specified. 
3.
Pregnancy tests will be collected pre-dose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening follow up, and Early Withdrawal. 
4.
Participants positive for anti- RVT-1401 antibody at Week 18 will be requested to return at approximately 6, 9, and 12 months post-dose for additional samples or until their result is no longer positive. However, for 
purposes of safety follow-up and database lock participation ends at the Week 18 visit. 
5.
Local injection site reactions will be assessed at approximately 10 minutes post dose and participants will be monitored for up to 1 hour post dose. 
6.
GO assessments will be assessed pre-dose when collected on dosing days. 
7.
Photographs will be assessed post each dose. 
8.
The baseline orbital scan should be scheduled once all entry criteria haven been met. Scans can be performed within +/- 7 days of the scheduled visit.


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
40 
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 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. 
8.3.3. 
Vital Signs 
Vital signs will be measured in semi-supine position and will include temperature, 
systolic and diastolic blood pressure and pulse rate.  
8.3.4. 
Electrocardiogram (ECG) 
ECGs will be measured in semi-supine position. 
Twelve-lead ECGs will be obtained during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.  
Refer to Section 6.8.3 for QTcF criteria and additional QTcF readings that may be 
necessary. 
 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
41 
 
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 
White Blood Cell (WBC) Count 
(absolute)  
Mean 
corpuscular 
hemoglobin 
(MCH) 
Lymphocytes 
Reticulocyte Count 
Mean 
corpuscular 
hemoglobin 
concentration 
(MCHC) 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
Clinical Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
AST (SGOT) 
Total and direct bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose fasting 
[on Day 1 
(baseline) and 
Week 7 only] 
Total carbon 
dioxide (CO2 ) 
Gamma 
glutamyltransferase 
(GGT) 
Albumin 
Sodium 
Calcium 
(corrected) 
Alkaline phosphatase 
Total Protein 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
42 
Serum 
complement 
(CH50, C3) 
Immunoglobulin 
M (IgM) 
Immunoglobulin A 
(IgA) 
TSH, Free T3, Free T4 
Immunoglobulin G 
(IgG) 
 
 
 
  NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Appendix 2: Liver Safety Required Actions and Follow up Assessments.  
Routine Urinalysis 
Specific gravity, pH 
glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 
 
Other tests 
Viral Serology [HIV1/HIV2, Hepatitis B (HBsAg), Hepatitis B (Core antibody), Hepatitis C (Hep C 
antibody] 
FSH (as needed for confirmation of postmenopausal status) 
Pregnancy Tests:  serum test at screening and follow up and urine dipstick pre-dose and 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 site (detailed 
in the SRM). 
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.   


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
43 
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 (detailed 
in the SRM).  If Anti-RVT-1401 antibody titers are detected, they will be further 
characterized using a validated cell based Nab assay 
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 
Blood samples for exploratory biomarker analysis will be collected at times indicated in 
the Time and Event Table (Section 8.1).  
Exploratory Biomarkers 
Gene Expression Analysis 
Pro-inflammatory Biomarker Multiplex 
Receptor Occupancy 
Anti-TPO 
Anti-thyroglobulin 
Anti-IGF-1R 
Anti-TSHR (ratio of total to Activating – cell based) 
Anti-IGF-1R (ratio of total to Activating – cell based) 
The actual date and time of each blood sample collection will be recorded. The timing of 
samples may be altered and/or samples may be obtained at additional time points to 
ensure thorough biomarker assessment. These samples may be used for the analysis of 
additional exploratory biomarkers. Samples will be collected, labelled, stored, and 
shipped as detailed in the SRM or lab manual. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
44 
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 ≥ 4.  At Screening, the 7-item scale and at all other visits the 10-item scale will 
be utilized.  Specific details on scoring the CAS can be found within the SRM. 
8.4.2. 
Proptosis 
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). 
8.4.3. 
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). 
8.4.4. 
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). 
8.4.5. 
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. 
8.4.6. 
External Photographs 
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 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
45 
8.4.7. 
Orbital CT Scan  
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. Details can be found within the SRM. 
 
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 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. 
Grade IV – Constant diplopia: This is present on straight and level gaze but is not 
correctable with prisms.   
Specific details can be found within the SRM. 
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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
46 
10.
STATISTICAL CONSIDERATIONS AND DATA
ANALYSES
10.1. 
Sample Size Considerations
The sample size for this study was not determined using statistical methods.  The sample 
size was chosen based on clinical and recruitment considerations.    
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.   
This will be the population for all PD parameters. 
Safety Population 
All participants who enroll in the study and receive at least one dose of study treatment 
will be included in the Safety Population.  Participants will be summarized by actual 
treatment group. 
This will be the population for the safety analyses, as well as for presentation and 
summarization of baseline/demographic characteristics. 
Pharmacokinetic Population 
The PK Population will include all participants who undergo plasma PK sampling and 
have evaluable concentration-time data for analysis. 
Pharmacodynamic Population 
The PD population will include all participants who have baseline measure, along with a 
post baseline measure and receive at least one dose of study treatment 
10.2.2. 
Interim Analysis 
An interim analysis will occur after the last subject completes the Week 7 visit of the 
study.  All endpoints will be evaluated for this analysis.    Since this analysis is occurring 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
47 
at the end of the treatment phase, no adjustments of the alpha level are necessary.  This 
analysis will serve as the primary analysis and a second analysis will occur, summarizing 
the endpoints after the treatment-free phase. 
10.3. 
Final Analysis 
Final analysis will be performed after the completion of the study and the database is 
locked. 
Data will be listed and summarized.  Treatment will be assigned based on the dosing 
schedule and included in the data listings.  Listings will be sorted by participant, day, and 
time; summaries will be presented by treatment, day, and time.  
Unless stated otherwise, descriptive summaries for continuous variables will include n, 
mean, standard deviation (SD), median, first and third quartiles, minimum, and 
maximum.  The geometric mean with associated 95% confidence interval (CI), and the 
between-participant CV (%CVb) for PK parameters only will also be included.  For 
categorical variables, n and percent will be used as summary statistics. Baseline is the last 
available assessment prior to time of the first dose unless it is specified otherwise.  If 
there are multiple assessments collected on the same scheduled time, the average of these 
assessments will be used.  For tabulated safety summaries, only the scheduled 
assessments will be included in the summary tables. 
Version 9.4 or higher of the SAS system will be used to analyze the data as well as to 
generate tables, figures, and listings. 
Complete details will be documented in the Statistical Analysis Plan (SAP). 
10.3.1. 
Primary Endpoint  
The primary endpoints will be defined as follows: 
1.) 
the percentage change from Baseline in total IgG and IgG subclasses (1-4) at 
Week 7.  
2.) 
change from baseline in levels of anti-TSHR antibodies at Week 7 
Each of the endpoints will be summarized at Week 7 using a 6-number summary 
including the sample size, mean, standard deviation, median, minimum and maximum 
values 
10.3.2. 
Secondary Endpoints 
Analysis of the secondary endpoints for efficacy: 
•
Change from baseline in proptosis will include the actual value, change from
baseline and percentage change from baseline summarized by visit using the n,
mean, SD, median, first and third quartiles, minimum, and maximum values.


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
48 
•
The number of proptosis responders and the percentage will be summarized using
those participants who had a value at each time point.
•
Immunogenicity determined by number of participants with positive anti-RVT-
1401 antibodies and characterization of any anti-RVT-1401 antibodies to confirm
neutralization potential at Week 7.
10.3.3. 
Exploratory Endpoints 
For each of the continuous exploratory endpoints, the actual value, change from baseline 
and percentage change from baseline for all exploratory endpoints will be summarized by 
visit and treatment group using the n, mean, SD, median, first and third quartiles, 
minimum, and maximum values.   
For categorical exploratory 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.   
10.3.4. 
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. 
10.3.5. 
Pharmacokinetic Analyses 
Serum compound concentration-time data will be analyzed by non-compartmental 
methods with Phoenix WinNonlin or other PK software programs.  Calculations will be 
based on the actual sampling times recorded during the study.  From the plasma 
concentration-time data, the following primary PK parameters will be determined (if 
possible):  
AUC(0-t), Cmax, tmax, t1/2 
Additional PK parameters may be calculated.  PK data will be presented in graphical and 
tabular form and will be summarized descriptively.   


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
49 
10.3.6. 
Pharmacodynamic Analyses 
All participants in the ITT population will be included in the summaries of PD data.  The 
actual value, change from baseline and percentage change from baseline for all PD 
parameters will be summarized by visit and treatment group using the n, mean, SD, 
median, first and third quartiles, minimum, and maximum values.  Statistical testing may 
be performed between the two treatment groups using mixed models.  Details will be 
provided in the Statistical Analysis Plan.   
Serum IgG, IgG subclass (1-4), and anti-TSHR and anti-IGF-1R 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.   
10.3.7. 
Other Analyses 
The analysis of the exploratory endpoints will include all participants in the ITT 
population.   
Gene expression data will be analyzed using NanoString nSolver software or other 
appropriate method. Gene expression data will be presented in graphical and tabular form 
and summarized descriptively. Serum cytokine and chemokine concentrations will be 
analyzed with High Sensitivity Bead‐Based Multiplex Assays using the Luminex 
technology.  Cytokine/chemokine data will be presented in graphical and tabular form 
and will be summarized descriptively.  
Receptor occupancy will be assessed by flow cytometry and analyzed using FlowJo v10 
or higher. Receptor occupancy data will be presented as contour plots with 5% outliers, 
as well as graphical and tabular form and will be summarized descriptively.   
 
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. 
 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
50 
11.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a participant or clinical investigation 
participant, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. 
Events meeting the definition of an AE include but are not limited to: 
•
Any clinically significant, new or worsened, abnormal laboratory test results
(hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g.,
ECGs, radiological scans, vital signs measurements). Clinical significance is
determined based on the medical and scientific judgement of the Investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including an
increase in frequency and/or intensity of the condition.
•
Signs, symptoms, or the clinical sequelae of a suspected interaction (e.g. with
medications or food).
•
Signs, symptoms, or the clinical sequelae of a overdose of either investigational
product or a concomitant medication (overdose without an AE should be reported
as a protocol deviation).
Events that do not meet the definition of an AE include: 
•
Anticipated day-to-day fluctuations of pre-existing condition(s), including the
disease under study, that do not represent a clinically significant exacerbation or
worsening.
•
Abnormal or worsening laboratory, imaging, or other safety findings that are not
clinically significant.
•
Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition
that leads to the procedure is an AE.
•
Situations where an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
11.2. 
Definition and Reporting of Serious Adverse Events 
Serious adverse events must be marked as a SAE within the AE eCRF form, which will 
send an immediate auto notification to 
 and the Medical Monitor.  
If the eCRF is not available, the site must email 
and the Medical Monitor within 24 hours 
of the study site personnel’s knowledge of the event.  
A SAE is any untoward medical occurrence that, at any dose: 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
51 
• 
Results in death 
• 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization 
Hospitalization planned prior to signing the informed consent is not considered an SAE.  
Surgeries and other interventions that were under consideration prior to signing the 
informed consent are not considered an SAE if the underlying condition has not changed 
from baseline. 
“Hospitalization” includes admission to the hospital of any duration.  It does not include 
emergency room visits. Complications that occur during hospitalization are AEs and are 
SAEs if they prolong hospitalization or fulfill any other serious criteria. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
• 
Results in disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may jeopardize the subject or may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definition. Examples of such events are allergic bronchospasm, blood dyscrasias or 
convulsions where treatment prevents the need for hospitalization. 
 
The following should always be considered serious:  invasive or malignant cancers, and 
development of drug dependency or drug abuse. 
  
11.3. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
AEs will be collected from the time of informed consent until the follow-up contact, 
at the timepoints specified in the Section 8.1, Time and Events Table. 
• 
Medical occurrences that begin prior to any 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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
52 
•
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?”
•
“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:  


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
53 
Criteria for Determining the Grade/Severity of Adverse Event Terms 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated  
2/Moderate 
Minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily 
living  
3/Severe or medically 
significant  
Not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living  
4/Life-threatening 
Life threatening consequences; urgent intervention 
indicated  
5/Death 
Death related to adverse event 
Adverse event severity should be recorded in the appropriate section of the AE eCRF and 
in the participant’s source documents. 
11.6. 
Assessing Causality of AEs and SAEs 
Regulatory authorities require that both investigator and sponsor assess whether there is a 
reasonable possibility that the study treatment caused each AE.  This assessment requires 
careful medical consideration of each event in relationship to the timing of drug 
administration, the presence of other factors which may have caused the event 
(underlying illness, concomitant medication, complications, exposure to other toxins or 
allergens, environmental factors, etc.), and the effects of stopping and/or restarting the 
study treatment.  The following definitions are to be used for the relationship of the AE to 
Study Treatment: 
The investigator will assess the causality of each reported AE as follows: 
•
Probably related: an AE occurring at a reasonable time following administration of a
drug, where other causes are unlikely, there is evidence to suggest that the drug
caused the event, and/or where the event recurs after reintroduction of the drug
(without other explanation for the recurrence).
•
Possibly related: an AE occurring at a reasonable time following administration of a
drug and for which there is a reasonable possibility that the drug caused the event,
e.g. there is some evidence to suggest a causal relationship.
•
Not related: an AE with poor or no relationship to the timing of drug administration,
or where another cause such as underlying disease, complications, or other
medications reasonably explains the event, or where the event does not recur after
continued administration or reintroduction of the drug for an adequate period.
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 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
54 
AEs will be followed until resolution, or until the condition stabilizes or until the 
participant is lost to follow-up. Where necessary, repeated laboratory testing should be 
requested to confirm resolution. Ongoing AEs where no further information is likely to 
be available may be closed after consultation between the Sponsor and Medical Monitor. 
11.8. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of SAEs/adverse event of special 
interest (AESIs) is essential so that legal obligations and ethical responsibilities towards 
the safety of subjects and the safety of a product under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. The 
Sponsor will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC and Investigator. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and are forwarded to the 
Investigators in accordance with local regulations. 
The Investigator who receives an Investigator safety report describing a SAE(s)/AESI(s) 
or other specific safety information (e.g., summary or listing of SAEs) from the Sponsor 
will file it with the IB and will notify the IRB/IEC, as appropriate according to local 
requirements. 
11.9. 
Overdose 
Overdose is less likely in a study where the drug is administered within a clinical unit by 
a healthcare provider.  If there are no symptoms of an overdose, it may be recorded as a 
protocol deviation.  Overdose with symptoms should be recorded as an AE or SAE, as 
appropriate. 
12.
PREGNANCY REPORTING
All female participants will be tested for pregnancy prior to study drug dosing. 
Participants testing positive for pregnancy will be ineligible for study participation. 
Any pregnancies in a subject, or the partner of a subject, between the time of informed 
consent and study termination must be reported to the Sponsor within 24 hours of 
learning of the pregnancy. Information on the status and health of the mother, the 
pregnancy and its outcome, and the child will be recorded on the form provided. In case 
of a partner pregnancy, the partner of the study subject will be asked to sign a partner 
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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
55 
13.
RESPONSIBILITIES
13.1. 
Principal Investigator Responsibilities 
13.1.1. 
Good Clinical Practice (GCP) 
The Principal Investigator will ensure that this study is conducted in accordance with the 
principles of the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, 
Hong Kong, and South Africa), International Conference on Harmonisation (ICH) 
guidelines, or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the study participant.  For studies 
conducted under a United States IND, the Principal Investigator will ensure that the basic 
principles of “Good Clinical Practice,” as outlined in 21 Code of Federal Regulations 
(CFR 312), subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 
1998, and 21 CFR, part 56, 1998, are adhered to.  These standards are consistent with the 
requirements of the European Community Directive 2001/20/EC. 
Since this is a “covered” clinical trial, the Principal Investigator will ensure that 21 CFR, 
Part 54, 1998, is adhered to; a “covered” clinical trial is any “study of a drug or device in 
humans submitted in a marketing application or reclassification petition participant to this 
part that the applicant or FDA relies on to establish that the product is effective 
(including studies that show equivalence to an effective product) or that make a 
significant contribution to the demonstration of safety.”  This requires that Principal 
Investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the Sponsor, or proprietary interests in the drug being 
studied.  This documentation must be provided before participation of the Principal 
Investigator and any sub-investigator.  The Principal Investigator and sub-investigator 
agree to notify the Sponsor of any change reportable interests during the study and for 
one year following completion of the study. Study completion is defined as the date that 
the last participant has completed the protocol defined activities. 
13.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval 
This protocol and any accompanying material to be provided to the participant (such as 
informed consent form, advertisements, participant information sheets, or descriptions of 
the study used to obtain informed consent) will be submitted by the Principal Investigator 
to an IRB or IEC.  Approval from the IRB or IEC must be obtained before starting the 
study and should be documented in a letter to the Principal Investigator specifying the 
protocol number, protocol version, protocol date, documents reviewed, and date on which 
the committee met and granted the approval. 
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: 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
56 
•
Providing written summaries of the status of the study to the IRB/IEC on an
annual basis or more frequently in accordance with the requirements, policies, and
procedures established by the IRB/IEC.
•
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
procedures established by the IRB/IEC.
13.1.3. 
Informed Consent 
The Principal Investigator or designee is responsible for obtaining written informed 
consent from each individual participating in this study after adequate explanation of the 
aims, methods, objectives, and potential hazards of the study and before undertaking any 
study-related procedures. The Principal Investigator must utilize an IRB or IEC-approved 
consent form for documenting written informed consent. Each informed consent will be 
appropriately signed and dated by the participant and the person obtaining consent.  
Participants must be re-consented to continue their participation in the study if a protocol 
amendment is made that substantially alters the study design or the potential risks or 
burden to the participant. 
13.1.4. 
Confidentiality 
The Principal Investigator must assure that participants’ anonymity will be strictly 
maintained and that their identities are protected from unauthorized parties.  Only 
participant number (i.e., not names) and month and year of birth (as allowed) should be 
recorded on any form or biological sample submitted to the Sponsor, IRB or IEC, or 
laboratory. The Principal Investigator must keep a screening log showing codes, names, 
and addresses for all participants screened and for all participants enrolled in the trial. 
The Principal Investigator must keep a screening log showing codes, names, and 
addresses for all participants screened and for all participants enrolled in the trial. 
The Principal Investigator agrees that all information received from the Sponsor, 
including but not limited to the IB, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of the Sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to 
any third party (except employees or agents directly involved in the conduct of the study 
or as required by law) without prior written consent from the Sponsor. The Principal 
Investigator further agrees to take all reasonable precautions to prevent the disclosure by 
any employee or agent of the study site to any third party or otherwise into the public 
domain. 
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, 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
57 
staff curriculum vitae and authorization and training forms, and other appropriate 
documents and correspondence. 
The required source data should include the following for each participant: 
•
participant identification (name, month and year of birth, gender);
•
documentation that participant meets eligibility criteria, i.e., history, physical
examination, and confirmation of diagnosis (to support inclusion and exclusion
criteria);
•
participation in trial (including trial number);
•
trial discussed and date of informed consent;
•
dates of all visits;
•
documentation that protocol specific procedures were performed;
•
results of efficacy parameters, as required by the protocol;
•
start and end date (including dose regimen) of trial medication (preferably drug
dispensing and return should be documented as well);
•
record of all 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.  


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
58 
When source documents are required for the continued care of the participant, 
appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the 
Sponsor for a period up to 10 years for purposes of this study. 
13.1.6. 
Electronic Case Report Forms (eCRF) 
For each participant enrolled, an eCRF must be completed and signed by the Principal 
Investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection.  This also applies to records for those participants who fail to complete the 
study (even during the screening period if an eCRF was initiated).  If a participant 
withdraws from the study, the reason must be noted on the eCRF.  If a participant is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome. 
13.1.7. 
Drug Accountability 
The Principal Investigator or designee (i.e., pharmacist) is responsible for ensuring 
adequate accountability of all used and unused investigational product.  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. 
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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
59 
13.2. 
Sponsor Responsibilities 
13.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study 
participants, may be made only by the Sponsor. 
13.2.2. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies).  The 
Sponsor will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated 
report may be prepared in certain cases. 
13.2.3. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of participants begins.  Results will be posted as required. 
13.3. 
Joint Investigator/Sponsor Responsibilities 
13.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have 
direct access to the Principal Investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on them.  The monitor should have 
access to any participant records needed to verify the entries on the eCRFs.  The Principal 
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 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
60 
Principal Investigator will assure that adequate consideration is given to the protection of 
the participants’ interests. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
61 
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. 
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. 
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. 
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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
62 
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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
63 
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 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
64 
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 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
65 
Trademark Information 
Trademarks of Immunovant Sciences 
GmbH 
Trademarks not owned by Immunovant 
Sciences GmbH 
WinNonlin 
SAS 
FlowJo 
nSolver 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
66 
15.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments 
Liver chemistry stopping criteria have been designed to assure participant safety and to 
evaluate liver event etiology (in alignment with the FDA Drug-induced Liver Injury: 
Premarketing Clinical Evaluation). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Liver Safety Process 
The procedures listed below are to be followed if a participant has ALT, bilirubin and/or 
INR elevations that meet the definition of a SAE (as defined in Section 11): 
• 
Notify the medical monitor within 24 hours of learning of the abnormality to confirm 
follow-up. 
• 
Complete the liver event case report forms.  
• 
Upon completion of the safety follow-up withdraw the participant from the study 
unless further safety follow up is required. 
• 
Make every reasonable attempt to have participants return to the clinic within 24 
hours for repeat liver chemistries, additional testing, and close monitoring (with 
specialist or hepatology consultation recommended). 
• 
Monitor participants twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
• Obtain viral hepatitis serology including: 
• 
Hepatitis A IgM antibody. 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM).  
• 
Hepatitis C ribonucleic acid (RNA).   
• 
Cytomegalovirus IgM antibody. 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing). 
• 
Hepatitis E IgM antibody. 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Assess eosinophilia 
• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
on the AE eCRF. 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
eCRF. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
67 
•
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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
68 
15.3. 
Appendix 3: Protocol Amendment Summary of Changes 
Amendment 03 Changes 
Rationale for the amendment: 
This protocol has been amended to shift the assessment of anti-IGF-1R antibodies to an 
exploratory endpoint since the exact role of any antibodies against IGF-1R is still being 
investigated.  Therefore, the presence of anti-IGF-1R antibodies was removed as an 
inclusion criterion and the change in levels of anti-IGF-1R antibodies moved to 
exploratory.  
In addition, the definition for proptosis response was updated so that subjects with <2 
mm of improvement will no longer be considered a responder, in line with the 
standardized definition used in the literature.    
The Ophthalmic Exam was updated to allow the ophthalmologist to conduct additional 
investigations if needed, based on their judgement of whether significant negative 
changes are being observed in the study. 
Measurements of proptosis and motility were added to the Graves’ Ophthalmopathy 
Assessments. 
A window of +/- 1 week was added to the collection of the CT orbital scan to allow 
flexibility for scheduling. 
Other administrative changes were also made. 
Change #1:  Section 2 Protocol Summary for RVT-1401-1002, Section 4 Objectives 
and Endpoints, and Section 10.3.1 Primary Endpoint 
Assessing the change in serum levels of anti-IGF-1R antibodies was moved from a 
primary objective and endpoint to an exploratory objective and endpoint  
Change #2:  Section 2 Protocol Summary for RVT-1401-1002, Section 4 Objectives 
and Endpoints 
The following was removed from the secondary endpoint for proptosis: 
For subjects with proptosis < 3 mm at baseline, response will be defined as returning to 
normal limits for race and gender. 
Change #3: Section 6.2 Inclusion Criteria #6 
Original text: 
Documented evidence at Screening of detectable autoantibodies (anti-TSHR-Ab, anti-
IGF-1R-Ab, or both). 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
69 
Revised text:  
Documented evidence at Screening of detectable autoantibodies (anti-TSHR-Ab). 
Change #4: Section 6.3 Exclusion Criteria #5 
Original text: 
Use of selenium 3 months prior to Baseline and use during the clinical trial (this includes 
multivitamins that include selenium). 
Revised text: 
Use of selenium 3 weeks prior to Baseline and use during the clinical trial (multivitamins 
that include selenium are allowed). 
Change #5: Section 8.1 Time and Events Table 
Added proptosis and motility assessments to the Time and Events Table 
Change #6: Section 8.1 Time and Events Table, Footnote #8 
Original text: 
The baseline orbital scan should be scheduled once all entry criteria haven been met.  
This scan can be performed during the screening period or up to 2 days post the first 
dose. 
Revised text: 
The baseline orbital scan should be scheduled once all entry criteria haven been met. 
Scans can be performed within +/- 7 days of the scheduled visit.   
Change #7: Section 8.3.2 Ophthalmic Exams 
Original 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).   
Revised 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. 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
70 
Change #8: Section 8.3.8 Pharmacodynamics 
Original text: 
Pharmacodynamic Markers 
Total IgG, and differentiation by class: 
IgG subclasses (IgG1, 2, 3, and 4)  
Anti-TSHR (Total & Activating) 
Anti-IGF-1R (Total & Activating) 
 
Revised text: 
Pharmacodynamic Markers 
Total IgG, and differentiation by class: 
IgG subclasses (IgG1, 2, 3, and 4)  
Anti-TSHR  
 
Change #9: Section 8.3.9 Exploratory Biomarkers 
Original text: 
Exploratory Biomarkers 
Gene Expression Analysis 
Pro-inflammatory Biomarker Multiplex 
Receptor Occupancy 
Anti-TPO 
Anti-thyroglobulin 
 
Revised text: 
Exploratory Biomarkers 
Gene Expression Analysis 
Pro-inflammatory Biomarker Multiplex 
Receptor Occupancy 
Anti-TPO 
Anti-thyroglobulin 
Anti-IGF-1R 
Anti-TSHR (ratio of total to Activating – cell based) 
Anti-IGF-1R (ratio of total to Activating – cell based) 
 
Change #10: Section 8.4 Graves’ Ophthalmopathy Assessments- Added Proptosis 
and Motility Assessments  
Added text: 
Section 8.4.2 Proptosis 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
71 
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). 
Section 8.4.3 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). 
 
Amendment 02 Changes 
Rationale for the amendment: 
This protocol has been amended based on Health Canada review and feedback.  
Additional administrative changes were also made as noted below. 
Change #1:  Section 3.3.1 Risk Assessment Table, First Potential Risk of Clinical 
Significance, Monitoring and Stopping Criteria or Management Criteria 
Original text: 
Participants will be closely monitored for reactions for up to 1 hr post-dose before they 
leave the clinic. If during the course of study administration, the participant experiences a 
drug related AE of Grade 3 (severe) or greater severity, study drug administration will be 
stopped.  
Revised text: 
Participants will be closely monitored for reactions for up to 1 hr post-dose before they 
leave the clinic. If during the course of study drug administration, the participant 
experiences a drug related AE of Grade 3 (severe) or greater severity, study drug 
administration will be stopped.  
Change #2:  Section 5.2 Study Schematic 
Corrected an error noted within the schematic 
Original schematic: 




Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
73 
This protocol has been amended based on emerging data involving transient albumin 
reductions within healthy subjects at the 680 mg RVT-1401 dose.  While the reductions 
were not considered clinically significant nor were they associated with any signs or 
symptoms, a decision was made to revise the dosing regimen to one that would maintain 
serum albumin levels within normal limits for most participants and still maintain IgG 
reduction at a potentially therapeutic level. 
Due to the lack of placebo response on proptosis improvement that has been observed in 
previous clinical studies, the endpoints related to proptosis have been moved from 
exploratory to secondary objectives and the study has been updated from Phase 1b to 
Phase 2a.  
Change #1:  Title Page, Sponsor Signature Page, Section 2 Protocol Summary, 
Section 5.1 Overall Study Design 
Updated the study phase from Phase 1b to Phase 2a  
Change #2: Section 2 Protocol Summary and Section 4 Objectives and Endpoints 
Moved exploratory objectives and endpoints related to proptosis to secondary objectives 
and endpoints 
Previous Exploratory Objectives 
To examine the effect of RVT-1401 on mean change in proptosis 
To examine the effect of RVT-1401 on proptosis responder rate  
Previous Exploratory Endpoints 
Change from baseline in proptosis  
Proptosis responder rate (defined as percentage with ≥2 mm reduction in study eye 
without deterioration (≥2 mm increase) in fellow eye). For subjects with proptosis < 3 
mm at baseline, response will be defined as returning to normal limits for race and 
gender.    
Revised Secondary Objectives 
To examine the effect of RVT-1401 on mean change in proptosis 
To examine the effect of RVT-1401 on proptosis responder rate  
Revised Secondary Endpoints 
Change from baseline in proptosis  
Proptosis responder rate (defined as percentage with ≥2 mm reduction in study eye 
without deterioration (≥2 mm increase) in fellow eye). For subjects with proptosis < 3 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
74 
mm at baseline, response will be defined as returning to normal limits for race and 
gender.    
Change #3: Section 3.2.2 Dose Rationale, 3rd and 4th paragraphs 
Original text: 
RVT-1401 will be administered as a weekly 680 mg SC injection. This dose represents 
the upper limit of doses which can be administered as two SC injections (680 mg) per 
week.  In the proposed study, weekly administration of 680 mg SC dose is predicted to 
result in a maximum IgG reduction of ~75-80% following the 3rd or 4th dose and would 
be maintained following the 6th dose before rising back to baseline over the next 6 to 8 
weeks.  
Since a weekly 680 mg dose of RVT-1401 produces 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 the highest dose that can be administered via 2 SC 
injections and which has shown to be well-tolerated while producing robust reductions in 
total IgG in healthy participants.      
Revised text: 
RVT-1401 will be administered as a weekly 680 mg SC injection for two weeks followed 
by weekly 340 mg SC injection for four weeks. These doses represent the upper limit of 
RVT-1401 which can be administered as two SC injections (680 mg) and one SC 
injection (340 mg) per week.  In the proposed study, the first two weekly SC 
administrations of 680 mg is predicted to quickly reduce IgG to  ~64% below baseline 
and the following four weekly doses of 340 mg would maintain this level of IgG 
reduction before recovering back to baseline over the next 6 to 8 weeks.  This regimen 
would also be expected to maintain serum albumin levels within normal limits for most 
patients.  
This dosing regimen of RVT-1401 produces a significant reduction in total serum IgG 
within two weeks, which in GO patients would also include anti-TSHR IgG. Thus, 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 reduce serum IgG quickly with induction dosing 
and then maintain that reduction over the next 5 weeks.  The doses used in this regimen 
have been well-tolerated while producing robust reductions in total IgG in healthy 
participants.      
Change #4: Section 3.2.3.1 Clinical Experience: Safety, 1st paragraph 
Original text: 
RVT-1401 has been well tolerated.  As of the data cut-off of Nov 22, 2018, there were no 
serious adverse events (SAEs), no Grade 3 or 4 adverse events (AEs), and no withdrawals 


lmmunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
due to AEs. An SAE (Malpighian carcinoma neck) considered unrelated to study drng 
was received by the sponsor following the data cut-off (see fuvestigator's Brochme for 
description). 
Revised text: 
RVT-1401 has been well tolerated. There have been no Grade 3 or 4 adverse events 
(AEs) and no withdrawals due to AEs. An SAE (Malpighian carcinoma neck) considered 
unrelated to study drng was received by the sponsor following the data cut-off of Nov 22, 
2018 (see fuvestigator's Brochme for description). 
Change #5: Study Schematic, Figure 3 
Original: 
Figure 4 Study Design 
Screening 
Open-Label treatment 
-
·-
RVT-1401 680 mg 
C 
QJ 
N=S 
QJ 
V'l 
-
I Oy Oy I I 
BL 3 
S Wk 
Wk 
I I 
Week 
-3 to -6 
Revised: 
Figure 5 Study Design 
Screening 
 
-
-
1 
2 
Wk 
3 
Wk 
4 
Open-Label treatment 
RVT-1401 
I 
Wk 
5 
C: 
680 mg x 2 weeks + 340 mg x 4 weeks 
Q) 
Q) 
N=8 
-
I 
12 Week Follow Up 
lo!v olv I I I I I 
Wk 38 "°wk Wk Wk Wk 
Wk 
Jk 
6 
7 
8 
9 
10 
12 
14 
_j 
Wk 
Wk 
16 
18 
L__ 12 Week Follow Up _] 
Week 
-3 to-6 
day D)y I I
BL3 
Swk 
Wk 
I 
Wk 
3 
I I I olv olv I I I I I I
Wk 
Wk 
Wk 38 4¾ik Wk Wk Wk 
Wk 
Wk 
Wk 
Wk 
Confidential 
1 
2 
4 
5 
6 
7 
8 
9 
10 
12 
14 
16 
18 
75 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
76 
Change #6: Section 5.3 Treatment Arms and Duration 
Original text: 
Participants will receive RVT-1401 (680 mg), as two SC injections for 6 weeks. 
Revised text: 
Participants will receive RVT-1401 for 6 weeks (680 mg/weekly for 2 weeks followed by 
340 mg/weekly for 4 weeks). 
Change #7: Section 6.8.4 Albumin Monitoring Criteria 
Previous text: 
In addition to lowering IgG, treatment with RVT-1401 is also expected to reduce albumin 
levels (Section 3.2.3.3).  Since changes in albumin may potentially be unblinding, an 
unblinded medical monitor will review these laboratory data.  The unblinded medical 
monitor will utilize the following criteria to inform study drug discontinuation: 
•
Grade 3-4 (albumin levels are <2 g/dL): discontinue study drug
•
Grade 2 (albumin levels <3-2 g/dL): study drug should be interrupted or
discontinued if there are accompanying clinical signs and/or symptoms (edema,
hypotension, etc) attributable to decreased albumin.
Revised text: 
In addition to lowering IgG, treatment with RVT-1401 is also expected to reduce albumin 
levels (Section 3.2.3.3).  The site will utilize the following criteria to inform study drug 
discontinuation: 
•
Grade 3-4 (albumin levels are <2 g/dL): discontinue study drug
•
Grade 2 (albumin levels <3-2 g/dL): study drug should be interrupted or
discontinued if there are accompanying clinical signs and/or symptoms (edema,
hypotension, etc) attributable to decreased albumin.
Change #8: Section 7.1 Investigational Product 
Original text: 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
77 
The term study treatment is used throughout the protocol to describe RVT-1401.   
Study Treatment Name: 
RVT-1401 
Supplier: 
Dosage formulation: 
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 
Route of Administration 
SC injection 
Dosing instructions: 
The detailed methods are indicated in the Pharmacy Manual. 
Participants will be closely monitored for reactions for up to 1 hr 
post-dose before they leave the clinic. 
Dose Preparation 
The preparation procedure and expiry details will be included in 
the Pharmacy manual/product label. 
Revised text: 
The term study treatment is used throughout the protocol to describe RVT-1401.   
Study Treatment Name: 
RVT-1401 
Supplier: 
Dosage formulation: 
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: 1 mL RVT-1401 in one syringe for a total of 2 mL 
Route of Administration 
SC injection 
Dosing instructions: 
The detailed methods are indicated in the Pharmacy Manual. 
Participants will be closely monitored for reactions for up to 1 hr 
post-dose before they leave the clinic. 
Dose Preparation 
The preparation procedure and expiry details will be included in 
the Pharmacy manual/product label. 
Change #9: Section 7.2 Treatment Assignment 
Original text: 
All participants will receive open label RVT-1401 (680 mg), as two SC injections for 6 
weeks. 
Revised text: 
All participants will receive open label RVT-1401 for 6 weeks (680 mg/weekly for 2 
weeks followed by 340 mg/weekly for 4 weeks). 
Change #10: Section 8.3.10 Lid Retraction was moved to Section 8.4.2 with no 
revisions to the text 


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
 
 
 
Confidential 
78 
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). 
Change #11: Section 10.3.2 Secondary Endpoints 
Original text: 
The secondary endpoints for efficacy are Immunogenicity determined by number of 
participants with positive anti-RVT-1401 antibodies and characterization of any anti-
RVT-1401 antibodies to confirm neutralization potential at Week 7.   
Revised text: 
Analysis of the secondary endpoints for efficacy:  
• Change from baseline in proptosis will include the actual value, change from 
baseline and percentage change from baseline summarized by visit using the n, 
mean, SD, median, first and third quartiles, minimum, and maximum values.   
• The number of proptosis responders and the percentage will be summarized using 
those participants who had a value at each time point. 
• Immunogenicity determined by number of participants with positive anti-RVT-
1401 antibodies and characterization of any anti-RVT-1401 antibodies to confirm 
neutralization potential at Week 7.   
Change #12: Section 10.3.3 Exploratory Endpoints 
Original text: 
For each of the continuous exploratory 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.   
For categorical exploratory 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.   
Revised text: 
For each of the continuous exploratory endpoints, the actual value, change from baseline 
and percentage change from baseline for all exploratory endpoints will be summarized by 
visit and treatment group using the n, mean, SD, median, first and third quartiles, 
minimum, and maximum values.   


Immunovant Sciences GmbHRVT-1401-1002, Amendment 03, Version 4.0 
Confidential 
79 
For categorical exploratory 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.   

SAP_001.pdf: 
TMP-SOP-0202-001-03_SAP Template 
Page 1/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Statistical Analysis Plan 
Immunovant 
RVT-1401-1002 
A Phase 2a, Multicenter, Open-Label Study of RVT-1401 for the Treatment of Patients 
with Moderate to Severe Active Graves’ Ophthalmopathy 
Protocol Version: 07 Feb 2019 
Sponsor: 
Immunovant 
320 W. 37th St. 
New York, NY 10018 
Prepared by: 
Version 
Date 
Version 1 
23 SEP 2019 


Immunovant 
RVT-1401-1002 
syn t er aft 
Approval 
Statistical Analysis Plan 
23Sep2019 
Upon review of this document, including the table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are acceptable. 
Immunovant 
TMP-SOP-0202-001-03_SAP Template 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Date 
16OCT2019 
Page2/34 


 
Immunovant  
                                                              Statistical Analysis Plan 
RVT-1401-1002 
 
23Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 3/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................................. 6 
2. 
STUDY DOCUMENTS ......................................................................................................... 6 
3. 
STUDY OBJECTIVES .......................................................................................................... 6 
3.1 PRIMARY OBJECTIVES ........................................................................................................ 6 
3.2 SECONDARY OBJECTIVES ................................................................................................... 6 
3.3 EXPLORATORY OBJECTIVES ............................................................................................... 6 
4. 
STUDY DESIGN AND PLAN .............................................................................................. 7 
5. 
DETERMINATION OF SAMPLE SIZE .......................................................................... 13 
6. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................. 13 
7. 
ANALYSIS POPULATIONS .............................................................................................. 14 
8. 
STUDY POPULATION....................................................................................................... 14 
8.1 
SUBJECT DISPOSITION .................................................................................................. 14 
8.2 
PROTOCOL DEVIATIONS .............................................................................................. 14 
8.3 
ELIGIBILITY.................................................................................................................. 14 
8.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 14 
8.5 
MEDICAL HISTORY ...................................................................................................... 14 
8.6 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................. 15 
9. 
EFFICACY ANALYSES ..................................................................................................... 15 
9.1 
EFFICACY VARIABLES ................................................................................................. 16 
9.2 
BASELINE VALUES ....................................................................................................... 17 
9.3 
HANDLING OF DROPOUTS OR MISSING DATA ............................................................. 17 
9.4 
INTERIM ANALYSIS AND DATA MONITORING ............................................................. 18 
9.5 
EXAMINATION OF SUBGROUPS .................................................................................... 18 
9.6 
MULTIPLE COMPARISON/MULTIPLICITY ..................................................................... 18 
10. METHODS OF EFFICACY ANALYSIS .......................................................................... 18 
10.1 PRIMARY EFFICACY ANALYSES................................................................................... 18 
10.2 SECONDARY EFFICACY ANALYSES ............................................................................. 18 
10.3 EXPLORATORY ANALYSES .......................................................................................... 18 
11. PHARMACOKINETIC ANALYSES ................................................................................ 19 
12. SAFETY ANALYSES .......................................................................................................... 20 
12.1 EXTENT OF EXPOSURE ................................................................................................. 20 
12.2 ADVERSE EVENTS ........................................................................................................ 20 
12.3 INJECTION SITE REACTIONS ......................................................................................... 22 
12.4 CLINICAL LABORATORY EVALUATION ....................................................................... 22 
12.5 VITAL SIGNS ................................................................................................................ 23 
12.6 PHYSICAL EXAMINATION ............................................................................................ 23 
12.7 ELECTROCARDIOGRAM ................................................................................................ 23 
13. IMMUNOGENICITY ANALYSIS .................................................................................... 24
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................ 24 
15. REFERENCES ..................................................................................................................... 25 


 
Immunovant  
                                                              Statistical Analysis Plan 
RVT-1401-1002 
 
23Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 4/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
 
16. APPENDICES ...................................................................................................................... 26 
APPENDIX A: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS .................... 26 
APPENDIX B: SAS PROGRAMMING QC REQUIREMENTS ........................................................ 29 
APPENDIX C:  LIST OF TABLES, FIGURES, AND LISTINGS ...................................................... 30 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 5/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
LIST OF ABBREVIATIONS 
Abbreviation 
Full Notation 
ADA 
anti-drug antibodies 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
AUC0-t  
area under the concentration-time curve from zero to time t 
BLQ 
below the limit of quantitation 
CAS 
clinical activity score 
Cmax 
maximum serum concentration 
Ctrough 
concentration at end of dosing interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
%CVb 
between-participant coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FcRn 
fully human anti-neonatal FC receptor 
GO 
Graves’ ophthamalopathy 
GO-QOL 
Graves’ ophthamalopathy quality of life 
ICH 
International Council for Harmonisation 
IGF-1R 
insulin-like growth receptor 
IgG 
immunoglobuin G 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PKS 
Phoenix Knowledgebase Server 
Q1 
first quartile 
Q3 
third quartile 
QC 
quality control 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TSH 
thyroid-stimulating hormone 
TSHR 
thyroid-stimulating hormone receptor 
TLFs 
tables, listings, and figures 
tmax 
time to maximum serum concentration 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 6/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
1. INTRODUCTION
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Immunovant protocol RVT-1401-1002, A Phase 2a, Multicenter, 
Open-Label Study of RVT-1401 for the Treatment of Patients with Moderate to Severe Active 
Graves’ Ophthalmopathy (GO). The purpose of this plan is to provide specific guidelines from 
which the statistical analyses will proceed. Any deviations from this plan will be documented in 
the clinical study report. 
2.
STUDY DOCUMENTS
The following study documents are used for the preparation of the statistical analysis plan (SAP): 
x Protocol Amendment 3: Version 4.0, 07 FEB 2019 
x Annotated electronic case report form (eCRF), Version 3, 26 AUG 2019 
3. STUDY OBJECTIVES
3.1 Primary Objectives 
x To assess the safety and tolerability of RVT-1401 in subjects with moderate to severe active 
GO over a 6-week treatment period 
x To assess the change in serum levels of anti-thyroid stimulating hormone receptor (anti-
TSHR) antibodies, total immunoglobulin G (IgG), and IgG subclasses (1-4). 
3.2 Secondary Objectives 
x To examine the effect of RVT-1401 on mean change in proptosis 
x To examine the effect of RVT-1401 on proptosis responder rate 
x To examine RVT-1401 pharmacokinetics (PK) following repeat doses in subjects with 
moderate to severe active GO 
x To measure anti-RVT-1401 antibodies following repeat doses in subjects with moderate to 
severe active GO 
3.3 Exploratory Objectives 
x To assess the change in serum levels of anti-insulin-like growth receptor (anti-IGF-1R) 
antibodies 
x To examine the effect of RVT-1401 on the pro-inflammatory and fully human anti-neonatal 
FC receptor (FcRn) gene expression in peripheral blood mononuclear cells 
x To examine the effect of RVT-1401 on the level of circulating pro-inflammatory 
cytokines/chemokines 
x To assess FcRn receptor occupancy following RVT-1401 administration in whole blood 
x To assess the change in the ratio of stimulatory to total serum levels of anti-TSHR and anti-
IGF-1R antibodies 




Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 8/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
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 
subcutaneous injections for 6 weeks. No dose adjustments of RVT-1401 are allowed during the 
study. 
Following the initial dose at the Baseline Visit (Day 1), study visits will occur at Days 3 and 5 
and then weekly throughout the treatment period. Following the final dose at Week 6, two study 
visits will occur at Days 38 and 40, and then weekly through Week 10 and then every 2 weeks 
until Week 18. Safety, PK, PD, and clinical assessments will be collected throughout the study. 
Refer to Table 1 for the schedule of assessments.  
Optional home visits will be offered to collect (at a minimum) blood samples, vital signs, and 
review adverse events (AEs) 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 to 24 weeks ie, 3- to 
6-week screening period (prior to baseline), a 6-week treatment period, and a 12-week follow-up 
period.


Immunovant  
  Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 9/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Table 1 Schedule of Assessments 
Screening1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
With-
drawal 
Visit 
Study Timepoint 
(Weeks) 
Within 3-6 
weeks 
Day 1 
(Baseline) Day 3 Day 5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
Time Window (days) 
+1 
day
+1 
day
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1 
day
+1 
day
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 days 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X
X
Demographics, 
medical history, and 
smoking status 
X
Height 
X 
Body weight 
X 
X 
Complete physical 
examination 
X
X
Brief physical 
examination 
X
X 
Ophthalmic 
examination 
X
X
X 
 
X 
 
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 
X
X 
12-lead 
Electrocardiogram2 
X
X
X 
 
X 
 
X 
X
X 
Pregnancy test3
(females)
X
X
X 
X 
X 
X 
X 
X
X 
Viral Serology
X 
QuantiFERON® – 
TB GOLD 
X
Urinalysis2
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Blood chemistry and 
hematology2
X
X
X 
X 
X 
X 
X 
X 
X
X 


Immunovant  
  Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 10/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Screening1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
With-
drawal 
Visit 
Study Timepoint 
(Weeks) 
Within 3-6 
weeks 
Day 1 
(Baseline) Day 3 Day 5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
Time Window (days) 
+1 
day
+1 
day
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1 
day
+1 
day
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 days 
Serum complement 
(CH50, C3)2 
X
X 
X 
X 
X 
X 
X 
X
X 
Immunoglobulins 
(IgM, IgA)2 
X 
 
X 
X 
X 
X 
X 
 
X
X 
Anti-TPO and anti-
thyroglobulin 
antibodies2 
X
 
X 
 
X 
 
X
X 
TSH, Free T3, Free 
T42 
X
X
X 
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 
X 
X 
X
X 
Anti-TSHR (Cell 
based) 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Anti-IGF-1R2 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
RVT-1401 PK 
sampling2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total IgG2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Immunoglobins  
(IgG subclasses)2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X
X 
Gene Expression 
Analysis2 
X 
 
X 
X 
 
X 
 
X
X 
Pro-Inflammatory 
Biomarker Multiplex2 
X 
 
X 
X 
 
X 
 
X
X 
Receptor 
Occupancy2 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X
X 


Immunovant  
  Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 11/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Screening1 
Treatment Period Week 
1 
(Days) 
Treatment Period 
Weekly Visit 
(Weeks) 
Treatment Period 
Week 6 
(Days) 
Follow-up Period 
Weekly Visit 
(Weeks) 
Early 
With-
drawal 
Visit 
Study Timepoint 
(Weeks) 
Within 3-6 
weeks 
Day 1 
(Baseline) Day 3 Day 5 
2 
(Day 
8) 
3 
(Day 
15) 
4 
(Day 
22) 
5 
(Day 
29) 
6 
(Day 
36) 
Day 
38 
Day 
40 
7 
8 
9 
10 
12 
14 
16 
18 
Time Window (days) 
+1 
day
+1 
day
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+1 
day
+1 
day
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 days 
Anti- RVT-
1401antibody2,4 
X 
 
X 
 
X 
X 
X
X 
Nab Assessment2 
X 
X 
X 
X 
X
X 
Drug administration 
X 
X 
X 
X 
X 
X 
Injection site 
reactions5 
X
X 
X 
X 
X 
X 
Clinical Activity 
Score (CAS) 6 
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 
Motility6 
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 
GO-QOL6 
X 
X 
X 
X 
X 
X 
X
X 
External 
Photographs7 
X
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X
X 
Orbital CT Scan8 
X 
X 
X
X 
Lid retraction 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
Satisfaction 
Questionnaire  
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Concomitant 
medication 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
1.
Screening can take place over multiple days. 
2.
Vitals, ECG, and blood draws for safety, PK, and PD assessment will be collected predose on dosing days where specified. 
3.
Pregnancy tests will be collected predose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening, follow-up, and Early Withdrawal. 


Immunovant  
  Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 12/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
4.
Participants positive for anti-RVT-1401 antibody at Week 18 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 18 visit. 
5.
Local injection site reactions will be assessed at approximately 10 minutes postdose, and participants will be monitored for up to 1 hour postdose.
6.
GO assessments will be assessed predose when collected on dosing days. 
7.
Photographs will be assessed after each dose. 
8.
The baseline orbital scan should be scheduled once all entry criteria haven been met.  Scans can be performed within +/- 7days of the scheduled visit. 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 13/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
5. DETERMINATION OF SAMPLE SIZE
A sufficient number of subjects will be enrolled to achieve approximately 8 evaluable subjects. 
The sample size for this study was not determined using statistical methods. The sample size was 
chosen based on clinical and recruitment considerations. 
6. GENERAL ANALYSIS CONSIDERATIONS
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs. 
Continuous variables will be summarized with n, means, standard deviations, medians, first 
quartile (Q1) and third quartile (Q3), minimums, and maximums. The geometric mean with 
associated 95% confidence interval and the between-participant coefficient of variation (%CVb) 
for PK parameters only will also be included. 
In general, summary statistics for raw variables will be displayed as follows: minimums and 
maximums will be displayed to the same number of decimal places as the raw data. Means, 
medians, and quartiles will be presented to 1 more decimal place than the raw data, and standard 
deviations will be presented to 2 more decimal places than the raw data.  
Categorical variables will be summarized by counts and by percentage of subjects in 
corresponding categories. Percentages will be routinely based on the population count if not 
otherwise mentioned.  
Individual subject data obtained from the eCRFs, external vendors, central clinical laboratory, 
PK data, and any derived data will generally be presented by subject, date and day, and time in 
data listings. 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock. 
Post hoc analyses will be labeled as such on the output and identified in the clinical study report. 
All analyses and tabulations will be performed using SAS£ software Version 9.4 or higher (SAS 
Institute Inc, Cary, NC). Pharmacokinetic analyses will be performed using Phoenix® 
WinNonlin£ Version 8.1 or higher (Certara USA, Inc, Princeton, NJ). Tables, listings, and 
figures will be presented in RTF format.  
The process for SAS program validation and quality control (QC) for programs and outputs is 
documented in the Synteract working instruction “SAS programming quality control.” 
Study-specific QC requirements can be found in Appendix B: SAS programming QC 
requirements. 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 14/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
7. ANALYSIS POPULATIONS
The following subject population will be used for disposition analysis:  
x Enrolled population will include all subjects who signed informed consent. 
The following subject population will be used for all analyses except PK: 
x Safety population will include all subjects who received at least 1 dose of study drug. 
The following populations will be used for PK and PK/PD analyses: 
x PK population will include all subjects who undergo serum PK sampling and have 
evaluable concentration-time data for analysis.  
x PD population will include all subjects who have baseline measure, along with a 
postbaseline measure and receive at least 1 dose of study treatment. PD populations will 
be defined for each efficacy parameter. 
8. STUDY POPULATION
8.1 Subject Disposition 
Subject disposition information will be summarized for all enrolled subjects. Summaries will 
include the number of subjects screened, the number of subjects in each analysis population, the 
number of subjects completing the 6-week treatment period, the number of subjects completing 
the 12-week posttreatment follow-up period, and the primary reason for discontinuation. 
8.2 Protocol Deviations 
Protocol deviations will be listed. 
8.3 Eligibility 
A listing of subjects not fullfilling any eligibility criteria will be created. 
8.4 Demographic and Baseline Characteristics 
Demographic variables include age, sex, ethnicity, and race. Age will be calculated in years 
relative to the informed consent date.  
Other baseline characteristics include height, weight, body mass index, and smoking status. 
Descriptive statistics will be presented for age, height, weight, body mass index, CAS, GO-QOL 
subscales, and proptosis. Frequency counts and percentages will be presented for sex, ethnicity, 
race, smoking status, and Gorman score for diplopia. GO status at baseline will be summarized. 
8.5 Medical History 
Medical history data verbatim terms in the eCRFs will be mapped to preferred terms and system 
organ classes using the Medical Dictionary for Regulatory Activities (MedDRA) (Version 21.1). 
The data will be listed. 


 
Immunovant  
                                                              Statistical Analysis Plan 
RVT-1401-1002 
 
23Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 15/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
 
8.6 Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms in the eCRFs will be mapped to anatomical 
therapeutic chemical (ATC) class level 3 and preferred names using the WHODrug Global 
(version September 2018). 
 
Prior medications are defined with a start date prior to screening and stop date before the date of 
the start of study medication. Concomitant medications are defined as any medication used prior 
to screening and with a stop date at/or after date of first study medication, or which are ongoing 
from baseline, or which are taken at/after date of first study medication intake. If it cannot be 
determined whether the medication was a prior (or concomitant) medication due to a partial start 
or stop date, then it will be counted as concomitant; see Appendix A for the imputation of 
missing dates algorithm. 
 
Concomitant medications will be summarized by ATC class and preferred name. These 
summaries will present the number and percentage of subjects using each medication. Subjects 
may have more than 1 medication per ATC class and preferred name. At each level of subject 
summarization, a subject is counted once if he/she reported 1 or more medications at that level. 
Each summary will be ordered alphabetically by ATC class and descending order of incidence of 
preferred name within each ATC class. A summary of steroid or other GO treatments during 
follow-up will be provided. These treatments will include the following: 
x Preferred Name contains “TEARS” 
x Preferred Name equals “BOTULINUM TOXIN TYPE A” 
x Preferred Name contains “SELENIUM” 
x Preferred Name contains “PREDNISONE” or “PREDNISOLONE” 
x Preferred Name equals “METHYLPREDNISOLONE” and route is Intravenous 
x Preferred Name equals “CYCLOSPORINE” 
x Preferred Name contains “AZATHIOPRINE” 
x Preferred Name contains “MYCOPHENOLATE MOFETIL” 
x Preferred Name contains “RITUXIMAB” 
x Preferred Name equals “TOCILIZUMAB” 
x Preferred Name equals “RADIOTHERAPY” 
 
All medications will be listed along with a flag to indicate whether the medication is a prior 
medication or a concomitant medication. 
9. EFFICACY ANALYSES 
The primary efficacy analysis will be based on the PD population. 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 16/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
9.1 Efficacy Variables 
The primary efficacy variables are: 
x Percentage change from baseline in total IgG at Week 7 
x Percentage change from baseline in IgG1 at Week 7 
x Percentage change from baseline in IgG2 at Week 7 
x Percentage change from baseline in IgG3 at Week 7 
x Percentage change from baseline in IgG4 at Week 7 
x Change from baseline in anti-TSHR antibodies at Week 7  
Percentage change from baseline will be calculated as: 
Ψο ൌ൤ͳͲͲ  ൬ ͹ െ

൰൨ 
Secondary efficacy variables include the following: 
x Change from baseline in proptosis 
x Proptosis responder rate (defined as percentage with ≥2 mm reduction in study eye 
without deterioration (≥2 mm increase) in fellow eye from baseline at the same visit), 
including time to first proptosis response.  
The study eye is defined as the most severely affected eye at the baseline visit. In the event that 
both eyes are affected the same, the right eye will be deemed the study eye. Time to first 
proptosis response is defined as the (date of first proptosis response – date of first dose + 1)/7. 
Subjects who do not achieve a proptosis response will be censored at the date of their last 
proptosis measurement which occurred in both eyes. 
Exploratory efficacy variables include the following: 
x Change from baseline in anti-IGF-1R antibodies 
x Change from baseline in the level of gene expression 
x Change from baseline in the circulating level of pro-inflammatory cytokines/chemokines 
x FcRn receptor occupancy 
x Change from baseline in ratios of stimulatory to total anti-TSHR and anti-IGF-1R 
antibodies 
x Change from baseline in anti-thyroperoxidase and anti-thyroglobulin antibodies 
x Proportion of subjects with ≥2-point reduction in CAS (using a 7-point scale) and 
≥2 mm reduction in proptosis in the study eye 
x Change from baseline in CAS 
x Proportion of subjects with CAS of 0 or 1, including time to first CAS response 
x Proportion of patients with overall ophthalmic improvement defined as when at least 2 
of the following outcome measures improves in 1 eye, without worsening in any of these 
measures in either eye: 
a.
Reduction in proptosis by at least 2 mm


 
Immunovant  
                                                              Statistical Analysis Plan 
RVT-1401-1002 
 
23Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 17/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
 
b. Improvement of ≥8 degrees in motility in any duction or improvement in diplopia 
(disappearance or change in degree) 
c. Improvement in CAS by at least 2 points 
x Change from baseline in the Gorman Score for diplopia 
x Change from baseline in the GO-QOL visual functioning and appearance subscale 
scores 
x Change from baseline in methimazole (or other anti-thyroid treatment) dose 
x Change from baseline in computed tomography-measured muscle volume, fat volume, 
total orbital volume, and proptosis 
x Proportion of subjects with diplopia improvement ≥1 grade 
x Change from baseline in proptosis 
The analysis of the gene expression data will be handled in a separate plan.  
The ratios of stimulatory to total anti-TSHR and anti-IGF-1R antibodies are defined as the 
following: 
x Stimulatory anti-TSHR antibody level/total anti-TSHR antibody level 
x Stimulatory anti-IGF-1R antibody level/total anti-IGF-1R antibody level 
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 (Terwee et al): 
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. 
Time to first proptosis response is defined as the date of first proptosis response – date of first 
dose + 1. Subjects who do not achieve a proptosis response will be censored at the date of their 
last proptosis measurement. Time to first CAS response is defined as the date of first 
postbaseline CAS score of 0 or 1 – date of first dose + 1. Subjects who do not achieve a CAS of 
0 or 1 will be censored at the date of their last CAS measurement. 
9.2 Baseline Values 
Unless otherwise noted, baseline is defined as the last nonmissing value recorded prior to the 
first dose of study drug. Unscheduled visits will be used in the determination of baseline values 
when applicable. 
9.3 Handling of Dropouts or Missing Data 
No imputations will be made for missing values. Summaries will be based on observed data 
only. 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 18/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
9.4 Interim Analysis and Data Monitoring 
A readout of the topline results may occur at the end of 2019 depending on enrollment. 
An interim analysis will occur after the last subject completes the Week 7 visit of the study. All 
endpoints will be evaluated for this analysis.  
A final analysis will occur when the last subject completes or discontinues the study and the 
database is locked.  
9.5 Examination of Subgroups 
No subgroup analysis is planned. 
9.6 Multiple Comparison/Multiplicity 
No adjustments for multiplicity will be made in this study. 
10. METHODS OF EFFICACY ANALYSIS
10.1 Primary Efficacy Analyses 
The primary efficacy variables will be summarized descriptively (sample size, mean, standard 
deviation, median, Q1, Q3, minimum, and maximum) by visit. Line graphs over time of 
percentage/change from baseline for each of the primary endpoints will be provided.  
10.2  Secondary Efficacy Analyses 
Continuous efficacy variables will be summarized by visit descriptively (sample size, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum) and categorical variables will be 
summarized by visit using frequency counts and percentages. Additionally, the number of low 
responders, defined as having a proptosis measurement >1 mm and <2 mm, and the number of 
high responders, defined as having a proptosis measurement ≥3 mm, will be summarized. Line 
graphs over time of the change from baseline for proptosis will be provided. 
10.3 Exploratory Analyses 
Continuous exploratory efficacy variables will be summarized by visit descriptively (sample 
size, mean, standard deviation, median, Q1, Q3, minimum, and maximum). Categorical 
exploratory efficacy endpoints will be summarized descriptively by visit (number and percent of 
subjects). A shift from baseline table will be provided to assess change in Gorman Score for 
diplopia from baseline to each scheduled postbaseline visit. Time to first proptosis response and 
time to first CAS response will be analyzed using Kaplan-Meier methods. The number and 
percentage of subjects achieving the event, number and percentage of censored subjects, and 
Kaplan-Meier estimates of Q1, median, and Q3. Line graphs over time of the change from 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 19/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
baseline for anti-IGF-1R antibody level, pro-inflammatory cytokines/chemokines, CAS, and GO-
QOL subscales will be provided. 
Responses to the treatment satisfaction questionnaire will be listed. 
11. PHARMACOKINETIC ANALYSES
Serum concentration data will be summarized descriptively for each nominal time point. 
Individual serum concentration-time plots will be presented on linear and semi-log scales. For 
descriptive statistics and mean figures, concentrations that are below the limit of quantitation 
(BLQ) will be treated as zero, except when an individual BLQ falls between 2 quantifiable 
values, in which case it will be treated as missing data and will be excluded from the mean 
profile.  
Serum RVT-1401 concentration-time data will be analyzed by non-compartmental analysis, 
using actual sampling times recorded during study. The PK analysis and generation of TLFs will 
be performed using a validated installation of Phoenix WinNonlin version 8.1 and above as part 
of a  database system (Phoenix Knowledgebase Server [PKS]) compliant with United States 
Title 21 Code of Federal Regulations Part 11, and all the analysis will be stored on the PKS, with 
an audit trail for all the steps capturing the changes needed for the completion of the analysis and 
generation of the TLFs. 
The primary analysis of PK will be conducted on the PK population, which includes all patients 
who undergo serum PK sampling and have evaluable concentration-time data for analysis. The 
primary PK parameters to be calculated are area under the concentration-time curve from time 
zero to time t (AUC0-t), maximum serum concentration (Cmax), concentration at end of dosing 
interval (Ctrough), and time to maximum serum concentration (tmax) after the first and last dose on 
Week 1 and Week 6, respectively. The Cmax,, tmax, AUC0-t  will be estimated using linear-up log-
down method, as data permits. Additionally, Ctrough will be determined for every dosing interval 
(Week 2, Week 3, Week 4, and Week 5), where PK samples taken within 8 hours before the next 
dose administration will be considered for reporting. Additional PK parameters (eg, 
accumulation ratio for both Cmax and/or AUC (0-t) between Week 1 and Week 6) may be 
calculated if data permits. 
Pharmacokinetic parameters (AUC0-t, Cmax, Ctrough and tmax) will be summarized descriptively as 
follows: 
x Serum concentration data: sample size, number and percentage BLQ, mean, standard 
deviation, coefficient of variation (CV), median, minimum, and maximum 
x AUC0-t, Ctrough and Cmax: sample size, mean, standard deviation, CV, geometric mean, 
geometric CV, median, minimum, and maximum 
x tmax: sample size, median, minimum, and maximum 
Summaries of PK parameters and serum concentration data will be provided for the PK analysis 
population. Individual PK parameter and serum concentration data will also be listed for all 
subjects. 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 20/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
12. SAFETY ANALYSES
All safety analyses will be based on the safety population. 
12.1 Extent of Exposure 
Duration of exposure to study drug will be defined as (last dose date – first dose date + 1), 
regardless of temporary interrruptions in study drug administration, and will be expressed in 
days. Duration of exposure to study drug will be summarized using descriptive statistics (number 
of subjects, mean, standard deviation, median, minimum, and maximum) and as the number and 
percentage of subjects weeks of exposure. 
Study drug compliance will be defined as the number of doses received divided by the number of 
doses planned. 
Study drug compliance will be summarized using counts and percentages as categorized in the 
following categories: 
x >100%
x >90%-100%
x >80%-90%
x <80% 
12.2 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. Verbatim terms in the eCRFs will be mapped to preferred terms and 
system organ classes using MedDRA Version 21.1.  
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. 
The severity grade of events for which the investigator did not record severity will be 
categorized as “missing” for tabular summaries and data listings. 
Related AEs are those for which the investigator answers “Probably Related” or “Possibly 
Related” to the question “Is there a reasonable possibility that the study treatment caused or 
contributed to the adverse event?” Adverse events for which the investigator did not record 
relationship to study drug will be considered related to study drug. Data listings will show 
relationship as missing. 
Adverse events will be classified according to the following: 


 
Immunovant  
                                                              Statistical Analysis Plan 
RVT-1401-1002 
 
23Sep2019 
 
TMP-SOP-0202-001-03_SAP Template 
Page 21/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
 
x Pretreatment: AEs that either started prior to the date of the first dose of study drug or 
had no recorded start date and the stop date is prior to the first dose of study drug. 
x Treatment emergent: AEs that either started on or after the date of the first dose of study 
drug and on or before the date of the last dose of study drug + 42 days, or had no 
recorded start date and the stop date is in between date of first dose and the last dose of 
study drug + 42 days. 
x Posttreatment: AEs that started after the date of the last dose of study drug + 42 days. 
If it cannot be determined whether the AE is treatment emergent due to a partial onset date, then 
it will be counted as such; see Appendix A for the imputation of missing dates algorithm. 
Overall summaries of AEs will be provided to include the number and percentage of subjects 
who: 
x Had any AE, 
x Had any Grade 3 or higher AE, 
x Had any treatment-related AE,  
x Had any Grade 3 or higher treatment-related AE,  
x Had a serious AE (SAE),  
x Had any treatment-related SAE,  
x Permanently discontinued from study drug due to an AE, and  
x Died. 
Summaries (number and percent of subjects) of treatment-emergent AEs (by system orgran class 
and preferred term) will be provided for the following: 
x All AEs 
x All Grade 3 or higher AEs 
x All treatment-related AEs 
x All Grade 3 or higher treatment-related AEs 
x All serious adverse events (SAEs) 
x All treatment-related SAEs.  
Summaries that are displayed by system organ class and preferred terms will be ordered 
alphabetically by system organ class and descending order of incidence of preferred term within 
each system organ class.  
 
In addition to the AE summaries, data listings will be provided for the following: 
x Pretreatment AEs 
x Treatment-emergent AEs 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 22/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
x Posttreatment AEs 
x SAEs 
x Liver events 
x AEs leading to discontinuation or interruption of study drug 
x Deaths 
12.3 Injection Site Reactions 
Injection site reactions will be summarized (number and percentage of subjects) by maximum 
observed on treatment and visit, symptom, and toxicity grade.  Multiple events will be counted 
only once per subject at the maximum toxicity grade in each summary. Additionally, a summary 
of the number of subjects who experienced at least 1 injection site reaction during the study and 
at each visit will be provided. 
12.4 Clinical Laboratory Evaluation 
Hematology, clinical chemistry, thyroid functuion, and urinalysis parameters to be tested by 
central laboratory are as follows: 
Hematology 
Platelet count  
Red Blood Cell Indices: 
Automated White Blood Cell 
Differential: 
Red blood cell count 
Mean corpuscular volume  
Neutrophils 
White blood cell count 
(absolute)  
Mean corpuscular 
hemoglobin  
Lymphocytes 
Reticulocyte count 
Mean corpuscular 
hemoglobin concentration 
Monocytes 
Hemoglobin 
Eosinophils 
Hematocrit 
Basophils 
Clinical Chemistry 
Blood urea 
nitrogen  
Potassium 
Aspertate 
aminotransferase 
Total and direct 
bilirubin 
Creatinine 
Chloride 
Alanine aminotransferase  Uric acid 
Glucose fasting 
[on Day 1 
(baseline) and 
Week 7 only] 
Total carbon 
dioxide 
γ-Glutamyltransferase 
Albumin* 
Sodium 
Calcium (corrected) 
Alkaline phosphatase 
Total Protein 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 23/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Serum 
complement 
(CH50, C3) 
Immunoglobulin M 
Immunoglobulin A 
* Albumin collected from central lab will be graded to Grade 1 to 3 by National Cancer Institute Common
Terminology Criteria for Adverse Events (CTCAE) v5.0.
Thyroid Function Tests 
TSH, Free T3, Free T4 
Routine Urinalysis 
Specific gravity, pH 
Glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal) 
Laboratory parameters (serum chemistry, hematology, thyroid function, and urinalysis) will be 
summarized using descriptive statistics at baseline and at each postbaseline time point. Changes 
from baseline will also be summarized. Only results from the central laboratory will be 
summarized. 
In addition, shift from baseline tables (ie, low-normal-high at baseline versus low-normal-high at 
follow-up in a 3-by-3 contingency table) will be provided to assess changes in laboratory values 
from baseline to each scheduled postbaseline visit for all continuous parameters.  
Only results from the central laboratory will be summarized. All central and local laboratory 
clinical chemistry, hematology, and urinalysis values will be listed and flagged high or low 
relative to the normal range where appropriate.   
12.5 Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, temperature, and weight) 
will be summarized using descriptive statistics at baseline and at each postbaseline time point. 
Changes from baseline will also be summarized.  
12.6 Physical Examination 
Physical examination results will be included in data listings only.  
12.7 Electrocardiogram 
Electrocardiogram (ECG) results (heart rate, PR, QRS, QT, and corrected QT interval by 
Fredericia) will be summarized descriptively including baseline, postbaseline, and change from 
baseline values for each parameter and will be provided for all scheduled time points.  
Overall interpretation results for ECGs will be summarized using shift tables (Normal, Abnormal 
Not Clinically Significant, Abnormal Clinically Significant) comparing baseline with each 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 24/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
scheduled postbaseline visit. Descriptive statistics at baseline and at each postbaseline time point 
as well as changes from baseline will be summarized for each ECG parameter.  
13. IMMUNOGENICITY ANALYSIS
Immunogenicity analysis will be based on the safety population. The presence of anti-drug 
antibodies (ADA) will be determined using a 3-tiered approach: screening; confirmation; and 
titration. All samples will be brought through the tier 1 screening assay to determine the potential 
presence of anti-RVT-1401 antibody.  All samples determined potentially positive will be 
annalyzed in the tier 2 confirmation assay where presence of anti-RVT-1401 will be confirmed. 
The therapeutic antibody will be used to compare with the analytical responses of ADA to assess 
specificity of screened positive samples. After ADA confirmation, all samples that were 
confirmed positive for ADA will be analyzed in the tier 3 assay in order to characterize and 
determine antibody titers. Titration results will characterize the magnitude of the ADA response 
during the confirmatory assay. 
Interpretation of the result will first be performed with a descriptive count of the immunogenicity 
assessment with a summary of ADA titer confirmed positive and a summary of immunogenicity 
rate by anti-RVT-1401 from confirmatory assay. The neutralizing potential of ADA may be 
evaluated. 
Optional analysis on ADA incidence and PK parameter descriptive presentation in ADA 
negative and ADA positive confirmed subjects might be performed. 
14. CHANGES TO PROTOCOL-SPECIFIED ANALYSES
Note the following modifications and/or clarifications to the methodology specified in the 
protocol: 
x The intention-to-treat population was removed as there was no difference between it and 
the safety population. The PD population will be used instead for the efficacy endpoints. 
x Time to first CAS response, CAS response, and change from baseline in proptosis were 
added as exploratory endpoints. 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 25/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
15. REFERENCES
Terwee CB, Dekker FW, Mourits MP, et al. Interpretation and validity of changes in scores on 
the Graves’ ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. 
Clin Endcrinol. 2001 Mar;54(3):391-8. 
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for Industry ICH E9 Statistical principles 
for clinical trials. September 1998 [cited 2018 Aug 03]. Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
073137.pdf 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 26/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
16. APPENDICES
Appendix A: Presentation of Data and Programming Specifications 
General  
x Specialized text styles, such as bold, italics, borders, shading, superscripted, and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing. 
x Only standard keyboard or Greek characters are to be used in tables and data listings. 
x Special characters, such as nonprintable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
x All footnotes will be left justified and at the bottom of a page. Footnotes must be used 
sparingly and must add value to the table, figure, or data listing. 
Tables 
x Formal organization of tabulations may be changed during programming, if appropriate, 
eg, tables for the different variables may be combined into a single table, or tables with 
more than 1 variable may be split into several tables. 
x Means and medians will be presented to 1 more decimal place than the raw data. 
Standard deviations will be presented to 2 more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
x Percentages will be rounded and presented to the tenths place. 
x For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the patients discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0 and 
no percentage.  
x Percentiles (eg, 25%, 75%) must be presented to 1 decimal place more than the 
raw/derived data. 
x For all inferential analyses, P values will be rounded to 4 decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P values less than 0.0001 will be 
presented as “<0.0001.” 
x The last footnotes will be 
-
“Source: xxx”, where xxx indicates the source table number(s) if applicable (in case aggregated
results like mean or median are plotted) or the source listing(s) (in case individual responses are
plotted) and/or source datatset(s) (eg, AdaM).
-
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE:
DDMMYY hh:mm”.
where extract date is the datestamp of the data snapshot used.


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 27/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Figures 
x Legends will be used for all figures with more than 1 variable or item displayed.  
x Figures will be in black and white but can be in color to add value to the clarity and 
readability of a figure. Lines must be wide enough to see the line after being copied. 
x The last footnotes will be 
-
“Source: xxx”, where xxx indicates the source listing number(s) and/or source datatset(s) (eg, AdaM).
-
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE:
DDMMYY hh:mm”.
where extract date is the datestamp of the data snapshot used.
x Line graphs over time of change from baseline results will include a horizontal dashed 
reference line at zero. 
Listings 
x Formal organization of the listing may be changed during programming, if appropriate, 
eg, additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints. 
x If not otherwise specified, all data listings will be sorted by sequence/treatment, center, 
patient number, visit, and date/time, as appropriate.  
x All date values will be presented in a SAS date (eg, 29AUG2001) format. 
x All observed time values will be presented using a 24-hour clock HH:MM:SS format (eg, 
01:35:45 or 11:26). Seconds will only be reported if they were measured as part of the 
study. 
x The last footnote will be 
-
“PROGRAM SOURCE: …\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE:
DDMMYY hh:mm”.
where extract date is the datestamp of the data snapshot used.


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 28/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Missing or incomplete dates (ie, AEs and concomitant medications) 
The most conservative approach will be systematically considered. If the AE onset date is 
missing/incomplete, it is assumed to have occurred during the study treatment phase (ie, 
considered a treatment-emergent AE) except if the partial onset date or other data, such as the 
stop date, indicates differently. 
The following algorithms will be applied to missing and incomplete start and stop dates: 
Start Dates 
x If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first dose of study drug, provided the start month and year are the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the missing day portion will be estimated as 
“01.” 
x If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first dose of study drug, provided the start year is the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the event will be assumed to start on the first day 
of the given year (eg, ??-???-2013 is estimated as 01-JAN-2013).  
x If the start date is completely missing and the stop date is either after the first dose of 
study drug or completely missing, the start date will be estimated to be the first day of 
study drug dosing. Otherwise, the start date will be estimated to be the first day of the 
same year as the stop date. All other non-AE and nonconcomitant medication day 
calculations where only partial dates are available will be handled as follows: the first day 
of the month will be used in the calculations if the day part of a start date is missing while 
January 1 will be employed if both the month and day parts of a start date are missing. 
Stop Dates 
x If only the day of resolution is unknown, the day will be assumed to be the last of the 
month (eg, ??-JAN-2013 will be treated as 31-JAN-2013).  
x If both the day and month of resolution are unknown, the event will be assumed to have 
ceased on the last day of the year (eg, ??-???-2013 will be treated as 31-DEC-2013).  
x If the stop date is completely missing or the event is continuing, the event will be 
assumed to be after first dose of study drug and will be imputed using the last known date 
on the study. 


Immunovant  
    Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 29/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Appendix B: SAS programming QC requirements 
Derived datasets are independently programmed by two programmers. The separate datasets 
produced by the 2 programmers must match 100%. Detailed specifications for the derived 
datasets are documented in the study analysis dataset specifications provided to the client at 
study conclusion. 
Tables are independently reprogrammed by a second programmer for numeric results.  
Listings are checked for consistency against corresponding tables, figures, and derived datasets. 
Figures are checked for consistency against corresponding tables and listings, or independently 
reprogrammed if there are no corresponding tables or listings. 
The entire set of TLFs is checked for completeness and consistency prior to its delivery to the 
client by the lead biostatistician and a senior level, or above, reviewer. 


Immunovant  
Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 30/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Appendix C:  List of Tables, Figures, and Listings  
The following proposal for section 14 and 16.2 is completed according to ICH E3 guidelines. 
The ICH heading numbers and description are in bold. Minor changes from this planned index 
do not need to be amended in the SAP.   
Formal organization of tabulations may be changed during programming, if appropriate, eg, 
tables for the different variables may be combined into a single table, or tables with more than 1 
variable may be split into several tables. 
TABLES, FIGURES AND GRAPHS 
Output 
Number 
Output Title 
14 
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT 
INCLUDED IN THE TEXT 
DEMOGRAPHIC DATA 
14.1.1 
Disposition (Enrolled Population) 
14.1.2 
Demographic and Baseline Characteristics (Safety Population) 
14.1.3 
Graves' Orbitopathy Status at Baseline (Safety Population) 
14.1.4.1 
Concomitant Medications (Safety Population) 
14.1.4.2 
Steroid or Other GO Treatment During Follow-up (Safety Population) 
14.1.5 
Exposure (Safety Population) 
EFFICACY DATA 
14.2.1.1 
Percentage Change from Baseline in Total IgG by Visit (PD Population) 
14.2.1.2 
Percentage Change from Baseline in IgG1 by Visit (PD Population) 
14.2.1.3 
Percentage Change from Baseline in IgG2 at by Visit (PD Population) 
14.2.1.4 
Percentage Change from Baseline in IgG3 at by Visit (PD Population) 
14.2.1.5 
Percentage Change from Baseline in IgG4 at by Visit (PD Population) 
14.2.1.6 
Change from Baseline in anti-TSHR antibody level by Visit (PD Population) 
14.2.2.1.1 
Proptosis by Visit (PD Population) 
14.2.2.1.2 
Proptosis Responder Rate (PD Population) 
14.2.3.1 
Anti-TSHR Antibody Level by Visit (PD Population) 
14.2.3.2 
Pro-inflammatory Cytokines/Chemokines by Visit (PD Population) 
14.2.3.3 
FcRn Receptor Occupancy by Visit (PD Population) 
14.2.3.4 
Ratio of Stimulatory to Total Anti-TSHR and Anti-IGF-1R Antibodies by Visit 
(PD Population) 
14.2.3.5 
Anti-Thyroperoxidase (TPO) and Anti-thyroglobulin Antibodies by Visit (PD 
Population) 
14.2.3.6 
Clinical Activity Score (CAS) and Proptosis Responder Analysis by Visit (PD 
Population) 
14.2.3.7.1 
Clinical Activity Score (CAS) by Visit (PD Population) 


Immunovant  
Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 31/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Output 
Number 
Output Title 
14.2.3.7.2 
Proportion of Subjects with Clinical Activity Score (CAS) of 0 or 1 by Visit (PD 
Population) 
14.2.3.8 
Proportion of Subjects with Overall Ophthalmic Improvement by Visit (PD 
Population) 
14.2.3.9.1 
Gorman Score for Diplopia Shift from Baseline (PD Population) 
14.2.3.9.2 
Proportion of Subjects with Diplopia Improvement of at Least One Grade (PD 
Population) 
14.2.3.10 
GO-QOL and Subscales by Visit (PD Population) 
14.2.3.11 
Motility by Visit (PD Population) 
14.2.3.12 
Methimazole (or Other Anti-thyroid Treatment) Dose by Visit (PD Population) 
14.2.3.13 
Computed Tomography Measurements by Visit (PD Population) 
14.2.4.1 
Serum Concentrations (PK Population) 
14.2.4.2 
Pharmacokinetic Parameters (PK Population) 
SAFETY DATA 
Displays of Adverse Events 
14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety Population) 
14.3.1.1.2 
Overall Summary of Adverse Events - Follow-up Period (Safety Population) 
14.3.1.2.1 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Population) 
14.3.1.2.2 
Adverse Events by System Organ Class and Preferred Term – Follow-up Period 
(Safety Population) 
14.3.1.3.1 
Grade 3 or Higher Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Population) 
14.3.1.3.2 
Grade 3 or Higher Adverse Events by System Organ Class and Preferred Term – 
Follow-up Period (Safety Population) 
14.3.1.4.1 
Treatment-Related Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – Treatment Period (Safety Population) 
14.3.1.4.2 
Treatment-Related Adverse Events by System Organ Class and Preferred Term 
– Follow-up Period (Safety Population)
14.3.1.5.1 
Grade 3 or Higher Treatment-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term (Safety Population) 
14.3.1.5.2 
Grade 3 or Higher Treatment-Related Adverse Events by System Organ Class 
and Preferred Term – Follow-up Period (Safety Population) 
Serious and Significant Adverse Events 
14.3.2.1.1 
Serious Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
14.3.2.1.2 
Serious Adverse Events by System Organ Class and Preferred Term – Follow-up 
Period (Safety Population) 
14.3.2.2.1 
Treatment-Related Serious Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 


Immunovant  
Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 32/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Output 
Number 
Output Title 
14.3.2.2.2 
Treatment-Related Serious Adverse Events by System Organ Class and 
Preferred Term – Follow-up Period (Safety Population) 
14.3.2.3.1 
Injection Site Reactions by Symptom and Toxicity Grade (Safety Population) 
14.3.2.3.2 
Injection Site Reactions by Visit (Safety Population) 
Laboratory 
14.3.4.1.1 
Hematology (Safety Population) 
14.3.4.1.2 
Hematology Shift from Baseline (Safety Population) 
14.3.4.2.1 
Chemistry (Safety Population) 
14.3.4.2.2 
Chemistry Shift from Baseline (Safety Population) 
14.3.4.3 
Thyroid Function Tests (Safety Population) 
14.3.4.4 
Serum Complement (Safety Population) 
14.3.4.5 
Immunoglobulins (Safety Population) 
Other Safety Data 
14.3.6.1 
Vital Signs (Safety Population) 
14.3.6.2.1 
Electrocardiogram (Safety Population) 
14.3.6.2.2 
Electrocardiogram – Overall Interpretation Shift from Baseline (Safety 
Population) 
14.3.6.3 
Immunogenicity Analysis (Safety Population) 
 FIGURES EFFICACY DATA 
14.2.1.1 
Mean Percentage Change Total IgG by Visit (PD Population) 
14.2.1.2 
Mean Percentage Change IgG1 by Visit (PD Population) 
14.2.1.3 
Mean Percentage Change IgG2 by Visit (PD Population) 
14.2.1.4 
Mean Percentage Change IgG3 by Visit (PD Population) 
14.2.1.5 
Mean Percentage Change IgG4 by Visit (PD Population) 
14.2.1.6 
Mean Change Anti-TSHR Antibody Level by Visit (PD Population) 
14.2.2.1 
Mean Change Proptosis by Visit (PD Population) 
14.2.3.1 
Mean Change Anti-IGF-1R Antibody Level by Visit (PD Population) 
14.2.3.2 
Mean Pro-inflammatory Cytokines/Chemokines Level by Visit (PD Population) 
14.2.3.3 
Mean Change Clinical Activity Score (CAS) by Visit (PD Population) 
14.2.3.4.1 
Mean Change GO-QOL Visual-Functioning Subscale by Visit (PD Population) 
14.2.3.4.2 
Mean Change GO-QOL Appearance Subscale by Visit (PD Population) 
14.2.4.1.1 
Mean Serum Concentration Over Time – Linear (PK Population) 
14.2.4.1.2 
Mean Serum Concentration Over Time – Log-linear (PK Population) 
14.2.4.2.1 
Individual Serum Concentrations Over Time – Linear (PK Population) 
14.2.4.2.2 
Individual Serum Concentrations Over Time – Log-linear (PK Population) 
14.3.3.1 
Mean Albumin by Visit (Safety Population) 
14.3.3.2 
Mean Triiodothyronine (FT3) by Visit (Safety Population) 
14.3.3.3 
Mean Thyroxine Free (FT4) by Visit (Safety Population) 


Immunovant  
Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 33/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
Section 16.2: List of Data Listings 
ICH 
Listing 
Number 
Listing Title 
16.2 
PATIENT DATA LISTINGS 
16.2.1 
Discontinued patients 
16.2.1 
Disposition (Enrolled Population)  
 16.2.2 
Protocol Deviations 
16.2.2 
Protocol Deviations (Safety Population) 
 16.2.3 
Subjects Excluded from the Safety Analysis 
16.2.3 
Eligibility Criteria (Enrolled Population) 
 16.2.4 
Demographic and Baseline Data 
16.2.4.1 
Demographic and Baseline Characteristics (Safety Population) 
16.2.4.2 
Graves' Orbitopathy Status at Baseline (Safety Population) 
16.2.4.3 
Tobacco Use (Safety Population) 
16.2.4.4 
Medical History (Safety Population) 
16.2.4.5 
Thyroid History (Safety Population) 
16.2.4.6 
Graves' Orbitopathy History (Safety Population) 
16.2.4.7 
Concomitant Medications (Safety Population) 
16.2.4.8 
Steroids or Graves’ Orbitopathy Treatments During Follow-up 
(Safety Population) 
16.2.4.9 
Previous Thyroid Treatments (Safety Population) 
16.2.4.10 Current Thyroid Status (Safety Population) 
16.2.4.11 Procedures (Safety Population) 
 16.2.5 
Compliance and/or Drug Concentration Data 
16.2.5.1 
Exposure (Safety Population) 
16.2.5.2 
Treatment Satisfaction Questionnaire (Safety Population) 
 16.2.6 
Individual Efficacy Response Data 
16.2.6.1 
Total IgG and Subclasses (Safety Population) 
15.2.6.2 
Anti-TSHR Antibody Levels (Safety Population) 
16.2.6.3 
Proptosis (Safety Population) 
16.2.6.4 
Serum RVT-1401 Concentrations (PK Population) 
16.2.6.5 
Pharmacokinetic Parameters (PK Population) 
16.2.6.6 
Anti-IGF-1R Antibody Levels (Safety Population) 
16.2.6.7 
Pro-Inflammatory Cytokines/Chemokines (Safety Population) 
16.2.6.8 
Receptor Occupancy (Safety Population) 
16.2.6.9 
Anti-TPO and Anti-thyroglobulin Antibodies (Safety Population) 
16.2.6.10 Motility (Safety Population) 
16.2.6.11 Clinical Activity Score (Safety Population) 
16.2.6.12  Gorman Score for Diplopia (Safety Population) 
16.2.6.13 GO-QOL (Safety Population) 


Immunovant  
Statistical Analysis Plan 
RVT-1401-1002 
23Sep2019 
TMP-SOP-0202-001-03_SAP Template 
Page 34/34 
CONFIDENTIAL 
RVT-1401-1002 SAP Version 1 
ICH 
Listing 
Number 
Listing Title 
16.2.6.14 Computed Tomography (CT) Results (Safety Population) 
16.2.6.15 Lid Retraction (Safety Population) 
 16.2.7 
Adverse Events Listings 
16.2.7.1 
Pre-treatment Adverse Events (Safety Population) 
16.2.7.2 
Treatment-Emergent Adverse Events (Safety Population) 
16.2.7.3 
Follow-up Period Adverse Events (Safety Population) 
16.2.7.4 
Serious Adverse Events (Safety Population) 
16.2.7.5 
Adverse Events Leading to Discontinuation or Interruption of 
Study Drug (Safety Population) 
16.2.7.6 
Deaths (Safety Population) 
16.2.7.7 
Injection Site Reactions (Safety Population) 
16.2.7.8 
Liver Events (Safety Population) 
16.2.7.9 
Liver Imaging (Safety Population) 
16.2.7.10 Liver Biopsy (Safety Population) 
 16.2.8 
Laboratory and Other Data 
16.2.8.1 
Hematology (Safety Population) 
16.2.8.2 
Chemistry (Safety Population) 
16.2.8.3 
Urinalysis (Safety Population) 
16.2.8.4 
Thyroid Function Tests (Safety Population) 
16.2.8.5 
Serum Complement (Safety Population) 
16.2.8.6 
Immunoglobulins (Safety Population) 
16.2.8.7 
Pregnancy Test (Safety Population) 
16.2.8.8 
Viral Serology (Safety Population) 
16.2.8.9 
QuantiFERON-TB Gold (Safety Population) 
 16.2.9 
Other Safety Data 
16.2.9.1 
Vital Signs (Safety Population) 
16.2.9.2 
Electrocardiogram (Safety Population) 
16.2.9.3 
Physical Examination (Safety Population) 
16.2.9.4 
Ophthalmic Examination (Safety Population) 
16.2.9.5 
RVT-1401 Immunogenicity