Clinical trial NCT04253236
Conditions: Warm Autoimmune Hemolytic Anemia
Sponsor: Immunovant Sciences GmbH
Start date: 2020-08-11; Completion date: 2021-04-01
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 2 non-randomized, open-label study to investigate the efficacy, safety and tolerability of RVT-1401 in patients with Warm Autoimmune Hemolytic Anemia.

Detailed description:
This is a Phase 2, non-randomized, sequential, open-label study to investigate the safety, tolerability, PK, PD, and efficacy of RVT-1401 (680 mg/weekly and 340 mg/weekly) in patients with Warm Autoimmune Hemolytic Anemia that is worsening or refractory in spite of therapy with steroids and or immunosuppressants or worsening with steroid or immunosuppressant taper. Two cohorts of participants will be enrolled in a non-randomized sequential approach. Participants will be enrolled into Cohort 1 (680 mg/weekly) first followed by Cohort 2 (340 mg/weekly).

Following the initial dose at the Baseline Visit (Week 1, Day 1), study visits will occur weekly throughout the treatment period. Following the final dose at Week 12, visits will occur weekly through Week 14 and then at Week 16 and Week 20. Safety, PK, PD, and clinical assessments will be collected throughout the study.

Each participant will participate in the study for up to approximately 24 weeks: up to a 4-week screening period, a 12-week treatment period, and an 8-week follow up period.

Arms: arm 1: Dosing Regimen A - 680 mg weekly for 12 weeks via once weekly subcutaneous (SC) injections arm 2: Dosing Regimen B - 340 mg weekly for 12 weeks via once weekly subcutaneous (SC) injections
Interventions: intervention 1: RVT-1401 680 mg/weekly intervention 2: RVT-1401 340 mg/weekly
Intervention descriptions: intervention 1: Non-randomized subjects will receive subcutaneous injection of 680 mg weekly for 12 weeks of RVT-1401 intervention 2: Non-randomized subjects will receive subcutaneous injection of 340 mg weekly for 12 weeks of RVT-1401

Protocol documents:
Prot_000.pdf: 


Immunovant Sciences GmbH Protocol RVT-1401-2003, Amendment 2 Version 3.0 
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The information contained in this document, particularly unpublished data, is the property or under control of Sponsor, 
and is provided to you in confidence as an investigator, potential investigator or consultant, for review by you, your 
staff, and an applicable Institutional Review Board or Independent Ethics Committee. The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described in the protocol. You 
will not disclose any of the information to others without written authorization from Sponsor, except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 




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


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


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1. 
TABLE OF CONTENTS 
PAGE 
1. 
TABLE OF CONTENTS ........................................................................................... 6 
2. 
PROTOCOL SUMMARY FOR STUDY RVT-1401-2003 ........................................... 9 
3. 
INTRODUCTION .................................................................................................... 11 
3.1. 
Background ................................................................................................ 11 
3.2. 
Warm Autoimmune Hemolytic Anemia ........................................................ 11 
3.3. 
Rationale .................................................................................................... 12 
3.3.1. 
Study Rationale ........................................................................... 12 
3.3.2. 
Dose rationale ............................................................................. 12 
3.3.3. 
Clinical Experience ...................................................................... 13 
3.3.3.1. 
Safety ......................................................................... 14 
3.3.3.2. 
Pharmacokinetics ....................................................... 15 
3.3.3.3. 
Pharmacodynamics .................................................... 15 
3.4. 
Benefit: Risk Assessment ........................................................................... 17 
3.4.1. 
Risk Assessment ......................................................................... 17 
4. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 19 
5. 
STUDY DESIGN .................................................................................................... 20 
5.1. 
Overall Design ............................................................................................ 20 
5.2. 
Study Schematic ......................................................................................... 21 
5.3. 
Treatment Arms and Duration ..................................................................... 21 
6. 
PARTICIPANT POPULATION ................................................................................ 21 
6.1. 
Type and Number of Participants ................................................................ 21 
6.2. 
Inclusion Criteria ......................................................................................... 22 
6.3. 
Exclusion Criteria ........................................................................................ 23 
6.4. 
Other Eligibility Criteria Considerations ....................................................... 25 
6.5. 
Screening/Baseline Failures ....................................................................... 25 
6.6. 
Lifestyle Restrictions ................................................................................... 25 
6.6.1. 
Contraception .............................................................................. 25 
6.7. 
Withdrawal Criteria ..................................................................................... 26 
6.7.1. 
Reasons for Withdrawal ............................................................... 26 
6.7.2. 
Participant Withdrawal Procedures .............................................. 27 
6.8. 
Safety Management Criteria for Individual Participants ............................... 27 
6.8.1. 
Liver Chemistry Management Criteria .......................................... 27 
6.8.2. 
QTc Withdrawal Criteria ............................................................... 28 
6.8.3. 
Albumin Monitoring Criteria .......................................................... 29 
6.8.4. 
Other Individual Stopping Criteria ................................................ 29 
6.9. 
Toxicity Management Criteria ..................................................................... 30 
6.9.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and 
Injection Site Reactions) .............................................................. 30 
6.9.2. 
Management of Rescue Therapy ................................................. 31 
6.9.3. 
Other Management Criteria ......................................................... 32 
6.10. 
Participant and Study Completion ............................................................... 32 


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7. 
STUDY TREATMENT ............................................................................................ 32 
7.1. 
Investigational Product and Other Study Treatment .................................... 32 
7.2. 
Treatment Assignment ................................................................................ 32 
7.3. 
Blinding ....................................................................................................... 32 
7.4. 
Packaging and Labeling .............................................................................. 33 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 33 
7.6. 
Compliance with Study Treatment Administration ....................................... 33 
7.7. 
Treatment of Study Treatment Overdose .................................................... 34 
7.8. 
Treatment After the End of the Study .......................................................... 34 
7.9. 
Concomitant Medications and Non-Drug Therapies .................................... 34 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 35 
8.1. 
Time and Events Table ............................................................................... 36 
8.2. 
Screening and Critical Baseline Assessments ............................................ 39 
8.3. 
Study Assessments and Procedures .......................................................... 39 
8.3.1. 
Physical Exams ........................................................................... 39 
8.3.2. 
Vital Signs .................................................................................... 39 
8.3.3. 
Electrocardiogram (ECG) ............................................................. 39 
8.3.4. 
Clinical Safety Laboratory Assessments ...................................... 39 
8.3.5. 
Pharmacokinetics ........................................................................ 41 
8.3.6. 
Anti-Drug Antibody (ADA) and Neutralizing Antibody 
(NAb) ........................................................................................... 42 
8.3.7. 
Pharmacodynamics ..................................................................... 42 
8.3.8. 
Exploratory Biomarkers ................................................................ 42 
8.4. 
Rating Scales & Questionnaires ................................................................. 43 
8.4.1. 
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F) Scale ........................................................................... 43 
8.4.2. 
Medical Research Council (MRC) Breathlessness Scale ............. 43 
8.4.3. 
EQ-5D-3L Scale ........................................................................... 43 
8.4.4. 
Satisfaction Questionnaire ........................................................... 43 
9. 
DATA MANAGEMENT ........................................................................................... 44 
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ................................. 44 
10.1. 
Sample Size Considerations ....................................................................... 44 
10.2. 
Statistical Considerations ............................................................................ 44 
10.2.1. 
Analysis Populations .................................................................... 44 
10.3. 
Analysis ...................................................................................................... 45 
10.3.1. 
Baseline Demographics and Characteristics ................................ 45 
10.3.2. 
Primary Endpoint for Efficacy ....................................................... 45 
10.3.3. 
Secondary Endpoints for Efficacy ................................................ 46 
10.3.4. 
Safety Analyses ........................................................................... 46 
10.3.5. 
Pharmacokinetic Analyses ........................................................... 46 
10.3.6. 
Pharmacodynamic Analyses ........................................................ 47 
10.3.7. 
Other Analyses ............................................................................ 47 
11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAES) ................ 47 
11.1. 
Definition of Adverse Events ....................................................................... 47 
11.2. 
Definition and Reporting of Serious Adverse Events ................................... 48 
11.3. 
Time Period and Frequency for Collecting AE and SAE Information ........... 49 
11.4. 
Method of Detecting and Reporting AEs and SAEs .................................... 50 
11.5. 
Assessing Severity of AEs and SAEs ......................................................... 50 


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11.6. 
Assessing Causality of AEs and SAEs ........................................................ 51 
11.7. 
Follow-up of AEs and SAEs ........................................................................ 51 
11.8. 
Regulatory Reporting Requirements for SAEs ............................................ 52 
11.9. 
Overdose .................................................................................................... 52 
12. PREGNANCY REPORTING .................................................................................. 52 
13. RESPONSIBILITIES .............................................................................................. 53 
13.1. 
Principal Investigator Responsibilities ......................................................... 53 
13.1.1. 
Good Clinical Practice (GCP) ....................................................... 53 
13.1.2. 
Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) Approval ........................................................... 53 
13.1.3. 
Informed Consent ........................................................................ 54 
13.1.4. 
Confidentiality .............................................................................. 54 
13.1.5. 
Study Files and Retention of Records .......................................... 54 
13.1.6. 
Electronic Case Report Forms (eCRF) ........................................ 56 
13.1.7. 
Drug Accountability ...................................................................... 56 
13.1.8. 
Inspections .................................................................................. 56 
13.1.9. 
Protocol Compliance .................................................................... 57 
13.2. 
Sponsor Responsibilities ............................................................................. 57 
13.2.1. 
Protocol Modifications .................................................................. 57 
13.2.2. 
Study Report and Publications ..................................................... 57 
13.2.3. 
Posting of Information on Publicly Available Clinical Trial 
Registers ..................................................................................... 57 
13.3. 
Joint Investigator/Sponsor Responsibilities ................................................. 57 
13.3.1. 
Access to Information for Monitoring ............................................ 57 
13.3.2. 
Access to Information for Auditing or Inspections ......................... 58 
13.3.3. 
Study Discontinuation .................................................................. 58 
14. REFERENCES ....................................................................................................... 59 
15. APPENDICES ........................................................................................................ 60 
15.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 60 
15.2. 
Appendix 2: Liver Laboratory Trigger and Liver Event Definitions 
and Follow-up Requirements ...................................................................... 62 
15.3. 
Appendix 3: Protocol Amendment Summary of Changes ............................ 65 
 
 


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2. 
PROTOCOL SUMMARY FOR STUDY RVT-1401-2003  
Study Title 
A Phase 2, Multicenter, Non-Randomized, Open-Label 
Study of RVT-1401 for the Treatment of Patients with Warm 
Autoimmune Hemolytic Anemia 
Objectives 
Primary 
To examine the effect of RVT-1401 on proportion of 
responders (defined as Hb level ≥10g/dL with at least a ≥2 
g/dL increase from baseline without rescue therapy or 
blood transfusions in the previous two weeks) 
To assess the safety and tolerability of RVT-1401 in 
subjects with WAIHA 
Secondary 
To examine the effect of RVT-1401 on change in Hb levels 
To examine the effect of RVT-1401 on time to response  
To examine the effect of RVT-1401 on change in 
hematocrit levels 
To examine the effect of RVT-1401 on proportion of 
participants with Hb levels in the normal range   
To examine the effect of RVT-1401 on time to achieving Hb 
levels in the normal range  
To examine the effect of RVT-1401 on change in fatigue  
To examine the effect of RVT-1401 on change in dyspnea 
To examine the effect of RVT-1401 on change in health-
related quality of life 
To assess the change in serum levels of total IgG & IgG 
subclasses (I-IV) 
To examine RVT-1401 PK following repeated doses in 
patients with WAIHA  
To assess the changes in LDH, bilirubin, haptoglobin 
To measure anti-RVT-1401 antibodies following repeated 
doses in patients with WAIHA 
Study Phase 
Phase 2 
Target Population 
Warm Autoimmune Hemolytic Anemia 


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Number of Participants 
Planned 
Approximately 16 participants 
Number of Study 
Centers Planned 
Approximately 22 centers 
Study Design 
Non-randomized, open-label study to investigate the 
efficacy, safety and tolerability of RVT-1401  
Duration of Treatment 
12 weeks 
Criteria for Evaluation 
(Endpoints) 
Primary 
Proportion of responders at week 13  
Assessment of safety and tolerability by analysis of adverse 
event (AE) data and changes from baseline in vital signs, 
ECGs, and clinical laboratory values 
Secondary 
Change from baseline in Hb levels 
Time to response  
Change from baseline in hematocrit levels 
Proportion of participants with Hb levels in the normal range 
at week 13   
Time to achieving Hb levels in the normal range  
Change from baseline in FACIT-F score 
Change from baseline in Medical Research Council (MRC) 
breathlessness scale 
Change from baseline in EQ-5D-3L score  
Change from baseline in levels of total IgG & IgG 
subclasses (I-IV) 
Concentration of RVT-1401 pre-dose (Ctrough)  
Change from baseline in LDH, bilirubin, and haptoglobin 
Immunogenicity determined by change from pre-dose in 
anti-RVT-1401 antibodies, and characterization of any anti-
RVT-1401 to confirm neutralization potential 
 


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3. 
INTRODUCTION 
3.1. 
Background 
RVT 1401 is a fully human anti-neonatal Fc receptor (FcRn) monoclonal antibody. FcRn 
is critical to the regulation of immunoglobulin G (IgG) [Roopenian, 2007]. In addition to 
its central role in mediating the transport of IgG within and across cells of diverse origin, 
it also serves to rescue IgG from degradation, thereby prolonging its circulating half-life 
[Roopenian, 2007]. Targeting the FcRn pathway has been shown to dramatically reduce 
circulating IgG, including auto-antibodies (Ab) of the IgG subclass, 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. 
3.2. 
Warm Autoimmune Hemolytic Anemia 
Autoimmune hemolytic anemia (AIHA) is caused by increased red blood cell (RBC) 
destruction triggered by autoantibodies that react against RBC antigens with or without 
complement.  Antibodies in warm autoimmune hemolytic anemia (WAIHA) react 
optimally at 37 degrees Celsius and is the most common type of AIHA, comprising 
approximately 70-80% of all adult cases [Sokol, 1981].  The most common antibody 
isotype involved in WAIHA is IgG, with a greater prevalence of IgG1 and IgG3 [Kalfa,   
2016].  Intravascular destruction of RBCs through complement mediated mechanisms 
contributes in only a minor percentage of WAIHA patients. In most patients, erythrocytes 
coated by warm reacting IgG are bound by spleen macrophages via FcR, which causes 
them to be either phagocytosed or have part of their membrane removed in the spleen.  In 
the latter case they form microspherocytes that are then subject to further destruction 
during their next passage through the spleen [Kalfa,  2016].  CD8+ T cells, and natural 
killer (NK cells) may also contribute to RBC lysis through antibody dependent cell 
mediated cytotoxicity (ADCC). RVT-1401, by reducing the levels of anti-RBC IgG, is 
hypothesized to be effective for the treatment of patients with WAIHA. 
The clinical presentation of WAIHA is characterized by fatigue, exertional dyspnea, 
pallor, and splenomegaly.  Common laboratory findings include: decreased hemoglobin 
(Hb), reticulocytosis, elevated unconjugated bilirubin and lactate dehydrogenase, serum 
aspartate aminotransferase disproportionately higher than serum alanine 
aminotransferase, and decreased haptoglobin [Kalfa, 2016]. 
Based on a paucity of phase 3 trials, the treatment of WAIHA is primarily guided by 
retrospective reviews, case series, expert opinions and a few small phase 2 trials.  
Nevertheless, Kalfa, et al, conclude that available evidence demonstrates that WAIHA 
can be fatal due to an acute presentation or due to refractory disease in spite of multiple 
lines of therapy.  [Kalfa, 2016].  Experts recommend initial treatment with high dose 
steroids (60-100mg/day) and note that most patients will respond to these doses.  Experts 
also recommend steroid taper after patients respond, due to toxicity of steroids at this 
high dose.   Patients with worsening disease as steroids are tapered are candidates for 
further lines of therapy with immunosuppressants.  Finally, although transfusions are 
generally reserved for stabilizing patients in the acute phase of WAIHA, some patients 


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require chronic transfusions due to WAIHA that is refractory to prednisone and or 
immunosuppressants. [Jaeger, 2019] 
3.3. 
Rationale 
3.3.1. 
Study Rationale 
The purpose of the current study is to assess the efficacy and safety of RVT-1401 in the 
treatment of WAIHA that is worsening or refractory in spite of therapy with steroids and 
or immunosuppressants or worsening with steroid or immunosuppressant taper. Results 
from this study will be used to inform dosing and to support progression into a Phase 3 
study. 
 
3.3.2. 
Dose rationale 
Two dosing regimens of RVT-1401 will be assessed in this non-randomized open label 
study.  Both will involve once weekly subcutaneous (SC) injections: 
• Dosing Regimen A -680 mg weekly for 12 weeks, and  
• Dosing Regimen B - 340 mg weekly for 12 weeks   
Given that there is a practical limit on the volume that can be administered via SC 
injection, these two doses represent what can be administered as a single SC injection 
(340 mg) and two SC injections (680 mg) per week with the current formulation.  
Expected Treatment Effect  
The proposed dosing regimens are expected to provide a sustained total IgG reduction of 
approximately 75-80% and 65-70% for Regimen A and B respectively. It is expected that 
the nadir IgG reduction will be achieved by the 3rd-5th dose (depending on dose studied) 
and maintained following the remaining doses before rising back to baseline over the 
next 6 to 8 weeks after stopping treatment.  
These assumptions are supported by preliminary pharmacodynamic (PD) results, shown 
in Figure 1, from the Phase 1 clinical study RVT-1401-1001 (Section 3.3.3). Dosing 
regimen A (weekly 680 mg) represents the dose that is expected to achieve the maximal 
effect in IgG reduction. In healthy participants, 4 weekly SC injections of 680 mg of 
RVT-1401 produced the maximum PD response with an average total IgG percent 
reduction from baseline of 78%. This effect occurred prior to the 4th dose and no further 
reduction was observed after dosing, indicating maximal reduction and steady state 
response had been achieved. In the 340 mg repeat dose cohort, there were some 
individuals who did not achieve nadir IgG concentration until after the last dose, 
indicating they may have not reached steady state.  Data from this study will be used to 
support dose selection in future studies.   


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Figure 1: Mean(+/-SD) Serum IgG Reduction Following Multiple SC Doses of RVT-
1401  
 
3.3.3. 
Clinical Experience 
Two Phase 1 clinical studies to assess safety, tolerability, pharmacokinetics (PK), and PD 
have been conducted in healthy volunteers under the RVT-1401 clinical development 
program. A total of 99 healthy subjects participated in these two studies, 77 of whom 
received at least 1 dose of RVT-1401. Table 1 summarizes the doses of RVT-
1401administered in healthy subjects. The dosing and recovery phase of these two studies 
have been completed and the study reports are being finalized.  Three additional studies 
are ongoing, investigating RVT-1401 use in Graves’ Ophthalmopathy and myasthenia 
gravis.    
Refer to Investigator’s brochure (IB) for additional information on clinical experience 
with RVT-1401. 


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Table 1: RVT-1401 Doses in Healthy Subjects 
RVT-1401 Dose  
Duration 
Healthy Subjects 
0.1 mg/kg 
Single 1 hr IV Infusion 
4 
0.5 mg/kg 
Single SC injection 
3 
1.5 mg/kg 
Single SC injection 
6 
5.0 mg/kg 
Single SC injection 
6 
340 mg 
Single SC injection 
6 
500 mg 
Single SC injection 
6 
765 mg 
Single SC injection 
6 
100 mg  
Single 1 hr IV Infusion 
6 
340 mg 
Single 1 hr IV Infusion 
6 
765 mg 
Single 1 hr IV Infusion 
6 
1530 mg 
Single 1 hr IV Infusion 
6 
340 mg 
4 weeks of once weekly SC injections* 
8 
680 mg 
4 weeks of once weekly SC injections 
8 
Total for All Studies 
77 
Abbreviations: IV, Intravenous; SC, subcutaneous 
* Note: 1 subject received 3 weeks and 1 subject received 2 weeks of once weekly SC injections  
3.3.3.1. 
 Safety 
See Investigator’s Brochure for details. 
RVT-1401 has been well tolerated with no Grade 3 or 4 adverse events (AEs), and no 
withdrawals due to AEs. There have been two serious adverse events (SAEs) 
(Malpighian carcinoma in left side of the neck and appendicitis) considered unrelated to 
study drug. 
All other AEs in subjects receiving RVT-1401 have been reported as mild or moderate.  
The most frequently reported AE was injection site reactions (erythema and/or swelling).  
The rate of injection site reactions was similar between RVT-1401-treated and placebo-
treated subjects and was not dose-related. Injection site reactions have generally resolved 
within a few hours after dosing; there were two exceptions of mild swelling (one RVT-
1401- and one placebo-treated subject) that resolved after 3 and 4 days, respectively. 
Additionally, injection site reactions were not consistently observed following every 
injection in the repeat dose cohorts. 


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Preliminary data suggest no subject who has received RVT-1401 had clinically relevant 
changes in vital signs or laboratory results, or on electrocardiogram (ECG).   
3.3.3.2. 
Pharmacokinetics 
 
3.3.3.3. 
Pharmacodynamics 
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 albumin reductions occurred following the 765 mg SC dose (
) but 
were not considered to be clinically significant reductions as all patients remained within 
normal limits (3.5 g/dL to 5.5 g/dL) and levels recovered quickly, returning to baseline ~ 
2 weeks after nadir.  
The amount of IgG reduction has also been assessed following weekly SC administration 
of 340 and 680 mg of RVT-1401 or placebo for 4 weeks. There were 8 and 7 subjects 
with data included in the preliminary PD analysis for the 680 mg and 340 mg cohorts 
respectively. Data from one subject who received 2 doses of 340 mg prior to early study 
withdrawal due to personal reasons was not included. Across the two cohorts, there were 
4 subjects who received placebo with data that contributed to the analysis of PD 
endpoints. Figure 1 presents the mean IgG concentration-time profiles, as a percent of 


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pre-dose, for both weekly SC administration of 340 mg and 680 mg doses. While both 
340 mg and 680 mg cohorts showed a reduction in serum IgG, the placebo group 
demonstrated minimal changes in serum IgG. The reduction in serum IgG was more rapid 
following the 680 mg SC compared with 340 mg SC. The median IgG nadir 
concentration occurred prior to the last dose in the 680 mg cohort whereas for 340 mg, it 
occurred approximately 3 days after the last dose. The finding that the 680 mg cohort 
achieved nadir concentration following the 3rd dose and maintained serum IgG reduction 
after the 4th dose, indicates a maximum response has likely been achieved, and that 
higher doses or more frequent dosing would yield little additional benefit. This is 
consistent with data from other anti-FcRn agents in development that have observed a 
maximum percent reduction in serum IgG from baseline of ~ 75-80% [Howard, 2019; 
Kiessling, 2017; Ling,  2018].   
Preliminary data following the last dose across both cohorts shows that IgG levels were 
within normal range and within 30% of the baseline value by 5 weeks after the last dose 
(average (SD) IgG concentration was 8.64 (2.73) g/L, and 8.95 (2.03) g/L for the 340 mg 
and 680 mg cohorts, respectively). The return towards baseline indicates the effect of 
RVT-1401 is reversible.  
Additional information is available in the current Investigator’s Brochure.  


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3.4. 
Benefit: Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with RVT-
1401 can be found in the current IB.   
3.4.1. 
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 anaphylaxis 
(i.e., serious, life-threatening allergic 
reactions) are ineligible. 
Participants will be closely monitored for 
reactions for 30 min post-dose.  
 
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 a past medical history of 
primary immunodeficiency, T-cell or 
humoral, including common variable 
immunodeficiency. 
-History of or known infection with human 
immunodeficiency virus (HIV), hepatitis B 
virus (HBV), or Mycobacterium 
tuberculosis:   
- Participants must have negative 
test results for HBV surface antigen, 
HBV core antibody, HIV 1 and 2 
antibodies, and a negative 
QuantiFERON-TB Gold test at 
Screening.   
- Hepatitis C virus (HCV):  
- Participants must have a negative 
test result for HCV antibody 
or 
- Participants with a known history of 
HCV must have documented 
evidence of sustained virologic 
response that is consistent with cure 
of hepatitis C infection that is 
Total IgG levels will be monitored 
throughout the study (Section 8.1).    


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confirmed with a negative HCV RNA 
test at Screening. 
-Absolute neutrophil count <1000 
cells/mm3 
Sustained 
hypoalbuminemia 
Participants with baseline albumin levels 
<3.5 g/dL will be ineligible. 
 
Subjects with advanced liver disease 
including any diagnosis of cirrhosis of any 
stage will be ineligible. 
 
Non-alcoholic fatty liver disease (NAFLD) 
including non-alcoholic steatohepatitis 
(NASH) is allowable if there has been a 
recent (within 6 months) normal 
ultrasound, CT, or MRI.  If the ultrasound, 
CT, or MRI demonstrate fatty changes 
alone, the subject may be enrolled if s/he 
has a normal range fibroscan for liver 
fibrosis. 
 
AST or ALT ≥1.5x ULN at Screening. The 
subject may only be enrolled if s/he has a 
recent (within 6 months) normal 
ultrasound, CT, or MRI. If the ultrasound, 
CT, or MRI demonstrate fatty changes 
alone, the subject may be enrolled if s/he 
has a normal range fibroscan for liver 
fibrosis. 
Serum albumin levels will be monitored 
throughout the study (Section 8.1).  
Criteria that would require dose 
interruption and/or discontinuation for 
Grade 2 and Grade 3 albumin levels have 
been added (Section 6.8.3). 
 
 
 
 


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4. 
OBJECTIVE(S) AND ENDPOINT(S) 
Objectives 
Endpoints 
Primary 
To examine the effect of RVT-1401 on 
proportion of responders (defined as Hb level 
≥10g/dL with at least a ≥2 g/dL increase from 
baseline without rescue therapy or blood 
transfusions in the previous two weeks) 
 
To assess the safety and tolerability of RVT-
1401 in subjects with WAIHA 
Proportion of responders at week 13  
 
 
 
 
 
Assessment of safety and tolerability by 
analysis of adverse event (AE) data and 
changes from baseline in vital signs, ECGs, 
and clinical laboratory values 
Secondary 
To examine the effect of RVT-1401 on 
change in Hb levels 
 
To examine the effect of RVT-1401 on time to 
response  
 
To examine the effect of RVT-1401 on 
change in hematocrit levels 
 
To examine the effect of RVT-1401 on 
proportion of participants with Hb levels in the 
normal range   
 
To examine the effect of RVT-1401 on time to 
achieving Hb levels in the normal range  
 
To examine the effect of RVT-1401 on 
change in fatigue  
 
To examine the effect of RVT-1401 on 
change in dyspnea 
 
To examine the effect of RVT-1401 on 
change in health-related quality of life 
 
To assess the change in serum levels of total 
IgG & IgG subclasses (I-IV) 
 
To examine RVT-1401 PK following repeated 
doses in patients with WAIHA  
 
To assess the changes in LDH, bilirubin, 
Change from baseline in Hb levels 
 
 
Time to response  
 
 
Change from baseline in hematocrit levels 
 
 
Proportion of participants with Hb levels in the 
normal range at week 13   
 
 
Time to achieving Hb levels in the normal 
range  
 
Change from baseline in FACIT-F score 
 
 
 
Change from baseline in Medical Research 
Council (MRC) breathlessness scale 
 
 
Change from baseline in EQ-5D-3L score  
 
 
Change from baseline in levels of total IgG & 
IgG subclasses (I-IV) 
 
Concentration of RVT-1401 pre-dose 
(Ctrough)  
 
Change from baseline in LDH, bilirubin, and 


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haptoglobin 
 
To measure anti-RVT-1401 antibodies 
following repeated doses in patients with 
WAIHA 
 
haptoglobin 
 
 
Immunogenicity determined by change from 
pre-dose in anti-RVT-1401 antibodies, and 
characterization of any anti-RVT-1401 to 
confirm neutralization potential 
Exploratory 
 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a Phase 2, non-randomized, sequential, open-label study to investigate the safety, 
tolerability, PK, PD, and efficacy of RVT-1401 (680 mg/weekly and 340 mg/weekly) in 
patients with WAIHA. The study design is illustrated in Section 5.2.  
Two cohorts of participants will be enrolled in a non-randomized sequential approach.  
Participants will be enrolled into Cohort 1 (680 mg/weekly) first followed by Cohort 2 
(340 mg/weekly).  In the Phase I healthy volunteer study, both dosing regimens were well 
tolerated (Section 3.3.3). Since 680 mg/weekly has the greater likelihood of 
demonstrating clinical efficacy, this dosing regimen will be studied in Cohort 1. 
Following the initial dose at the Baseline Visit (Week 1, Day 1), study visits will occur 
weekly throughout the treatment period.  Following the final dose at Week 12, visits will 
occur weekly through Week 14 and then at Week 16 and Week 20. Safety, PK, PD, and 
clinical assessments will be collected throughout the study.  Refer to Section 8.1, Time 
and Events Table. 




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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. Diagnosis of primary or secondary WAIHA as documented by a positive direct 
antiglobulin test (DAT) specific for anti-IgG alone or anti-IgG plus C3d. 
3. Secondary WAIHA may only include Stage 0 chronic lymphocytic leukemia (CLL) 
in which separate treatment is not indicated, nor anticipated to require active 
management for the duration of the study. 
4. Have failed or not tolerated at least one prior WAIHA treatment regimen as per local 
standards (e.g., steroids, rituximab, azathioprine, cyclophosphamide, cyclosporine, 
mycophenolate mofetil (MMF), danazol, or vincristine).  Failure is defined as 
worsening or refractory disease despite steroids and or immunosuppressants.  
5. Participants with splenectomy ≥3 months from Day 1 who are up to date on 
vaccinations (based on age and local guidance) are allowed. 
6. Haptoglobin < lower limit of normal (LLN) and lactate dehydrogenase (LDH) 
>upper limit of normal (ULN). 
7. At Screening and Baseline, subject's hemoglobin level must be <10 g/dL and the 
subject must have documented symptoms related to anemia (e.g., weakness, 
dizziness, fatigue, shortness of breath, chest pain). 
8. Karnofsky Performance status ≥ 60. 
9. Subject's concurrent treatment for WAIHA may consist only of steroids (stable dose 
for at least two weeks prior to Day 1), immunosuppressant therapy (azathioprine, 
MMF, or cyclosporine) that has been at a stable dose for at least four weeks prior to 
Day 1, or erythropoietin (stable dose for at least 6 weeks prior to Day 1). [Note: 
starting doses of WAIHA therapy must be maintained throughout the study except in 
the case of a rescue medication as per local standards for safety.  Steroid taper down 
to 10 mg/day will be allowed for participants who achieve response for at least 2 
weeks.] 
10. 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. 


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11. 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. 
12. 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. Participants with other types of AIHA (e.g., cold antibody AIHA, cold agglutinin 
syndrome, mixed type AIHA, or paroxysmal cold hemoglobinuria). 
2. Participants requiring more than 2 units of RBC per week in the 2 weeks prior to 
Screening and Baseline.  
3. Use of rituximab, any monoclonal antibody for immunomodulation, or proteasome 
inhibitor, within the past 3 months prior to Screening. 
4. Immunoglobulins given by SC, IV (IVIG), or intramuscular route, or 
plasmapheresis/plasma exchange (PE) within 60 days before Screening. 
5. Total IgG level <6 g/L (at Screening). 
6. Absolute neutrophil count <1000 cells/mm3(at Screening). 
7. Albumin level <3.5 g/dL at Screening. 
8. Known advanced liver disease including any diagnosis of cirrhosis of any stage.  
 
Non- alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis 
(NASH) is allowable if there has been a recent (within 6 months) normal ultrasound, 
CT, or MRI. If the ultrasound, CT, or MRI demonstrate fatty changes alone, the 
participant may be enrolled if s/he has a normal range fibroscan for liver fibrosis. 
9. AST or ALT ≥1.5x ULN at Screening.  
The participant may only be enrolled if s/he has a recent (within 6 months) normal 
ultrasound, CT, or MRI. If the ultrasound, CT, or MRI demonstrate fatty changes 
alone, the participant may be enrolled if s/he has a normal range fibroscan for liver 
fibrosis. 
10. 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. 
11. Medical history of primary immunodeficiency, T-cell or humoral, including common 
variable immunodeficiency. 
12. Have an active infection, a recent serious infection (i.e., requiring injectable 
antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening. 


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13. History of or known infection with human immunodeficiency virus (HIV), hepatitis 
B virus (HBV), or Mycobacterium tuberculosis:   
- Participants must have negative test results for HBV surface antigen, HBV core 
antibody, HIV 1 and 2 antibodies, and a negative QuantiFERON-TB Gold test at 
Screening.   
- Participants with an indeterminate QuantiFERON-TB Gold test result will be 
allowed one retest; if not negative on retesting, the participant will be excluded. 
14. Infection with hepatitis C virus (HCV):  
- Participants must have a negative test result for HCV antibody. 
or 
- Participants with a known history of HCV must have documented evidence of 
sustained virologic response that is consistent with cure of hepatitis C infection.  
This is defined as undetectable or unquantifiable HCV RNA at least 12 weeks after 
stopping HCV treatment (HCV Guidance: Recommendations for Testing, Managing, 
and Treating Hepatitis C; 2014-2018, AASLD and IDSA).   This should be 
confirmed with a negative HCV RNA test at Screening. 
15. Active malignancy or history of malignancy in the 3 years prior to screening 
(exclusive of non-melanoma skin cancer and cervical cancer in situ). 
16. 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. 
17. Body Mass Index (BMI) at Screening ≥ 40 kg/m2. 
18. Use of investigational drug within 60 days or 5 half-lives of the drug (whichever is 
longer) before Screening.  
19. Participant has received a live vaccination within 2 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. 
20. History of sensitivity to any of the study treatments, or components thereof or a 
history of anaphylaxis (i.e., serious, life-threatening allergic reactions) that, in the 
opinion of the Investigator or Medical Monitor, contraindicates their participation. 
21. Pregnant or lactating females as determined by positive serum or urine human 
chorionic gonadotropin test at screening or baseline. 
22. QTcF interval >450 milliseconds for males and >470 milliseconds for females at 
Screening (a single repeat is allowed for eligibility determination).  QTcF >480 msec 
in participants with Bundle Branch Block. 
23. Diagnosis of concomitant idiopathic thrombocytopenia purpura (ITP)/ Evans 
syndrome with platelet count <100,000. 
 


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6.4. 
Other Eligibility Criteria Considerations 
To assess any potential impact on participant eligibility with regard to safety, the 
Principal Investigator must refer to the following document(s) for detailed information 
regarding warnings, precautions, contraindications, AEs, and other significant data 
pertaining to the investigational product(s) being used in this study: 
RVT-1401 Investigator’s Brochure 
 
6.5. 
Screening/Baseline Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently enrolled.  A minimal set of screen failure information is 
required including date of informed consent, 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). 
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% 
Hormonal  
• Female participants and female partners of male study participants stable for at 
least 4 weeks prior to screening on a combined hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal) PLUS a barrier 
method (i.e., condom or occlusive cap [diaphragm or cervical/vault caps]).   
• Female participants and female partners of male study participants stable for at 
least 4 weeks prior to screening on a Progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable) PLUS a 
barrier method (i.e., condom or occlusive cap [diaphragm or cervical/vault caps]). 
• Female participants and female partners of male study participants using a 
hormonal contraceptive must also use a barrier method (i.e., condom or occlusive 


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cap [diaphragm or cervical/vault caps]) and should have been stable on their 
hormonal contraceptive treatment for an appropriate period of time (as determined 
by the product label or Principal Investigator) prior to the start of dosing to 
sufficiently minimize the risk of pregnancy at that point.   
Long-Acting Reversible  
• Female participants and female partners of male study participants with an 
Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label. 
Male Contraception 
• 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.  
 
• Sterilized male participants who have had vasectomy with documented 
azoospermia post procedure can be included.  
Additional Considerations for Male Participants 
• Non-sterilized male participants who are sexually active with a female partner of 
childbearing potential must use effective method of double barrier contraception. 
Male participants practicing true sexual abstinence (when this is in line with the 
preferred and usual lifestyle of the participant) can be included. In addition, male 
participants must be advised not to donate sperm during this period from signing 
of Informed Consent Form (ICF), throughout the duration of the study, and for 90 
days after the last administration of study drug. 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring participants understand how to properly use these methods of contraception. 
Participants must be completely informed of the unknown risks of pregnancy and agree 
not to become pregnant during the time they are participating in this study. If there is any 
question that a participant will not be reliable in the use of appropriate contraceptive 
methods, they should not be entered into the study. 
 
6.7. 
Withdrawal Criteria 
6.7.1. 
Reasons for Withdrawal  
A Principal Investigator may discontinue/withdraw a participant from the study if any of 
the following criteria apply: 


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• 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 (e.g., non-compliance with concomitant 
medications) 
• Behavioral or administrative issue 
• 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 (IRB)/ Independent Ethics Committee (IEC) 
• 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 the study, 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.  In cases where the participant does not return for the 
rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the participant (3 documented telephone calls 
and if necessary a certified letter to the participant’s last known mailing address) so that 
they can appropriately be withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
 
6.8. 
Safety Management Criteria for Individual Participants 
6.8.1. 
Liver Chemistry Management Criteria 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential 
of an investigational drug, a standardized process for identification, monitoring and 
evaluation of liver events is to be followed. 


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The following two categories of abnormalities / adverse events are to be considered 
during the course of the study (irrespective of whether classified/reported as an AE or 
SAE): 
1. Liver laboratory triggers. These require repeated assessments of the abnormal 
laboratory parameter 
2. Liver events. These require close observation and follow-up monitoring. Contributing 
factors are to be recorded on the appropriate CRF(s). 
Please refer to Appendix 2 Table 4 for complete definitions of liver laboratory triggers 
and liver events. Every liver event defined in Appendix 2 Table 5 to be followed up by 
the investigator or designated personnel at the trial site, as summarized below. 
Additionally, required actions in case of liver laboratory triggers and liver events are 
outlined in Appendix 2, Table 5 (Follow up requirements for liver laboratory triggers and 
liver events). Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-
GT) regularly to confirm elevation and follow trends. 
The following additional follow up should also be considered: 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
• 
Obtain a history of concomitant drug use (including non-prescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 
• 
Exclude causes of underlying liver disease, as specified in Section 6.3 Exclusion 
Criteria 
• 
Perform imaging such as abdominal US, CT or MRI, as appropriate 
• 
Obtain a history of exposure to environmental chemical agents. 
• 
Consider gastroenterology or hepatology consultations. 
All follow-up information and procedures performed must be recorded as appropriate in 
the CRF. 
These liver chemistry repeats will be performed using the central laboratory. If results 
will not be available from the central laboratory, then the repeats can also be performed at 
a local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF. 
 
6.8.2. 
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 two repeated 
12-lead ECGs 
 


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6.8.3. 
Albumin Monitoring Criteria 
In addition to lowering IgG, treatment with RVT-1401 is also expected to reduce serum 
albumin levels (Section 3.3.3.3).  The following criteria are to be used to guide study 
drug administration: 
• 
Grade 2 (albumin levels 2.0 g/dL - 3.0 g/dL): If there are no accompanying clinical 
signs and/or symptoms, no action will be taken with study drug. 
• 
Grade 3 (albumin levels <2.0 g/dL):  
• 
Subjects with no signs/symptoms: study drug should be interrupted until 
albumin reached a level of 2.5 g/dL, at which point it may be restarted  
• 
Subjects with signs/symptoms limited to peripheral edema managed with 
diuretics: study drug should be interrupted until albumin reaches a level of 2.5 
g/dL, at which point it may be restarted.  
• 
Subjects with signs/symptoms requiring treatment beyond diuretics: discontinue 
study drug 
Grade 4 albumin levels:  permanent discontinuation of study drug  
6.8.4. 
Other Individual Stopping Criteria 
• 
Subject has signs or symptoms of a serious infective episode requiring 
hospitalization or iv antibiotic therapy. 
• 
Participant has a severe systemic allergic reaction (i.e., anaphylaxis) to study 
therapy. 


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6.9. 
Toxicity Management Criteria 
6.9.1. 
Toxicity Management Criteria (AEs, Cardiovascular, and Injection 
Site Reactions) 
The severity of each AE will be graded and managed according to the criteria in Table 2 
(CTCAE version 5.0). Study drug should be permanently discontinued for any grade 4 
toxicity other than hemoglobin decrease.  Management of hemoglobin < 7.0 g/dL or 
anemia in the presence of cardiovascular symptoms is described in section 6.9.2. For 
grade 3 TEAE not considered related to WAIHA signs/symptoms, study drug should be 
withheld. Study drug may only be restarted following a grade 3 TEAE after discussion 
with the medical monitor.Table 2 
Criteria for Determining the Grade/Severity of 
Adverse Event Terms 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations 
only; intervention not indicated 
2/Moderate 
Limiting age-appropriate instrumental activities of daily living; 
minimal, local, or noninvasive intervention as indicated 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care activities of 
daily living, intervention as indicated 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
 
Injection Site Reactions 
Injection site evaluations will be made by clinical staff following administration of RVT-
1401 as described below.  Additional details related to the specific injection site location 
will be included within a study specific manual. If an injection site reaction is observed, a 
physician will characterize and document the reaction as an AE. Review of the injection 
site will continue until the AE is resolved. Symptomatic treatment (e.g., warm 
compresses, topical steroids, antihistamines if itching is present, or NSAIDs) may be 
provided for injection site reactions at 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 3. 


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Table 3 
Criteria for Determining the Grade/Severity of Injection Site 
Reactions 
Grade 
Criteria 
1/Mild 
Tenderness with or without associated symptoms (e.g., warmth, 
erythema, itching) 
2/Moderate 
Pain; lipodystrophy; edema; phlebitis 
3/Severe or medically significant 
Ulceration or necrosis; severe tissue damage; operative 
intervention indicated 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Published: November 27, 2017. 
 
6.9.2. 
Management of Rescue Therapy 
Rescue therapy during the first 8 weeks of the Treatment Period is permitted for 
participants with haemoglobin levels <7.0 g/dL or in the presence of signs/symptoms of 
myocardial ischemia, hypoxia, or TIA/stroke. Participants requiring rescue therapy after 
the Week 8 visit will be discontinued and an early withdrawal visit scheduled.  
Blood Transfusion 
The date, time, and number of units transfused should be recorded, along with the results 
of cross-match testing.  Follow-up hemoglobin should be measured with 12 hours of the 
end of the transfusion. Hemoglobin values will be censored from efficacy analyses for the 
2 weeks following a blood transfusion. 
Prednisone/Prednisolone 
Prednisone/prednisolone rescue (up to a 50% increase from baseline for up to 5 days), is 
permitted as per the rescue therapy guidelines (Section 6.9.2).  The date, time, and dose 
should be recorded.  Hemoglobin values will be censored from efficacy analyses for the 2 
weeks following the last dose of prednisone/prednisolone rescue. 
Dexamethasone 
High dose dexamethasone (up to 40 mg daily for up to 4 days) is permitted as per the 
rescue therapy guidelines (Section 6.9.2). The date, time, and dose should be recorded.  
Hemoglobin values will be censored from efficacy analyses for the 2 weeks following the 
last dose of dexamethasone rescue.    
IVIG and Plasma Exchange 
Due to the mechanism of action for RVT-1401, the use of IVIG and Plasma exchange are 
not allowed. 
 


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6.9.3. 
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.  
• 
Initiation of rescue therapy (see Section 6.9.2) 
 
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. 
 
7. 
STUDY TREATMENT 
7.1. 
Investigational Product and Other Study Treatment 
Investigational Product 
Study Treatment Name: 
RVT-1401 
Manufacturer: 
 
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: 2 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 
Participants will receive either open-label RVT-1401 680 mg/weekly or 340 mg/weekly 
treatment for up to a maximum of 12 weeks.   
7.3. 
Blinding 
This is an open-label study. 




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The date and time of each dose administered along with the location of each injection 
will be recorded in the source documents.  The location of each injection and study 
participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study drug.  
 
7.7. 
Treatment of Study Treatment Overdose 
An overdose is defined when a participant receives >680 mg in a single visit.  The 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose the Investigator or treating physician should: 
• contact the Medical Monitor immediately, 
• closely monitor the participant for AEs/SAEs and laboratory abnormalities. 
• obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis) 
• document the quantity of the excess dose as well as the duration of the overdosing 
in the eCRF 
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
 
7.8. 
Treatment After the End of the Study 
Participants will not receive any additional treatment with the study treatment from the 
Sponsor after completion of the study because the long-term safety and efficacy of RVT-
1401 have not been established. 
The Principal Investigator is responsible for ensuring that consideration has been given to 
the post-study care of the participant’s medical condition.  
 
7.9. 
Concomitant 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 the study inclusion and exclusion criteria (Section 6.2 and Section 6.3) and the 
study manual for a list of permitted and prohibited medications.  


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
This section lists the procedures and parameters of each planned study assessment. All 
blood draws and rating scale assessments should be completed pre-dose (on dosing days).  
The timing of each assessment is listed in the Time and Events Table, Section 8.1.  
The following points must be noted:  
• 
The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form.  
• 
The total blood volume collected will be specified within the ICF. 
 


 
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8.1. 
Time and Events Table  
 
Screening1 
Treatment Period 
(Weeks) 
Follow-up Period 
(Weeks) 
Early 
Withdrawal Visit 
Study Timepoint 
(Weeks) 
Within 30 
days 
1 
(B/
L) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
20 
 
Time Window (days) 
 
 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
medical history9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead 
Electrocardiogram2 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Pregnancy test3 
(females) 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine Titers2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
QuantiFERON® – TB 
GOLD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis2, 4 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Blood chemistry and 
hematology2, 8 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Fasting Lipid Panel2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Serum complement 
(CH50, C3)2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Immunoglobulins (IgM, 
IgA)2 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 


 
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Screening1 
Treatment Period 
(Weeks) 
Follow-up Period 
(Weeks) 
Early 
Withdrawal Visit 
Study Timepoint 
(Weeks) 
Within 30 
days 
1 
(B/
L) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
20 
 
Time Window (days) 
 
 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
 
+/-2 
days 
 
+/-2 
days 
 
+/-2 
days 
 
+/- 
2 days 
 
RVT-1401 PK sampling2 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
Total IgG2,6 
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 
Anti- RVT-
1401antibody2, 5 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
NAb Assessment2 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Drug administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Injection Site Reaction7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
FACIT-F Scale2  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
MRC Breathlessness 
Scale2  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
EQ-5D-3L2  
 
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 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Screening can take place over multiple days. 
2. 
Assessments collected on dosing days will be collected pre-dose. 
3. 
Pregnancy tests will be collected pre-dose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening and the final follow up visit. 
4. 
Microalbumin/creatinine ratio at baseline, week 13, and week 20 only.   
5. 
Participants with treatment emergent positive results (change from baseline) for anti- RVT-1401 antibody at Week 20 will be requested to return at approximately 6, 9, and 12 months post-dose for additional samples or 
until their result is no longer positive. However, for purposes of safety follow-up and database lock participation ends at the Week 20 visit.  
6. 
Two samples for IgG will be collected: one will be sent to the central lab for safety monitoring, while the other sample will be sent to Intertek as the PD endpoint. 
7. 
Local injection site reactions will be assessed at approximately 10 minutes post dose. 


 
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8. 
Hematology, HbA1c and 
 will be drawn for site local laboratory analysis, at minimum, and results collected in the instance where central laboratory samples are received hemolyzed.  If other central laboratory tests 
are received hemolyzed, the local result will be captured in the eCRF. 
9. 
History of WAIHA and prior WAIHA treatments will be captured in the eCRF. 
 


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8.2. 
Screening and Critical Baseline Assessments 
Screening assessments are outlined in the Time and Events Table, (Section 8.1). The 
following demographic parameters will be captured: year and month of birth, sex, race 
and ethnicity. 
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. 
Vital Signs 
Vital signs will be measured in a supine position and will include temperature, systolic 
and diastolic blood pressure and pulse oximetry.  
 
8.3.3. 
Electrocardiogram (ECG) 
ECGs will be measured in a 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 6.8.2 for QTcF criteria and additional QTcF readings that may be 
necessary. 
 
8.3.4. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments must be conducted in accordance with a 
study manual or Laboratory Manual, and Protocol Time and Events Table (Section 8.1).   
Laboratory requisition/order 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 study manual or the laboratory manual.  Investigators will also 




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Lipid Panel 
(fasted)  
Week 1, Week 13, 
Final Follow 
up/Early 
Withdrawal only 
 
 
Total cholesterol  
Triglycerides  
HDL cholesterol  
LDL cholesterol (calculated using Martin-Hopkins equation) 
Cholesterol/HDL ratio  
Non-HDL cholesterol (calculated) 
CRP/ High sensitivity CRP 
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) 
Microalbumin/creatinine ratio at baseline, week 13, week 20 (if urine protein is abnormal) 
Other tests 
QuantiFERON®-TB Gold 
Viral Serology [HIV1/HIV2, Hepatitis B (HBsAg), Hepatitis B (Core antibody), Hepatitis C (Hep C 
antibody] 
Vaccine titers for: tetanus, diphtheria, Hepatitis A, Hepatitis B, Pneumococcal 
FSH (as needed for confirmation of postmenopausal status) 
Pregnancy Tests:  serum test at screening, Week 20, and early withdrawal and urine dipstick pre-
dose at other timepoints. Positive urine tests should be confirmed with a serum test. 
 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
Principal Investigator, the etiology should be identified, if possible and the Sponsor 
notified. 
 
8.3.5. 
Pharmacokinetics 
Blood samples for PK analysis of RVT-1401 will be collected at the time points indicated 
in Section 8.1, Time and Events Table.  The actual date and time of each blood sample 
collection will be recorded.     
Processing, storage and shipping procedures are provided in the study manual 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. 


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8.3.6. 
Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) 
Blood samples for ADA and NAb analysis will be collected at the time points indicated 
in Section 8.1, Time and Events Table.  The actual date and time of each blood sample 
collection will be recorded.   
Processing, storage and shipping procedures are provided in the study manual or lab 
manual. 
ADA analysis will be performed under the control of the Sponsor.  Anti-RVT-1401 
antibody titers will be determined in serum samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site.  If anti-
RVT-1401 antibody titers are detected, they will be further characterized using a 
validated NAb assay. 
Participants with treatment emergent positive results (change from baseline) for anti- 
RVT-1401 antibody at Week 20 will be requested to return at approximately 6, 9, and 12 
months post-dose for additional samples or until their result is no longer positive. 
However, for purposes of safety follow-up and database lock participation ends at the 
Week 20 visit. 
8.3.7. 
Pharmacodynamics 
Blood samples for PD analysis will be collected at times indicated in the Time and 
Events Table (Section 8.1).   
Pharmacodynamic Markers 
Total IgG, and differentiation by class: 
IgG subclasses (IgG1, 2, 3, and 4)  
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 study manual or lab manual. 
8.3.8. 
Exploratory Biomarkers 
Blood samples for exploratory biomarker analysis will be collected at times indicated in 
the Time and Events Table (Section 8.1).  
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 


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ensure thorough biomarker assessment. Samples will be collected, labelled, stored, and 
shipped as detailed in the study manual or lab manual. 
 
8.4. 
Rating Scales & Questionnaires 
8.4.1. 
Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F) Scale  
The FACIT-F scale is a validated scale which measures the physical, emotional and 
social implications of fatigue, one of the key clinical manifestations of warm autoimmune 
hemolytic anemia [Acaster, 2015; Webster, 2003]. Scores range from 0-52, with a higher 
score indicating a higher quality of life. A score of less than 30 would indicate severe 
fatigue. The scale takes approximately 5-10 minutes to complete.  
8.4.2. 
Medical Research Council (MRC) Breathlessness Scale  
The MRC Breathlessness scale is a questionnaire that consists of five statements about 
perceived breathlessness. The focus of the scale is to quantify the disability associated 
with breathlessness and not the severity of the breathlessness [Stenton, 2008]. This scale 
has undergone iterations with the current Modified MRC Subject Version, ranging from 
Grade 0 (limited to no disability) to Grade 4 (severe disability). This scale has been used 
in patients with chronic obstructive pulmonary disease (COPD), where the researchers 
further stratified on patients with low hemoglobin levels. Their data demonstrate that 
anaemic COPD patients had significantly higher MRC [Ferrari , 2015]. The scale can be 
self-administered by asking subjects to choose a phrase that best describes their 
condition. The score is the number that best fits the patient’s level of activity. A score can 
usually be obtained in less than a minute.  
8.4.3. 
EQ-5D-3L Scale  
The EQ-5D-3L is a validated measurement of health-related quality of life [Devlin, 2018; 
Hernandez , 2018]. The scale consists of 2 components, the EQ-5D descriptive system 
and the EQ visual analogue scale. The descriptive system evaluates mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. The scale can be self-
administered by subjects who select the most appropriate statement within each category. 
A lower score corresponds to better quality of life. The EQ VAS records the patient’s 
self-rated health on a vertical visual analogue scale where the endpoints are labelled ‘Best 
imaginable health state’ (100) and ‘Worst imaginable health state’ (0). The patient can 
select any number from 0-100. Completion of both components of the scale can be 
performed in under 5 minutes.   
8.4.4. 
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. 
 


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9. 
DATA MANAGEMENT 
For this study, participant data will be entered into a Sponsor-approved electronic 
database and combined with data provided from other sources (e.g., safety laboratory, PK 
and PD vendor, etc.) in validated datasets then transmitted electronically to the Sponsor 
or designee.   
Management of clinical data will be performed in accordance with applicable Sponsor 
approved standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data. 
Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and the World Health Organization 
Drug Dictionary Enhanced (WHO-DDE), respectively.   
The Principal Investigator will retain original source documents and the Sponsor will 
receive eCRF-required data as electronic datasets. Participant initials will not be collected 
or transmitted to the Sponsor. 
 
10. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
10.1. 
Sample Size Considerations 
The sample size for this study was not determined using statistical methods.  The sample 
size was chosen based on clinical and recruitment considerations for this Phase 2 study.   
10.2. 
Statistical Considerations 
10.2.1. 
Analysis Populations 
Intention-To-Treat (ITT) Population 
All enrolled participants who take at least one dose of study medication will be included 
in the ITT population.  Participants will be summarized by treatment group. 
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 


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The PK Population will include all participants who undergo PK sampling and have 
evaluable concentration-time data for analysis. 
Pharmacodynamic Population  
The PD population will include all participants who have baseline measure, along with a 
post baseline measure and receive at least one dose of study treatment. 
 
10.3. 
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 2-sided 95% confidence interval (CI), 
and the between-participant CV (%CVb) for PK parameters only will also be included.  
For categorical variables, n and percent will be used as summary statistics. Baseline is the 
last available assessment prior to time of the first dose unless it is specified otherwise.  If 
there are multiple assessments collected on the same scheduled time, the average of these 
assessments will be used.  For tabulated safety summaries, only the scheduled 
assessments will be included in the summary tables. 
Version 9.4 or higher of the SAS system will be used to analyze the data as well as to 
generate tables, figures, and listings. 
Complete details will be documented in the Statistical Analysis Plan (SAP), which will 
be signed off prior to the lock of the study database. 
 
10.3.1. 
Baseline Demographics and Characteristics 
Subjects baseline demographics and characteristics will be summarized by the treatment 
groups, and by overall.  
10.3.2. 
Primary Endpoint for Efficacy 
The primary endpoint will be defined as the proportion of responders at Week 13. The 
Fisher’s exact test will be used for the difference between the two treatment groups.  
The analysis of the primary endpoint will be performed on ITT based on all available 
data, without using any imputation method for missing data. 


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10.3.3. 
Secondary Endpoints for Efficacy 
For each of the continuous secondary endpoints, the actual value, change from baseline 
and percentage change from baseline for all secondary endpoints will be summarized by 
visit and treatment group using the n, mean, SD, median, first and third quartiles, 
minimum, and maximum values.  The comparison of the active arms (separately) will be 
performed using a Mixed Model for Repeated Measures (MMRM)/ Analysis of 
Covariance model with treatment, Visit, and baseline value in the model.  The least 
square means of the treatment difference, standard errors, 95% CI and p-value for the 
treatment will be presented at each visit. A 2-sided alpha of 0.05 will be used to 
determine statistical significance for Treatment.  If deemed appropriate, the two active 
arms may be combined to evaluate any treatment effect for the changes from the baseline. 
For categorical secondary endpoints, the number of participants who meet the endpoint 
and the percentage will be summarized.  The percentage will be calculated using those 
participants who had a value at the time point.  Statistical testing may be performed 
between the two treatments using a Fishers Exact Test.  If deemed appropriate, the two 
active arms may be combined to evaluate any treatment effect for the shift from the 
baseline.  
The analyses of the secondary endpoints will be performed on ITT based on all available 
data, without using any imputation method for missing data. 
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 on the Safety 
Population. 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 for the PK Population.  
From the plasma concentration-time data, Ctrough will be determined:  
Additional PK parameters may be calculated.  PK data will be presented in graphical and 
tabular form and will be summarized descriptively by Treatment.   


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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 and IgG subclass (1-4) levels will be summarized as both raw values as well 
as percent change from baseline (intra-participant assessment). Additional PK/PD and 
PD/PD relationships may be evaluated.  PD data will be presented in graphical and 
tabular form and will be summarized descriptively. The correlation coefficients will be 
generated between PK/PD parameters.  
10.3.7. 
Other Analyses 
The analysis of the exploratory endpoints will include all participants in the ITT 
population.   
 
11. 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE 
EVENTS (SAES) 
The Principal Investigator or site staff is responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.  All SAEs must be reported to 
the Sponsor within 24 hours of awareness of the event (Section 11.3). 
Once 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 notify the Sponsor at 
within 24 hours of awareness. 
 
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: 


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• 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. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction (e.g. with 
medications or food). 
• Signs, symptoms, or the clinical sequelae of an overdose of either investigational 
product or a concomitant medication (overdose without an AE should be reported 
as a protocol deviation). 
Events that do not meet the definition of an AE include: 
• Anticipated day-to-day fluctuations of pre-existing condition(s), including the 
disease under study. 
• 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 entered within 24 hours of awareness and 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: 
• 
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 immediate 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. 


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“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 participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. Examples of such events are allergic bronchospasm, blood 
dyscrasias or convulsions where treatment prevents the need for hospitalization. 
The following should always be considered serious:  invasive or malignant cancers, and 
development of drug dependency or drug abuse. 
 
• 
Deaths considered to be the result of progression of WAIHA or failure of treatment 
should be recorded as SAEs; the most prominent event (e.g. autoimmune hemolytic  
anemia or thrombosis due to WAIHA) should be recorded as the event term with an 
outcome of death. 
• 
Hospitalization for urgent transfusion or treatment of symptoms associated with 
recurrence of WAIHA; the most prominent event should be recorded as the event 
term. 
11.3. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
AEs will be collected from the time of informed consent through the follow-up 
period, at the timepoints specified in the Section 8.1, Time and Events Table. 
• 
Medical occurrences that begin prior to any study procedure but after obtaining 
informed consent may be recorded on the Medical History/Current Medical 
Conditions section of the eCRF. 
• 
All SAEs will be recorded and reported to the Sponsor within 24 hours of site 
awareness. 
• 
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to investigational 
product will be recorded from the time a participant consents to participate in the 
study up to and including any follow-up contact.  
 


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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.  After the diagnosis is determined, individual symptoms 
of that diagnosis may be removed from the database. All relevant seriousness criteria 
should be entered for each SAE. 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 
 after redacting all personally identifying 
information regarding patient or hospital staff (per European Global Data Protection 
Regulation). 
 
11.5. 
Assessing Severity of AEs and SAEs 
Severity describes the intensity of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical 
significance, such as a severe headache.  This is not the same as “serious,” which is based 
on participant/event outcome or action taken.  
The Investigator must determine the severity of each AE according to the following 
criteria:  
Criteria for Determining the Grade/Severity of Adverse Event Terms  
Grade  
Criteria  
1/Mild  
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated  
2/Moderate  
Minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily 
living  
3/Severe or medically 
Not immediately life-threatening; hospitalization or 


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significant  
prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living  
4/Life-threatening  
Life threatening consequences; urgent intervention 
indicated.  
(Note that the seriousness criteria “life-threatening” applies 
only if the event is immediately life-threatening; an event 
such as cancer or neutropenia may be Grade 4 but not meet 
seriousness criteria of Life-threatening) 
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 
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 


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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 should be recorded as 
a protocol deviation.  Overdose with symptoms should be recorded as an AE or SAE, as 
appropriate. 
 
12. 
PREGNANCY REPORTING 
All female participants will be tested for pregnancy prior to study drug dosing. 
Participants testing positive for pregnancy will be ineligible for study participation.  
Any pregnancies in a participant, or the partner of a participant, between the time of 
informed consent and study termination must be reported to the Sponsor within 24 hours 
of learning of the pregnancy. Information on the status and health of the mother, the 
pregnancy and its outcome, and the child will be recorded on the form provided. In case 
of a partner pregnancy, the partner of the study participant will be asked to sign a partner 
pregnancy consent form in order to collect pregnancy and outcome information. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Follow-up will be done for the newborn at birth and 12 months of age with parental 
consent.  Any premature termination of the pregnancy will be reported. Complications of 
the pregnancy affecting either the mother or fetus that meet seriousness criteria (Section 
11.2) should be reported as an SAE.  A planned abortion is not considered an SAE. 


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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: 


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• 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 


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


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If the Principal Investigator cannot guarantee this archiving requirement at the study site 
for any or all of the documents, special arrangements must be made between the Principal 
Investigator and the Sponsor to store these in sealed containers outside of the site so that 
they can be returned sealed to the Principal Investigator in case of a regulatory audit.  
When source documents are required for the continued care of the participant, 
appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the 
Sponsor for a period up to 10 years for purposes of this study. 
 
13.1.6. 
Electronic Case Report Forms (eCRF) 
For each participant enrolled, an eCRF must be completed and signed by the Principal 
Investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection.  This also applies to records for those participants who fail to complete the 
study (even during the screening period if an eCRF was initiated).  If a participant 
withdraws from the study, the reason must be noted on the eCRF.  If a participant is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome. 
 
13.1.7. 
Drug Accountability 
The Principal Investigator or designee (i.e., pharmacist) is responsible for ensuring 
adequate accountability of all used and unused investigational product.  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 return all unused investigational 
medicinal product supplies.  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 


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representatives, to IRBs or IECs, or to regulatory authority or health authority inspectors. 
 
13.1.9. 
Protocol Compliance 
The Principal Investigator is responsible for ensuring the study is conducted in 
accordance with the procedures and evaluations described in this protocol. 
 
13.2. 
Sponsor Responsibilities 
13.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study 
participants, may be made only by the Sponsor. 
13.2.2. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies).  The 
Sponsor will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated 
report may be prepared in certain cases. 
 
13.2.3. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers within 21 days of enrollment of the first participant.  Results will be posted as 
required. 
 
13.3. 
Joint Investigator/Sponsor Responsibilities 
13.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have 
direct access to the Principal Investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on them.  The monitor should have 
access to any participant records needed to verify the entries on the eCRFs.  The Principal 
Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
 


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13.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the Sponsor may conduct inspections or 
audits of the clinical study.  If the Principal Investigator is notified of an inspection by a 
regulatory authority the Principal Investigator agrees to notify the Sponsor medical 
monitor immediately.  The Principal Investigator agrees to provide to representatives of a 
regulatory agency or the Sponsor access to records, facilities, and personnel for the 
effective conduct of any inspection or audit. 
 
13.3.3. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be 
necessary, the Sponsor will arrange discontinuation procedures and notify the appropriate 
regulatory authority (ies), IRBs, and IECs.  In terminating the study, the Sponsor and the 
Principal Investigator will assure that adequate consideration is given to the protection of 
the participants’ interests. 
Reasons for stopping the study may include but are not limited to:  
• 
New evidence that, in the opinion of the sponsor, makes continuation of the study 
unnecessary or unethical 
• 
The sponsor discontinues development of RVT-1401 
• 
Insufficient patient enrollment 


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14. 
REFERENCES 
Acaster S, Dickerhoof R, Debusk K, Bernard K, Strauss W, Allen L. Qualitative and 
Quantitative Validation of the FACIT-Fatigue Scale in Iron Deficiency Anemia. Health 
& Quality of Life Outcomes, 13(1), 60-69, 2015. 
Devlin N, Shah K, Feng Y et al. Valuing health-related quality of life: an EQ‑5D‑5L 
value set for England. Health Economics 27(1): 7-22, 2018. 
Ferrari M, Manea L, Anton K, et al. Anemia and hemoglobin serum levels are associated 
with exercise capacity and quality of life in chronic obstructive pulmonary disease. BMC 
Pulmonary Medicine (2015) 15:58. 
Hernandez A, Pudney S, Wailoo A. Quality Review of a Proposed EQ-5D-5L Value Set 
for England. EEPRU Report [online; accessed November 2018]. 
Howard J, Bril V, et al. Randomized Phase 2 Study of FcRn Antagonist Efgartigimod in 
Generalized Myasthenia Gravis. 2019 American Academy of Neurology, Volume 92, 
Number 23. June 4, 2019.  
 
Kalfa, T. Warm Antibody Autoimmune Hemolytic Anemia. American Society of 
Hematology. 2016. 
Kiessling P, Lledo-Garcia R, Watanabe S, Langdon G, Tran D, Bar, M, Christodoulou L, 
Jones E, Price G, Smith B, Brennan F, White I, Jolles S. The FcRn inhibitor 
rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. 
Science Translational Medicine, 9, eaan1208 November 2017. 
Ling L, Hillson J, Tiessen R, et. al. M281, an Anti-FcRn Antibody: Pharmacodynamics, 
Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-
Human Study. Clinical Pharmacology & Therapeutics, Volume 105: Number April 2019. 
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev 
Immunol. 2007 Sep;7(9):715-25. 
Sokol RJ, S Hewitt S, Stamps B, B.  Autoimmune Haemolysis: An 18-Year Study of 865 
cases Referred to a Regional Transfusion Centre.  British Medical Journal, Volume 282 
20. June1981. 
Stenton, Chris. Occupational Medicine;2008; 58:226–227 doi:10.1093/occmed/kqm162. 
Webster, K., & Cella, D., & Yost, K. (2003). The functional assessment of chronic illness 
therapy (FACIT) measurement system: Properties, applications, and interpretation. 
Health and Quality of Life Outcomes, 1(79), 1-7. 
 


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15. 
APPENDICES 
15.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
ADA 
Anti-drug antibody 
ADCC 
Antibody dependent cell mediated cytotoxicity 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIHA 
Autoimmune hemolytic anemia  
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence intervals 
CLL 
Chronic lymphocytic leukemia 
CO2 
Carbon dioxide 
CPK 
Serum creatine phosphokinase 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAT 
Direct antiglobulin test 
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 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
IEC 
Independent ethics committee  
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational new drug 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
ITP 
Idiopathic thrombocytopenia purpura 
ITT 
Intent to treat 
IUD 
Intrauterine device 


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IUS 
Intrauterine system 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
IXRS 
Interactive Response System 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MMF 
Mycophenolate mofetil 
MRC 
Medical Research Council 
MSDS 
Material safety data sheet 
NAb 
Neutralizing Antibody 
NAFLD 
Non-alcoholic fatty liver disease 
NSAID 
Non-steroidal anti-inflammatory agents 
PD 
Pharmacodynamic 
PE 
Plasma exchange 
PK 
Pharmacokinetic 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SUSAR 
Suspected unexpected serious adverse reactions  
TB 
Tuberculosis 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
WAIHA 
Warm autoimmune hemolytic anemia  
WBC 
White blood cell 
WHO-DDE 
World health organization drug dictionary enhanced 
 
 
Trademark Information 
Trademarks of Immunovant Sciences 
GmbH 
 
Trademarks not owned by Immunovant 
Sciences GmbH 
 
 
WinNonlin 
 
 
SAS 
 
 
FlowJo 
 
 
nSolver 
 


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15.2. 
Appendix 2: Liver Laboratory Trigger and Liver Event 
Definitions and Follow-up Requirements 
 
Table 4: Definitions of liver laboratory triggers and liver events  
  
Definition/ threshold  
LIVER LABORATORY 
TRIGGERS 
• 
ALT / AST 3x to  ≤ 5x ULN 
• 
TBL 1.5x to ≤ 2 x ULN 
LIVER EVENTS 
•       ALT or AST > 5 × ULN 
 
•       ALP > 2 × ULN (in the absence of known bone pathology) 
 
•       TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
•       ALT or AST > 3 × ULN and INR > 1.5 
 
•       Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL 
> 2 × ULN [mainly conjugated fraction] without notable increase in ALP 
to > 2 × ULN) 
 
•       Any clinical event of jaundice (or equivalent term) 
 
•       ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
•       Any adverse event potentially indicative of a liver toxicity* 
*These events include: hepatic failure, fibrosis, cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver 
neoplasms  
TBL: total bilirubin; ULN: upper limit of normal 
 
Table 5: Follow up requirements for liver laboratory triggers  and liver events  
Criterion 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
•       Discontinue the study treatment 
immediately 
•       Hospitalize, if clinically 
appropriate 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
ALT or AST 
> 8 × ULN 
•       Discontinue the study treatment 
immediately 
•       Hospitalize if clinically appropriate 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 × ULN and INR > 
1.5 
•       Discontinue the study treatment 
immediately 
•       Hospitalize, if clinically 
appropriate 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 


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Criterion 
Actions required 
Follow-up monitoring 
in the appropriate CRF 
> 5 to ≤ 8 × ULN 
•       Repeat LFT within 48 hours 
•       If elevation persists, continue 
follow-up monitoring 
•       If elevation persists for more than 
2 weeks, discontinue the study 
drug 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 × ULN 
accompanied by 
symptomsb 
•       Discontinue the study treatment 
immediately 
•       Hospitalize if clinically appropriate 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 × ULN 
(subject is 
asymptomatic) 
•       Repeat LFT within the next week 
•       If elevation is confirmed, initiate 
close observation of the subject 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
bone pathology) 
•       Repeat LFT within 48 hours 
•       If elevation persists, establish 
causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
•       Repeat LFT within 48 hours 
•       If elevation persists, discontinue 
the study drug immediately 
•       Hospitalize if clinically appropriate 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
Test for hemolysis 
(e.g., reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN 
(subject is 
asymptomatic) 
•       Repeat LFT within the next week 
•       If elevation is confirmed, initiate 
close observation of the subject 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Jaundice 
•       Discontinue the study treatment 
immediately 
•       Hospitalize the subject 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
Any AE potentially 
indicative of a liver 
•       Consider study treatment 
interruption or discontinuation 
•       Hospitalization if clinically 
Investigator discretion 


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Criterion 
Actions required 
Follow-up monitoring 
toxicity* 
appropriate 
•       Establish causality 
•       Record the AE and contributing 
factors (e.g., conmeds, med hx, lab) 
in the appropriate CRF 
Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP 
to > 2 × ULN b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash 
with eosinophilia cResolution is defined as one of the following: (1) return to baseline 
values, (2) stable values at three subsequent monitoring visits at least 2 weeks apart, 
(3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, 
and (5) death. 
 
At the investigator’s discretion, investigation(s) for contributing factors to the liver event 
may include: serology tests, imaging, pathology assessments, hepatologist consultation; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, and exclusion of underlying liver disease. 


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SAP_001.pdf: 
 
 
RVT-1401-2003 Statistical Analysis Plan 
Final Analysis – Cohort 1 
Version 3.0  
10 December 2021 
 
A Phase 2, Multicenter, Non-Randomized, Open Label Study of RVT-1401 for 
the Treatment of Patients with Warm Autoimmune Hemolytic Anemia 
Protocol (Version 3) Dated 23 December 2019 
 
 
 
Immunovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written consent of Immunovant Sciences 
GmbH is strictly prohibited except to the extent required under applicable laws or regulations.  Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by them.  


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
ABBREVIATIONS .........................................................................................................................4 
APPROVAL ....................................................................................................................................6 
1 
INTRODUCTION ....................................................................................................................7 
2 
OBJECTIVES AND ENDPOINTS ..........................................................................................7 
2.1 
Objectives ............................................................................................................................7 
2.2 
Endpoints .............................................................................................................................7 
2.2.1 
Primary Endpoints ........................................................................................................7 
2.2.2 
Secondary Endpoints ....................................................................................................7 
2.2.3 
Exploratory Endpoints ..................................................................................................8 
3 
STUDY DESIGN .....................................................................................................................8 
3.1 
Sample Size and Statistical Power Consideration ...............................................................8 
3.2 
Study Diagram and Flow Chart ...........................................................................................9 
3.3 
Time and events table ........................................................................................................10 
4 
ANALYSIS POPULATIONS (ANALYSIS SETS) ..............................................................14 
4.1 
Efficacy Population ............................................................................................................14 
4.2 
Safety Population ...............................................................................................................14 
4.3 
Pharmacokinetic Population ..............................................................................................14 
4.4 
Pharmacodynamic Population ...........................................................................................14 
5 
TREATMENT DESCRIPTIONS ...........................................................................................14 
6 
STATISTICAL ANALYSIS METHODS AND ISSUES ......................................................14 
6.1 
Statistical Methods .............................................................................................................14 
6.2 
Missing Data  .....................................................................................................................14 


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6.3 
Data Issues .........................................................................................................................15 
6.4 
Baseline Definition ............................................................................................................16 
7 
DISPOSITION, DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...................16 
7.1 
Subject Disposition and Exposure .....................................................................................16 
7.2 
Demographics and Baseline Characteristics ......................................................................16 
7.3 
Prior WAIHA treatment .....................................................................................................16 
8 
ANALYSIS OF EFFICACY ENDPOINTS ...........................................................................16 
9 
ANALYSIS OF SAFETY ENDPOINTS ...............................................................................17 
9.1 
Adverse Events ..................................................................................................................17 
9.2 
Vital Signs ..........................................................................................................................17 
9.3 
Laboratory Test Results .....................................................................................................17 
9.3.1 
Hematology .................................................................................................................17 
9.3.2 
Clinical Chemistry ......................................................................................................18 
9.3.4 
Lipid Panel ..................................................................................................................18 
9.4 
Concomitant Medications, Rescue Therapy, and Procedures ............................................19 
9.5 
Electrocardiogram ..............................................................................................................19 
9.6 
Physical Examination.........................................................................................................19 
9.7 
Pregnancy Testing ..............................................................................................................19 
9.8 
COVID-19 Impact .............................................................................................................19 
10 ANALYSIS OF PHARMACOKINETIC, PHARMACODYNAMIC, AND ANTI-DRUG 
ANTIBODY ENDPOINTS ....................................................................................................19 


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ABBREVIATIONS 
ADA                 Anti-drug antibody 
ADCC              Antibody dependent cell mediated cytotoxicity 
AE                    Adverse event 
AESI                 Adverse event of special interest 
AIHA                Autoimmune hemolytic anemia 
ALT                  Alanine aminotransferase 
AST                  Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATP                  Adult treatment panel 
BMI                  Body mass index 
BUN                 Blood urea nitrogen 
CI                      Confidence intervals 
CLL                  Chronic lymphocytic leukemia 
CO2                   Carbon dioxide 
CPK                  Serum creatine phosphokinase 
CTCAE            Common Terminology Criteria for Adverse Events 
ECG                  Electrocardiogram 
FSH                  Follicle stimulating hormone 
GCP                  Good Clinical Practice 
GGT                 Gamma glutamyl transferase 
Hb                     Hemoglobin 
HBV                 Hepatitis B virus 
HCV                 Hepatitis C virus 
HIV                  Human immunodeficiency virus 
IB                      Investigator’s brochure 
ICF                   Informed consent form 
ICH                   International conference on harmonization 
IEC                   Independent ethics committee 
IgA                   Immunoglobulin A 
IgG                   Immunoglobulin G 
IgM                   Immunoglobulin M 
IND                  Investigational new drug 
INR                   International normalized ratio 


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IP                      Investigational product 
IRB                   Institutional review board 
ITP                    Idiopathic thrombocytopenia purpura 
ITT                   Intent to treat 
IUD                  Intrauterine device 
LDH                 Lactic acid dehydrogenase 
MCH                Mean corpuscular hemoglobin 
MCHC              Mean corpuscular hemoglobin concentration 
MCV                Mean corpuscular volume 
MedDRA          Medical Dictionary for Drug Regulatory Activities 
MRC                 Medical Research Council 
PD                    Pharmacodynamics 
PK                    Pharmacokinetics 
RBC                  Red blood cell 
SAP                  Statistical analysis plan 
SGOT               Serum glutamic-oxaloacetic transaminase 
SGPT                Serum glutamic-pyruvic transaminase 
TBL                  Total bilirubin 
TEAE               Treatment-emergent adverse event 
WAIHA            Warm Autoimmune Hemolytic Anemia 
WBC                White blood cell 
WHO                World Health Organization 


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APPROVAL 
 
Authored and approved by  
 
 
 
 
 
 
 
 
 
 
Approved by 
 
 
 
 
 
 


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1 INTRODUCTION 
This statistical analysis plan (SAP) contains the analysis information for the definition of the 
analysis populations, derivation of variables, convention of analysis scope, and statistical 
methodology for the analyses of safety and efficacy of RVT-1401 in the treatment of subjects 
with Warm Autoimmune Hemolytic Anemia (WAIHA). Based upon a composite review and 
data suggesting a drug-related effect of RVT-1401 on lipids, the study was paused, and a final 
analysis of Cohort 1 is being conducted based on the analyses outlined in this SAP. Subjects 
whose treatment was paused are referred to as curtailed. 
At the time of the pause, 5 subjects had been enrolled in Cohort 1; 2 subjects completed the 
study through the Week 20 visit, 1 subject Early Terminated after Week 3, and 2 subjects were in 
the treatment period at the time of the pause. The analyses outlined in this plan pertain to the 
analysis of available data for Cohort 1. 
The SAP Version 2.0 was created during the writing of the interim CSR for Cohort 1. A Sponsor 
decision was made to only include listings in the CSR given the small number of subjects, and 
SAP Version 2.0 reflects this decision. 
This version of the SAP (Version 3.0) made further changes (such as removing all derived 
variables) to the SAP Version 2.0 to better align with the decision made to only include listings 
in the CSR. 
2 
OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
The objective of the study is to investigate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), and efficacy of RVT-1401 (680 mg/weekly and 340 mg/weekly) in 
subjects with WAIHA. 
2.2 Endpoints 
2.2.1 Primary Endpoints 
The primary endpoints are as follows: 
 The proportion of responders at Week 13 (defined as Hb level ≥10g/dL with at least a ≥2 
g/dL increase from baseline without rescue therapy or blood transfusions in the previous 
two weeks).  
 Assessment of safety and tolerability by analysis of adverse event (AE) data and changes 
from baseline in vital signs, ECGs, and clinical laboratory values. 
2.2.2 Secondary Endpoints 
 Change from baseline in Hb levels, 
 Time to response, 
 Change from baseline in hematocrit levels, 


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 Proportion of subjects with Hb levels in the normal range at Week 13, 
 Time to achieving Hb levels in the normal range, 
 Change from baseline in FACIT-F score, 
 Change from baseline in Medical Research Council (MRC) breathlessness scale, 
 Change from baseline in EQ-5D-3L score, 
 Change from baseline in levels of total IgG & IgG subclasses (1-4), 
 Concentration of RVT-1401 at pre-dose, 
 Change from baseline in LDH, bilirubin, and haptoglobin, and 
 Immunogenicity determined by change from pre-dose in anti-RVT-1401 antibodies, and 
characterization of any anti-RVT-1401 antibodies to confirm neutralization potential. 
2.2.3 Exploratory Endpoints 
 
 
 
 
 
3 
STUDY DESIGN 
This is a Phase 2, non-randomized, sequential, open-label study to investigate the safety, 
tolerability, PK, PD, and efficacy of RVT-1401 (680 mg/weekly and 340 mg/weekly) in subjects 
with WAIHA. Two cohorts of subjects will be enrolled in a non-randomized sequential 
approach. Subjects will be enrolled into Cohort 1 (680 mg/weekly) first followed by Cohort 2 
(340 mg/weekly). (See 5.2 Study Diagram and Flow Chart) 
Following the initial dose at the Baseline Visit (Week 1, Day 1), study visits will occur weekly 
throughout the treatment period. Following the final dose at Week 12, visits will occur weekly 
through Week 14 and then at Week 16 and Week 20. Safety, PK, PD, and clinical assessments 
will be collected throughout the study. 
3.1 Sample Size and Statistical Power Consideration 
The sample size for this study was not determined using statistical methods. The sample size was 
chosen based on clinical and recruitment considerations for this Phase 2 study. 
PPD


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3.2 Study Diagram and Flow Chart 
 
 


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3.3 Time and events table 
Screening1 
Treatment Period 
(Weeks) 
Follow-up Period 
(Weeks) 
Early 
Withdrawal Visit 
Study Timepoint 
(Weeks) 
Within 30 
days 
1 
(B/ 
L) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
20 
Time Window (days) 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
Day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 days 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X 
X 
Demographics and 
medical history9 
X 
Height 
X 
Body weight 
X 
X 
Complete physical 
examination 
X 
X 
Brief physical 
examination 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead 
Electrocardiogram2 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test3 
(females) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral Serology 
X 
Vaccine Titers2 
X 
X 
X 
X 
QuantiFERON® – TB 
GOLD 
X 
Urinalysis2, 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry and 
hematology2, 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Lipid Panel2 
X 
X 
X 
X 


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Screening1 
Treatment Period 
(Weeks) 
Follow-up Period 
(Weeks) 
Early 
Withdrawal Visit 
Study Timepoint 
(Weeks) 
Within 30 
days 
1 
(B/ 
L) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
20 
Time Window (days) 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
Day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 days 
Serum complement 
(CH50, C3)2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulins (IgM, 
IgA)2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening1 
Treatment Period 
(Weeks) 
Follow-up Period 
(Weeks) 
Early 
Withdrawal Visit 
Study Timepoint 
(Weeks) 
Within 30 
days 
1 
(B/ 
L) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
20 
Time Window (days) 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
Day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-1 
day 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/- 
2 days 
RVT-1401 PK sampling2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total IgG2,6 
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 
Anti- RVT- 
1401antibody2, 5 
X 
X 
X 
X 
X 
X 
X 
NAb Assessment2 
X 
X 
X 
X 
X 
X 
X 
Drug administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Reaction7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACIT-F Scale2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRC Breathlessness 
Scale2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-3L2 
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 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Screening can take place over multiple days. 
2. 
Assessments collected on dosing days will be collected pre-dose. 


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3. 
Pregnancy tests will be collected pre-dose (via urine dipstick) on dosing days where specified. Serum pregnancy tests should be collected at screening and the final follow up visit. 
4. 
Microalbumin/creatinine ratio at baseline, Week 13, and Week 20 only. 
5. 
Subjects with treatment emergent positive results (change from baseline) for anti- RVT-1401 antibody at Week 20 will be requested to return at approximately 6-, 9-, and 12-months post-dose for additional 
samples or until their result is no longer positive. However, for purposes of safety follow-up and database lock participation ends at the Week 20 visit. 
6. 
Two samples for IgG will be collected: one will be sent to the central lab for safety monitoring, while the other sample will be sent to Intertek as the PD endpoint. 
7. 
Local injection site reactions will be assessed at approximately 10 minutes post dose. 
8. 
Hematology, HbA1c and 
 will be drawn for site local laboratory analysis, at minimum, and results collected in the instance where central laboratory samples are received hemolyzed. If other central 
laboratory tests are received hemolyzed, the local result will be captured in the eCRF. 
9. 
History of WAIHA and prior WAIHA treatments will be captured in the eCRFs.


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4 ANALYSIS POPULATIONS (ANALYSIS SETS) 
The populations defined in this section guide the selection of subjects for a given set of listings. 
4.1 Efficacy Population 
All subjects who enroll in the study and receive at least one dose of study treatment and have a 
post-baseline visit will be included in the efficacy population. 
4.2 Safety Population 
All subjects who enroll in the study and receive at least one dose of study treatment will be 
included in the Safety Population. This will be the population for the safety analyses, as well as 
for presentation and summarization of baseline/demographic characteristics and subject 
disposition. 
4.3 Pharmacokinetic Population 
The PK Population will include all subjects who undergo PK sampling and have evaluable 
concentration-time data for analysis.  
4.4 Pharmacodynamic Population 
The PD population will include all subjects who have a baseline measure, along with a post 
baseline measure and receive at least one dose of study treatment. 
5 
TREATMENT DESCRIPTIONS 
Unless otherwise indicated, the treatment will be identified by RVT-1401 680 mg/week 
(Cohort 1). 
6 
 STATISTICAL ANALYSIS METHODS AND ISSUES 
6.1 Statistical Methods 
All available data will be presented in the data listings. 
6.2 Missing Data  
Other than missing dates as described below, no imputation methods will be used for missing 
data. 
Missing dates are imputed in the following cases: 
For the analysis of safety variables, only partial dates may be imputed; otherwise, missing data 
will be treated simply as missing. The algorithms for imputation of partial dates depend upon the 
parameter.  
Adverse Event Onset 


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 If onset date is completely missing, date is set to date of first dose. If onset time is 
missing, the time will not be imputed. 
 If year is present and month and day are missing or year and day are present and month is 
missing: 
 If year = year of first dose, then set month and day to month and day of first dose. 
 If year < year of first dose, then set month and day to December 31. 
 If year > year of first dose, then set month and day to January 1. 
 If month and year are present and day is missing:  
 If year = year of first dose and 
 month = month of first dose, then set day to day of first dose date. 
 month < month of first dose, then set day to last day of month. 
 For all other cases, set date to date of first dose.  
Adverse Event End Date 
 If year is present and month and day are missing or year and day are present and month is 
missing, set end month and day to December 31. 
 If month and year are present and day is missing, set the day to last day of the month. 
 If fatal event, date is set to minimum of imputed end date and death date. 
 For all other cases, set date to missing. 
The imputed dates must be logical, ensuring that no end date is after database lock or death or 
before the start date. 
If site queries fail to resolve partial dates for laboratory values and vital signs, the date is missing 
and will not be imputed. 
6.3 Data Issues 
Unless otherwise noted, values reported as greater than or less than some quantifiable limit (e.g., 
<1.0) will include the sign in all listings. 
If there are multiple assessments collected on the same scheduled time, all values will be 
displayed. All data from all visits will be eligible for inclusion in the listings. 
Study day is the day relative to the date of first dose. Day 1 is defined as the date of first dose, 
unless otherwise specified for the calculation of baseline. 
For visits (or events) after first dose, day is calculated as: 
• 
Study day = visit (or event) date - date of first dose + 1 
For visits (or events) before first dose, day is calculated as: 
• 
Study day = visit (or event) date - date of first dose 


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6.4 Baseline Definition 
Baseline is the last available assessment prior to time of the first dose unless it is specified 
otherwise. 
Subject’s age in years at baseline is defined as the age derived at Screening in the EDC system. 
7 DISPOSITION, DEMOGRAPHICS AND BASELINE 
CHARACTERISTICS 
7.1 Subject Disposition and Exposure 
The disposition listing will include the disposition of treatment and discontinuation of study by 
each subject. For discontinuations, the listing will include the reason for discontinuation.  
Disposition of subjects in the Follow-up Period will be presented in listings. 
Administration of RVT-1401 will be presented in listings denoting each visit and dose, and the 
treatment satisfaction questionnaire will be listed by treatment and by visit. 
WAIHA treatment listing will also be provided. 
7.2 Demographics and Baseline Characteristics 
The demographics (age, gender, race, ethnicity, and childbearing potential if female) and 
baseline characteristics (height, weight, body mass index) will be presented in listings. 
7.3 Prior WAIHA treatment 
Based on the coded data of prior WAIHA medication(s) using the World Health Organization 
(WHO) Drug Reference List, the data will be presented in listings per the Anatomical 
Therapeutic Chemical (ATC) classification.  
8 
ANALYSIS OF EFFICACY ENDPOINTS 
Each endpoint noted below will be presented in a listing. 
 FACIT-F score 
 MRC breathlessness scale 
 EQ-5D-3L score 


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9 ANALYSIS OF SAFETY ENDPOINTS 
Safety analyses will be performed on the Safety population unless otherwise indicated. 
9.1 Adverse Events 
The adverse events (AEs) will be coded by the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) version 22.1 or higher. A treatment-emergent adverse event (TEAE) is 
defined as any AE onset post first treatment. A listing of all subjects reporting TEAEs will be 
presented. A separate listing of serious TEAEs will be provided. A by-subject listing containing 
the AEs by the MedDRA system organ class and preferred term will be created. This listing will 
include start and end dates of the event, severity, and relationship to study drug. Injection site 
reactions will also be presented in a separate listing. 
The AE data will not be imputed other than a missing date. 
9.2 Vital Signs 
The vital signs (systolic / diastolic blood pressure, pulse rate, pulse oximetry, and body 
temperature) will be presented in a listing at each visit. 
9.3 Laboratory Test Results 
The test results of clinical chemistry, hematology, and urinalysis (including the lipid panel) are to 
be presented in listings by visit.  
All test results will be presented in listings. 
9.3.1 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 
Haptoglobin 
 


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9.3.2 Clinical Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
AST (SGOT) 
Total (TBL) 
and direct 
bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Total Protein 
Total carbon dioxide 
(CO2) 
Gamma glutamyl 
transferase (GGT) 
Albumin 
Sodium 
Calcium (corrected) 
Alkaline phosphatase (ALP) 
Lactic acid 
dehydrogenase 
(LDH) 
Serum 
complement 
(CH50, C3) 
Immunoglobulin 
M (IgM) 
Immunoglobulin 
A (IgA) 
Immunoglobulin 
G (IgG) 
HbA1c 
9.3.3 Routine Urinalysis 
 Specific gravity, pH 
 Glucose, protein, blood, and ketones by dipstick 
 Microscopic examination (if blood or urine protein is abnormal) 
 Microalbumin/creatinine ratio at baseline, Week 12, and Week 20, only if urine protein is 
abnormal 
9.3.4 Lipid Panel 
 Total cholesterol 
 HDL cholesterol 
 LDL cholesterol (calculated) 
 Non-HDL cholesterol (calculated) 
 Triglycerides 
 Total cholesterol/HDL cholesterol ratio (calculated) 
 LDL / HDL cholesterol ratio (calculated) 
Analyses will include the following: 
 Listings of raw lipid values will be provided. 
 Listings for the full lipid panel will be presented. 


RVT-1401-2003 SAP 2.0 
 
          Immunovant, Inc 
Dated 10 December 2021 
Page 19 of 19 
Confidential 
9.4 Concomitant Medications, Rescue Therapy, and Procedures 
Based on the coded data of concomitant medication using the WHO Drug Reference List, the 
concomitant medications and rescue therapy will be presented in a listing per the ATC 
classification. 
Procedures will be listed by treatment and by subject. 
9.5 Electrocardiogram 
The parameters of electrocardiography will be presented in a listing by visit. The overall 
evaluation (Normal/Abnormal) will be included as well. 
9.6 Physical Examination 
Physical examination listing will be provided by treatment and by visit. 
9.7 Pregnancy Testing 
Pregnancy testing will be listed by treatment and by visit. 
9.8 COVID-19 Impact 
COVID-19 impact on study visits and the reason for impact will be listed by treatment and by 
visit. 
COVID-19 impact on study and treatment discontinuation will be listed by treatment and by 
visit. 
10 ANALYSIS OF PHARMACOKINETIC, PHARMACODYNAMIC, AND 
ANTI-DRUG ANTIBODY ENDPOINTS 
 Serum total IgG concentrations will be listed by subject and visit and will include 
treatment, date and time of sample collection, and the actual time (days) that the PD 
sample was collected relative to the prior dose. 
 Serum RVT-1401 concentrations will be listed by subject and visit and will include 
treatment, date and time of sample collection, and the actual time (days) that the PK 
sample was collected relative to the prior dose. 
Anti-drug antibody results will be listed by subject and visit and will include treatment and date 
and time of sample collection. 


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